Calcium Ions Aggravate Alzheimer’s Disease Through the Aberrant Activation of Neuronal Networks, Leading to Synaptic and Cognitive Deficits

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized by the production and deposition of β-amyloid protein (Aβ) and hyperphosphorylated tau, leading to the formation of β-amyloid plaques (APs) and neurofibrillary tangles (NFTs). Although calcium ions (Ca²⁺) promote the formation of APs and NFTs, no systematic review of the mechanisms by which Ca²⁺ affects the development and progression of AD has been published. Therefore, the current review aimed to fill the gaps between elevated Ca²⁺ levels and the pathogenesis of AD. Specifically, we mainly focus on the molecular mechanisms by which Ca²⁺ affects the neuronal networks of neuroinflammation, neuronal injury, neurogenesis, neurotoxicity, neuroprotection, and autophagy. Furthermore, the roles of Ca²⁺ transporters located in the cell membrane, endoplasmic reticulum (ER), mitochondria and lysosome in mediating the effects of Ca²⁺ on activating neuronal networks that ultimately contribute to the development and progression of AD are discussed. Finally, the drug candidates derived from herbs used as food or seasoning in Chinese daily life are summarized to provide a theoretical basis for improving the clinical treatment of AD.

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease with cognitive deficit as the main characteristic (Elgh et al., 2006). During the course of AD development and progression, calcium ion (Ca²⁺) concentrations are obviously increased in the brains of patients with AD and APP/PS1 Tg mice (Cao et al., 2019). One report has shown that β-amyloid protein (Aβ)_1–40 has the ability to increase Ca²⁺ influx in rat cortical synaptosomes and cultured cortical neurons (MacManus et al., 2000). Similar to Aβ_1–40, Aβ_1–42 induce the Ca²⁺ influx via RyRs in primary cultured hippocampal neurons (Marcantoni et al., 2020). Furthermore, the Aβ_25–35 peptide promotes Ca²⁺ influx by activating L- and T-type Ca²⁺ channels in rat hippocampal slices (Li et al., 2010). The APP intracellular domain (AICD), a APP cleavage fragment, may act as a transcription factor to activate the Ca²⁺ signaling system (Cao and Südhof, 2001; Leissring et al., 2002). Because of the self-aggregating characteristics of Aβ, Aβ oligomers can promote Ca²⁺ influx through N-methyl-D-aspartic acid receptor (NMDAR) channels in a short period of time (Kelly and Ferreira, 2006). More directly, Arispe et al. (2010) found that the aggregates of Aβ_1–40 and Aβ_1–42 form a cation channel on the surface of an artificial lipid membrane that allows the passage of Ca²⁺. The pore formation ability of Aβ was confirmed and corroborated by atomic force microscopy (Lin et al., 2001), electron microscopy (Lashuel et al., 2002, 2003), and a theoretical model (Durell et al., 1994; Jang et al., 2008).

Reciprocally, Ca²⁺ is not a passive contributor to the development and progression of AD. In PS-mutant AD brain tissue, a Ca²⁺ metabolic disorder was evident before the formation of APs or NFTs (Etcheberrigaray et al., 1998), which indicated that the metabolic disorder caused by Ca²⁺ located in the cytoplasm might be the cause of AD. Based on this hypothesis, previous studies have shown that Ca²⁺ influx increases the production and aggregation of Aβ and the phosphorylated tau protein, which affects the learning and memory of patients with AD (Etcheberrigaray et al., 1998; Zempel et al., 2010; Tong et al., 2018). Moreover, Ca²⁺ imbalance leads to dysregulated metabolism that affects many neurophysiological functions related to AD, including the regulation of neuroinflammation, response to neuronal injury, neuronal regeneration, neurotoxicity and autophagy (Wahlestedt et al., 1993; Liu and Zukin, 2007; Decuypere et al., 2011a; Sama and Norris, 2013; Song et al., 2019). These actions of Ca²⁺ may finally contribute to neuronal death, which results in cognitive decline during the course of AD development and progression.

Given the multiple functions of Ca²⁺ in AD, its transporters in the cell membrane, endoplasmic reticulum (ER), mitochondria and lysosomes must be involved in regulating the development and progression of AD. As an antagonist of NMDAR, a Ca²⁺ transporter on the surface of the nerve cell membrane, memantine significantly inhibits Ca²⁺ influx and was the first Food and Drug Administration (FDA)-approved drug for the treatment of moderate to severe AD in patients (Bullock, 2006). Regarding the important reservoir of Ca²⁺ in neurons, the ER has been reported to release Ca²⁺ to the cytosol, which contributes to the development and progression of AD (Guan et al., 2021). Although direct evidence showing the relationship between Ca²⁺ transport from mitochondria and lysosomes and the learning ability of patients with AD is unavailable, voltage-dependent anion channel protein 1 (VDAC1) is a hub protein that interacts with phosphorylated tau, Aβ, and γ-secretase, and it contributes to their toxic effects on triggering cell death and potentially leading to the dementia that is a characteristic of AD (Shoshan-Barmatz et al., 2018). All this evidence prompted us to summarize the roles of Ca²⁺ transporters located in different organelles in regulating the development and progression of AD.

Therefore, this review mainly summarizes the molecular mechanisms by which a Ca²⁺ imbalance in individuals with AD affects the regulation of neuroinflammation, neuronal injury, neuronal regeneration, neurotoxicity, neuroprotection, and autophagy, specifically from the perspective of Ca²⁺ transporters in the cell, mitochondria, endoplasmic reticulum and lysosomal membranes. By addressing these mechanisms, we will fill the gaps between increased Ca²⁺ concentrations and the fate of neurons, which results in dementia.

Crosstalk Between Factors Responsible for Ca²⁺ Dyshomeostasis and Neuroinflammation

Ca²⁺ Increases the Production of Proinflammatory Cytokines

Neuroinflammation is widely accepted to be mediated by Ca²⁺ dyshomeostasis and induces the cognitive decline associated with AD. This process is studied to understand the inherent mechanisms by which Ca²⁺ exerts an effect. For example, Ca²⁺ increases the production of interleukin (IL)-1β and tumor necrosis factor α (TNF-α) via calcineurin (CaN) in glial cells (Sama and Norris, 2013). Consistently, an indirect blockade of Ca²⁺ entry into lipopolysaccharide (LPS)-activated microglia stimulates the production of proinflammatory cytokines, such as TNF-α and IL-6 (Dolga et al., 2012). These observations revealed critical roles for Ca²⁺ in inducing neuroinflammation by concurrently increasing the production of proinflammatory cytokines and decreasing the levels of anti-inflammatory cytokines.

Transporters on the Cell Membrane Mediate the Effects of Ca²⁺ on the Secretion of Proinflammatory Cytokines

Based on these observations, Ca²⁺ transporters were found to be involved in regulating neuroinflammation. More specifically, NMDAR is critical for mediating the effects of Ca²⁺ on stimulating the production of proinflammatory cytokines, such as IL-1β and TNF-α, in primary mouse hippocampal neurons and lamina II neurons of isolated spinal cord slices (Kawasaki et al., 2008; Huang et al., 2011). By deactivating NMDAR, sevoflurane, an NMDAR antagonist, inhibits the production of IL-1β, TNF-α, IL-6, and IL-8, whereas the addition of the NMDAR agonist D-cycloserine restores the suppression of ageing phenotype acquisition in rats (Yang Z. Y. et al., 2020). NMDAR overexpression in primary cultured microglial cells was induced to synthesize nitric oxide (NO) by activating the NF-κB signaling pathway and to exclude the nonspecific action of these pharmacological interventions (Murugan et al., 2011). In the context of inflammation, NMDAR blockade attenuates the clinical symptoms of glutamate excitotoxicity, suggesting that NMDAR exerts potential neuroprotective effects (Wallström et al., 1996). Similar to this observation, blocking the AMPA/kainate receptor also results in the neuroprotection of encephalomyelitis-sensitized mice (Pitt et al., 2000; Smith et al., 2000). Based on this observation, researchers have readily deduced that α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) might also be involved in regulating neuroinflammation. In SG neurons and lamina II neurons isolated from spinal cord slices, AMPAR was reported to mediate Ca²⁺-stimulated secretion of proinflammatory cytokines, such as IL-1β and TNF-α (Liu et al., 2013). Perampanel, an AMPAR antagonist, concurrently suppressed the expression of proinflammatory cytokines, including IL-1β and TNF-α, and upregulates the expression of anti-inflammatory cytokines, including IL-10 and Transforming Growth Factor Beta 1 (TGF β1), in a rat model of traumatic brain injury (TBI; Chen T. et al., 2017).

In addition to glutamate receptors serving as transporters of Ca²⁺, some Ca²⁺ transporters in the cell membrane are reported to be involved in regulating neuroinflammation. For example, the blockade of L-type voltage-gated calcium channels (L-VGCC) by bepridil, nitrendipine or nimodipine attenuates neuroinflammation by deactivating astrocytes and microglial cells in LPS-stimulated or artificial cerebrospinal fluid (aCSF)-injected (i.c.v.) rats and astrocytes from the CA1 region of the hippocampus (Brand-Schieber and Werner, 2004; Daschil et al., 2013; Espinosa-Parrilla et al., 2015; Hopp et al., 2015). These observations were corroborated by the ability of Ca²⁺ to induce TNF-α production in cultured rat hippocampal neurons through an L-VGCC-dependent mechanism (Furukawa and Mattson, 1998). In addition, transient receptor potential channels (TRPs) have been identified in mammals and are grouped into six families associated with the onset of neurodegenerative diseases of the central nervous system (CNS): vanilloid TRP (TRPV), melastatin TRP (TRPM), ankyrin TRP (TRPA), polycystin TRP (TRPP), and canonical or classical TRP (TRPC) channels (Morelli et al., 2013). Among these channels, TRPM2 deletion suppresses cytokine production by deactivating microglial cells in TRPM2-knockout mice (Miyanohara et al., 2018; Kakae et al., 2019). Activation of the TRPV1 channel increases the production of proinflammatory cytokines, such as IL-6, in microglial cells (Sappington and Calkins, 2008). The roles of TRPV4 in inflammation are still being debated. By blocking TRPV4 channels, the release of IL-1β and TNF-α is inhibited because of the reduced Ca²⁺ influx, leading to the attenuation of glial cell-mediated inflammation (Shi et al., 2013). In contrast, the opening of TRPV4 channels by a selective TRPV4 agonist, 4α-phorbol 12, 13-didecanoate (4α-PDD), prevents microglial activation and TNF-α release after LPS treatment, and TRPV4 knockdown eliminates the inhibitory effect of agonists on the release of TNF-α from cultured microglial cells (Konno et al., 2012). According to these findings, TRPV4 activation may be induced by microglial cell swelling after activation with LPS. Channel activation may thus serve as an autoregulator to avoid excess microglial activation. In addition, TRPC1-mediated negative regulation may exert an immunosuppressive effect by blocking the initiation of inflammatory pathways in primary microglial cells (Sun Y. et al., 2014; Figure 1). Although Apolipoprotein E4 (APOE4) is not regarded as a canonical Ca²⁺ transporter, human APOE4 increases the activity of microglial cells by inducing the expression of IL-1β in E4F AD mice (Rodriguez et al., 2014). In contrast to APOE4, other isoforms of APOEs inhibit the synthesis of inflammatory mediators, including COX-2, PGE₂, and IL-1β, in primary cultured microglia obtained from the adult rat brain cortex (Chen et al., 2005).

Figure 1

The Endoplasmic Reticulum Is Involved in Regulating the Production of Proinflammatory Cytokines and Represents Intracellular Ca²⁺ Stores

Regarding intracellular stores, genetic ablation of type 2 inositol 1,4,5-triphosphate receptor (InsP3R2) increases the production of cytokines in SOD1^G93A mice (Staats et al., 2016). By blocking the activity of Ryanodine Receptor (RyR) with dantrolene, the secretion of inflammatory markers is attenuated because of the deactivation of microglia in LPS-infused rats (Hopp et al., 2015). Treatment with PK11195, a mitochondrial ligand, inhibits store-operated calcium entry (SOCE)-mediated Ca²⁺ influx, resulting in the downregulation of COX-2 expression in human microglial cells (Hong et al., 2006). Thus, the endoplasmic reticulum (ER), as an intracellular Ca²⁺ store, is critical for regulating neuroinflammation via InsP3R-, RyR- and SOCE-dependent mechanisms. Interferon α/β (IFNα/β) induce cell apoptosis through Ca²⁺ release-activated Ca²⁺ (CRAC; Yue et al., 2012). As an important component of the mitochondrial permeability transition pore (mPTP), cyclophilin (CypD) knockdown decreases the secretion of proinflammatory cytokines, including Vascular Cell Adhesion Molecule 1 (VCAM-1), IL-6 and TNF-α, in the arteries of mice (Liu et al., 2019; Figure 3).

Figure 2

Figure 3

With opposite effects, proinflammatory cytokines have the ability to modulate the Ca²⁺ balance via their transporters. For example, TNF-α, IL-1β, and IFNγ increase the influx of Ca²⁺ into microglial cells, which indicates crosstalk between Ca²⁺ and neuroinflammatory factors in cultured hippocampal neurons (Goghari et al., 2000; McLarnon et al., 2001; Franciosi et al., 2002). IL-1β increases the expression of AMPAR on the cell surface, which potentially contributes to the entry of Ca²⁺ into hippocampal neurons (Viviani et al., 2003; Simões et al., 2012). In contrast to AMPAR, IL-1β inhibits L-VGCC activity by suppressing the protein expression of Ca²⁺ channels in primary cultured neurons (Zhou et al., 2006; Zhou, 2010). In addition, IL-1β is responsible for increasing the expression of TRPM2, leading to the influx of Ca²⁺ to microglial cells (Fonfria et al., 2006). Similar to IL-1β, IL-6 potentiates Ca²⁺ entry through NMDARs in hippocampal neurons (Orellana et al., 2005). Although IL-6 is not expressed in neuronal cells, it downregulates the expression of SERCA2, which blocks Ca²⁺ entry into the ER, thus maintaining high levels of cytosolic Ca²⁺ in cardiac myocytes (Villegas et al., 2000). Similar to other cytokines, TNF-α increases Ca²⁺ currents through NMDARs in cultured rat hippocampal neurons (Furukawa and Mattson, 1998). In addition, TNF-α induces the rapid insertion of AMPAR into the membranes of hippocampal pyramidal neurons (Ogoshi et al., 2005). In addition, the colocalization of GluA1, GluA2 and GluA4 and synaptophysin on the neural crest also indicates the transportation of AMPAR to synapses (Wigerblad et al., 2017). In contrast, TNF-α decreases Ca²⁺ influx by inhibiting the activity of L-VGCCs in cultured rat hippocampal neurons and hippocampal CA1 neurons (Furukawa and Mattson, 1998; Sama et al., 2012). Regarding the regulation of intracellular stores, impaired TNF-α signaling disrupts the effects of InsP3R on mediating Ca²⁺ release from the ER to the cytosol in 3xTg mice (Park et al., 2010). Moreover, calcineurin (CaN) is activated by the proinflammatory cytokine TNF-α in astrocytes (Fernandez et al., 2007; Sama et al., 2008; Furman et al., 2012). TNF-α activates a more complicated mechanism to regulate Ca²⁺ currents. In addition to TNF-α itself, the TNF-α receptor mobilizes Ca²⁺ through an RyR-dependent mechanism in cultured neonatal rat dorsal root ganglion (DRG) neurons (Pollock et al., 2002). In addition to proinflammatory cytokines, most investigations have focused on the roles of anti-inflammatory cytokines on Ca²⁺ transporters. Based on this information, researchers also found that anti-inflammatory cytokines, such as IL-10, reduced the intracellular Ca²⁺ levels in microglial cells by decreasing Ca²⁺ release from the ER through the deactivation of the InsP3R-dependent mechanism in cultured hippocampal neurons (Turovskaya et al., 2012). Therefore, the existence of crosstalk between Ca²⁺ and neuroinflammation will result in the aggravation of AD (Figure 2).

Proinflammatory Cytokines Reciprocally Regulate the Activities of Transporters Expressed on Lysosomes to Regulate the Basal Ca²⁺ Levels in Glial Cells

In SH-SY5Y cells, IFNγ also induces Ca²⁺ influx by activating TRPM2, leading to the apoptosis of cultured neurons (Sama et al., 2012). Furthermore, IFNγ reduces the activity of ATPase Sarcoplasmic/Endoplasmic Reticulum Ca²⁺ Transporting 2b (SERCA2b) in IL-1β-stimulated OSCC cells (Cardozo et al., 2005; Gkouveris et al., 2018). In addition to these cytokines, inflammatory factors, such as H₂O₂, increase TRPM2 activity, which might lead to increased basal Ca²⁺ levels in cultured rat microglial cells (Kraft et al., 2004). Poly ADP-ribose polymerase-1 (PARP-1) induces Ca²⁺ influx by activating TRPM2 in PARP-2 knockout mice (Kraft et al., 2004). All this evidence revealed crosstalk between Ca²⁺ and neuroinflammatory factors, which aggravates AD via the actions of different transporters (Table 1).

Ca²⁺ Signaling Impairs Neuronal Function

The Effects of Ca²⁺ on Impairing Neuronal Functions

Given the crosstalk between Ca²⁺ and neuroinflammatory factors, we continued to elucidate the roles of Ca²⁺ in impairing neuronal functions and its effects on the relationship between neuroinflammation and neuronal apoptosis and death (Table 2). For example, accumulating evidence has revealed that appropriate activation of microglial cells may exert beneficial effects by attenuating neuronal apoptosis, increasing neurogenesis, and promoting functional recovery after cerebral ischaemia (Neumann et al., 2008). In contrast, overactivation of microglial cells may result in the apoptosis or death of neurons (Brown and Neher, 2014). Based on these findings, excessive release of Ca²⁺ initially protects neuronal cells from death by inducing the expression of Bcl-2 through the activated transcription factor NF-κB (Pahl and Baeuerle, 1996; Mattson and Furukawa, 1997), whereas sustained increases in cytosolic Ca²⁺ concentrations induced by neuronal depolarization result in Aβ_1–42 production and subsequent neuronal death (Pierrot et al., 2004). Moreover, a series of studies reviewed in our previous work described the effects of Ca²⁺ on cell apoptosis via multiple signaling pathways, and this information is not repeated in the present review (Wang and Wang, 2017).

Proinflammatory Cytokines Induce Neuronal Apoptosis or Death via Ca²⁺ Transporters Located on the Cell Membranes

However, transporters have not been considered critical for mediating the effects of Ca²⁺ on the apoptosis or death of neurons. Therefore, we further addressed the roles of different types of Ca²⁺ transporters in regulating the apoptosis or death of neuronal cells, especially during the course of AD development and progression. Due to its close association with neuroinflammation, neuronal apoptosis in the rat hippocampus is induced by IL-1β through an NMDAR-mediated Ca²⁺ influx mechanism (Dong et al., 2017). By coculturing glial cells with primary hippocampal neurons, IL-1β secreted from glial cells triggers neuronal death via tyrosine phosphorylation and NMDAR trafficking mechanisms (Viviani et al., 2006; Dong et al., 2017). In contrast to the action of IL-1β, IL-6 reduces Ca²⁺ overload by deactivating NMDARs, which resulted in the death of cultured cerebellar granule neurons (CGNs) via the JAK/CaN pathways (Ma et al., 2015). As another type of glutamate receptor involved in Ca²⁺ transport, AMPAR, which is trafficked to the plasma membrane, mediates the effects of TNF-α on exacerbating the effects of spinal cord injury on cell death (Ferguson et al., 2008; Beattie et al., 2010). By inhibiting the activities of L-VGCC, Gas6 or nimodipine suppresses Aβ-induced neuronal apoptosis by attenuating Ca²⁺ influx into primary cultured cortical and hippocampal neurons (Ueda et al., 1997; Yagami et al., 2002). In addition, NMDARs and L-VGCCs mediate the effects of perfluorohexanesulfonate (PFHxS) on activating the AMPK and ERK pathways, leading to the apoptosis of P12 cells (Lee et al., 2016). Among the Ca²⁺ transporters located in the cell membrane, TRPV1 overexpression disrupts mitochondrial function and induces cytochrome c release, which results in the death of a human microglial cell line (HMO6; Kim et al., 2006; Zhang and Liao, 2015). Similarly, ectopically expressed TRPV4 in glial cells induces neuronal damage via an apoptotic mechanism (Shi et al., 2013). Consistent with these findings, pharmacological or genetic interventions targeting TRPV4 suppress neuronal cell death by decreasing the expression of proinflammatory cytokines, such as IL-1β and TNF-α (Konno et al., 2012; Shi et al., 2013). As another type of TRP family protein, TRPM2 is activated to induce Ca²⁺ influx, resulting in the death of RIN-5F rat insulinoma cells and rat cortical neurons (Kaneko et al., 2006). TRPM2 knockdown reduces the toxicity of Aβ and subsequent death of primary rat neuron cultures (Fonfria et al., 2005; Li and Jiang, 2018; Figure 1).

Ca²⁺ Transporters Located on the ER Membrane Are Responsible for Regulating Neuronal Apoptosis

Although APOE4 is not a canonical Ca²⁺ transporter, APOE4 overexpression induces Ca²⁺ influx, resulting in neuronal apoptosis (Veinbergs et al., 2002; Jiang et al., 2015). Through a more complicated mechanism, APOE4 induces neuronal apoptosis in APOE4 knockout mice by activating NMDAR-mediated Calcium/Calmodulin dependent protein kinase II (CaMKII) pathways (Qiao et al., 2017). Moreover, TBI induces apoptosis in the cortex and hippocampus of Tg mice overexpressing human APOE4 by activating APOE4 (Giarratana et al., 2020). In addition, ER stress also mediates the effects of the unfolded protein response (UPR) and misfolded proteins on inducing apoptosis through mechanisms related to Ca²⁺ influx (Nishitoh et al., 2009; Moreno et al., 2013). Specifically, Ca²⁺ transporters located on the ER membrane, including InsP3R and RyR, are reported to be involved in regulating neuronal apoptosis. For example, type 3 InsP3R regulates cell death by modulating Ca²⁺ release from the ER to the cytosol in postnatal cerebellar granule cells (Blackshaw et al., 2000; Wang and Zheng, 2019). Isoflurane treatment induces Ca²⁺ influx, leading to caspase-3 activation by cleavage in DT40 cells (Joseph et al., 2014). Upon the stimulation of P2X7R by isoflurane and sulforaphane, InsP3R mediates the effects of Ca²⁺ on inducing apoptosis or cell death of NG108-15 and PC12 neuronal cells and cells in nude mice (Wei et al., 2008; Chao et al., 2012; Hudecova et al., 2016). Specifically, Aβ_25–35 induces the apoptosis of murine astrocytes via InsP3R- and Ca²⁺-activating pathways (Oseki et al., 2014). In addition to InsP3R, the posttranslational modification of RyR2 by S-glutathionylation increases channel activity, resulting in the death of rat cortical neurons (Bull et al., 2008). In contrast, the suppression of RyR3 expression in TgCRND8 neurons increases the neuronal death rate, which suggests a protective role for RyR in the late stages of AD pathogenesis (Supnet et al., 2010).

Based on these observations, ethanol dose-dependently increases the intracellular Ca²⁺ concentration, which damages HepG2 hepatocytes by upregulating the expression of the Orai1 and Stromal interaction molecule 1 (Stim1) mRNAs and proteins (Liu et al., 2012). Although the pathophysiological effects of decreased Store-operated calcium entry (SOCE) levels in AD remain unclear, several lines of evidence have shown that SOCE deficits lead to neuronal cell death and decreased synaptic plasticity (Soboloff and Berger, 2002; Calvo-Rodriguez et al., 2020). As expected, Stim1 silencing alleviates the apoptosis of H₂O₂-treated endothelial progenitor cells (Wang et al., 2016). Moreover, the downregulation of Stim1 by an siRNA concurrently increases neuronal viability and inhibits apoptotic cell death by decreasing the intracellular Ca²⁺ levels (Selvaraj et al., 2016). In PC3 and DU145 cells, both Stim1 and Orai1 separately mediate the effects of resveratrol (RSV), a natural polyphenol, on activating autophagic cell death (Selvaraj et al., 2016). In addition, resveratrol can mediate the release of Ca²⁺ from intracellular stores (Santoro et al., 2020). As a method to exclude nonspecific effects of pharmacological interventions, silencing the expression of Stim1 and Orai1 reduces the apoptosis rate of LPS-treated pulmonary microvascular endothelial cells by blocking SOCE in pulmonary microvascular endothelial cells (Wang et al., 2016). Researchers excluded the effects of Stim1 on cell apoptosis by transfecting Orai1 mutants and observed decreases in both SOCE and the rate of thapsigargin-induced apoptosis in human prostate cancer (PCa) cells (Flourakis et al., 2010; Figure 2).

Mitochondrial Dysfunction Is Also Involved in Mediating the Effects of Ca²⁺ on Neuronal Apoptosis

However, ER stress is not the only mechanism by which the effects of Ca²⁺ on neuronal apoptosis are mediated: mitochondrial dysfunction is also reported to be involved in this process (Yoon et al., 2011). Consistently, Stim1 or Orai1 knockdown attenuates the intracellular Ca²⁺ overload, restores the mitochondrial membrane potential, decreases the release of cytochrome c and inhibits ethanol-induced apoptosis (Cui et al., 2015). Without affecting ER stress, curcumin protects mitochondria from oxidative damage by attenuating the apoptosis of cortical neurons (Zhu et al., 2004). In primary cultured spinal neurons, salidroside (Sal) treatment decreases apoptosis by activating PINK-Parkin pathways, leading to mitophagy of mitochondria (Gu et al., 2020). Similar to its effects on AD, Aβ_1–42 induces neuronal apoptosis by concurrently upregulating mitochondrial fission protein dynamin-related protein 1 (Drp1) and downregulating mitofusin 1/2 (Mfn1/2) and dynamin-like GTPase (OPA-1) in primary cultures of mouse cerebral cortical neurons (Han et al., 2017). In addition, Aβ_25–35 induces cytochrome c-mediated apoptosis of NT2 cells through a functional mitochondria-dependent mechanism (Morais Cardoso et al., 2002). In this mechanism, Ca²⁺ transport by InsP3R to mitochondria induced by opening the mPTP induces the release of cytochrome c, which results in the apoptosis of cells (Szalai et al., 1999). In fact, mPTP opening induces matrix swelling, the subsequent rupture of the outer membrane, and nonspecific release of proteins in the intermembrane space into the cytosol upon cannabidiol (CBD) induction of human monocyte apoptosis (Wu et al., 2018). By inhibiting the opening of the mPTP in mitochondria, mortalin overexpression blocks Aβ-induced SH-SY5Y cell apoptosis (Qu et al., 2012). In AD mice, CyPD knockout decreases the cell death rate by attenuating the opening of the mPTP in mitochondria (Du et al., 2008; Pahrudin Arrozi et al., 2020).

VDAC1 expression induces cell death and apoptosis by activating the Ca²⁺ signaling cascade in A549 cells (Weisthal et al., 2014). VDAC is involved in the apoptosis of lymphoblastoid cells carrying a mitochondrial DNA mutation (Yuqi et al., 2009). Through a direct interaction with Bax, VDAC induces the transport of cytochrome c through membranes (Shimizu et al., 1999). Moreover, the cleavage of the pro-apoptotic protein Bid by caspase-8 induces the closure of VDAC, which leads to protein release from mitochondria and apoptosis (Rostovtseva et al., 2004). In contrast, Bcl-xL promotes the opening of the VDAC, which results in a reduced apoptosis rate of cultured FL5.12 cells (Vander Heiden et al., 2001; Bessou et al., 2020). Fatty acid binding protein 5 (FABP5), which is expressed in oligodendrocytes, induces mitochondrial macropore formation through VDAC-1 and Bax, thus accelerating mitochondria-induced glial cell death. These two proteins mediate mitochondrial outer membrane permeability, resulting in the release of mitochondrial DNA and cytochrome c into the cytoplasm and activation of apoptotic caspases (Cheng et al., 2020). More interestingly, BAPTA-AM, a Ca²⁺-chelating reagent, inhibits mitochondria-mediated apoptosis by decreasing the oligomerization of VDAC1 in HeLa and T-REx-293 cells (Keinan et al., 2013). Consistent with this observation, anion transport inhibitors, including 4’-diisothiocyano-2,2’-stilbenedisulfonic acid (DIDS), SITS, H₂DIDS, DNDS, and DPC, inhibit apoptosis-associated VDAC1 oligomerization (Ben-Hail and Shoshan-Barmatz, 2016). In addition, blockade of plasmalemmal VDAC1 with a specific antibody suppresses Aβ-induced neuronal apoptosis (Thinnes, 2011; Lim et al., 2021a). In THP-1 macrophages, DIDS disodium salt, an inhibitor of VDAC1, attenuates the apoptosis of THP-1 macrophages by decreasing intracellular Ca²⁺ levels (Chen et al., 2014). Similarly, Ca²⁺ transporters generally mediate the regulatory effects of Ca²⁺ on neuronal apoptosis, especially in the context of AD (Figure 3).

Ca²⁺ Inhibits The Regulation of Neuronal Stem Cells

Ca²⁺ Modulates Neuronal Differentiation, Migration and Self-renewal During the Course of Neurogenesis

During the course of AD development and progression, neurogenesis is markedly inhibited in the brains of patients with AD and mouse models (Rash et al., 2016). Given the potential roles of Ca²⁺ in AD, we summarize the effects of Ca²⁺ on neurogenesis during the course of AD development and progression. Indeed, higher frequencies of Ca²⁺ oscillations increase the differentiation of hippocampus-derived neural stem cells (NSCs) into neurons in adult rats (Wang Q. et al., 2015). Moreover, Epac2 mediates PACAP-induced differentiation of neural progenitor cells (NPCs) into astrocytes along with an increase in intracellular Ca²⁺ levels, which also activated the signaling pathway for astrocytogenesis in Epac2-knockout (KO) mice (Seo and Lee, 2016). NSC differentiation is closely related to the expression of VGCC, especially Caveolin 1 (Cav1) through regulating Ca²⁺ influx (D’Ascenzo et al., 2006). Moreover, exposure in extremely low-frequency electromagnetic fields (ELFEF) promotes the differentiation of NSCs by upregulating the expression and function of Cav1 (Piacentini et al., 2008c). Furthermore, bidirectional radial Ca²⁺ activity elongates the fiber of radial glial cells (RGCs) and simultaneously induces neurogenesis during early cortical column development (Rash et al., 2016). By upregulating the Notch signaling pathway after brain injury, Ca²⁺ waves generated in neighboring astrocytes propagate to NPCs, inducing neurogenic behavior, including the self-renewal and migration of progenitor cells (Kraft et al., 2017). Based on these observations, Ca²⁺ induces neuronal differentiation, migration and self-renewal during the course of neurogenesis.

Ca²⁺ Transporters Located on the Cell Membranes Are Required for Neurogenesis

Given the key roles of Ca²⁺ in neurogenesis, its transporters are also required for neurogenesis. In the developing cerebellum, granule cell precursors differentiate upon activation of a homodimeric G protein-coupled receptor that is sensitive to Ca²⁺ levels called calcium-sensing receptor (CaSR). CaSR activation in vivo induces the homing of granule cell precursors during differentiation, mainly through CaSR interactions with integrin complexes (Tharmalingam et al., 2016). Among these CaSRs, the lower activity of NMDARs in NR1^+/– mice contributes to increased cell proliferation and neurogenesis compared to the activity in the brains of adult NR1^+/+ mice (Bursztajn et al., 2007). In contrast, intraperitoneal injection of the NMDAR agonist NMDA (2 mg/kg/day) promotes cell proliferation in the subventricular zone (SVZ) of rats (Fan et al., 2012). Unfortunately, the researchers did not extend their investigations to Ca²⁺, although NMDAR affects neurogenesis. Compared to NMDARs, the roles of AMPARs in neurogenesis are relatively simple. In rats administered chronic corticosterone (CORT), S47445, a novel AMPAR-positive allosteric modulator (AMPA-PAM), exerted significant neurogenic effects on the proliferation, survival and maturation of new hippocampal neurons (Mendez-David et al., 2017). Moreover, AMPAR mediates kainate-induced radial glia-like stem cell proliferation (Shtaya et al., 2018). Human NPCs contain Ca²⁺-permeable AMPARs; however, AMPARs were engineered to become Ca²⁺-impermeable receptors during the course of differentiation from NPCs to neurons or astrocytes through RNA editing of the AMPA receptor subunit GluR2 at the Q/R site (Whitney et al., 2008). Then, the NMDAR subunits NR1 and NR2B and the AMPAR subunit GluR2 in Ca²⁺-impermeable AMPARs were upregulated at the mRNA level in differentiated neuroepithelial precursors, indicating their likely contribution to neurotransmission after first establishing neuronal networks (Muth-Köhne et al., 2010; Wang et al., 2018).

In addition to NMDARs and AMPARs, different types of VGCCs and TRPs in cell membranes are also involved in regulating neurogenesis. For example, the differentiation of dental pulp stem cells (DPSCs) into neural cells is markedly inhibited by regulating the levels of the distal C-terminus (DCT) upon treatment with nimodipine and knock down of Cav1.2 expression (Ju et al., 2015). In the dentate gyrus (DG) region, deletion of Cav1.2 decreases the numbers of doublecortin-positive adult-born neurons, suggesting important roles for Cav1.2 in adult neurogenesis (Temme et al., 2016). Consistent with these findings, Cav1.3 knockout impairs hippocampal neurogenesis and inhibits neuronal differentiation (Marschallinger et al., 2015). More importantly, Ca²⁺ mediates the effects of L-VGCC on the neurogenesis of interneurons in nifedipine-treated NPCs (Brustein et al., 2013). Similar to L-VGCCs, blockade of other types of VGCCs, such as N- and T-VGCCs, decreases the migration and neurite extension of developing neurons (Komuro and Rakic, 1992; Louhivuori et al., 2013). On the other hand, TRPs are also reported to be involved in regulating neurogenesis. For instance, TRPM2 deficiency results in impaired embryonic neurogenesis because it regulates neural progenitor self-renewal through an SP5-dependent mechanism (Li and Jiao, 2020). In addition, the antisense oligonucleotide-mediated knockdown of TRPC1 expression reduces the effects of bFGF on the proliferation of embryonic rat NSCs (Fiorio Pla et al., 2005; Toth et al., 2016). Blocking SOCE activity with YM-58483 (BPT2) decreases the proliferation of SVZ and neural stem cells (Domenichini et al., 2018). By stereotactically injecting a recombinant adeno-associated virus expressing TRPC1 into the DG of the bilateral hippocampus, we observed that neurogenesis, LTP induction, and cognitive enhancement related to environmental enrichment (EE) were effectively rescued in TRPC1 knockout mice (Du et al., 2017). Consistent with this observation, TRPC3 knockout reduces the effect of Ca²⁺ on mGluR5-mediated radial glial processes, reducing the neuronal migration rate (Louhivuori et al., 2015; Toth et al., 2016). In addition to these classical Ca²⁺ transporters in the cell membrane, both APOE1–3 knockout and APOE4 overexpression suppress neurogenic responses in vivo (Hong et al., 2013; Rijpma et al., 2013; Geffin et al., 2017). Based on this evidence, transporters are involved in mediating the effects of Ca²⁺ on the neurogenesis of NPCs and NSCs (Figure 1).

Intracellular Ca²⁺ Stores Mediate the Effects of Ca²⁺ on Neurogenesis

The ER and mitochondria are major intracellular Ca²⁺ stores and thus mediate the regulatory effects of Ca²⁺ on neurogenesis. In PC12 cells, ER stress and BDNF-TrkB signaling pathways are involved in the induction of neurogenesis by 3β, 23, 28-trihydroxy-12-oleanene 3β-caffeate from Desmodium sambuense (Cheng et al., 2019). In addition, ER stress mediates the effects of tunicamycin and HRD1 deletion on the aberrant induction of neuronal differentiation and inhibition of dendrite outgrowth in retinoic acid-treated P19 mouse embryonic carcinoma cells (Kawada et al., 2014). More interestingly, transcripts encoding the three main isoforms of the two families of intracellular calcium release channels, namely, InsP3R and RyR, were detected during early neurogenesis in the mouse cerebral cortex (Faure et al., 2001). In particular, an antagonist of the InsP3 pathway, wortmannin, prevents neurogenesis in neural crest cells (Evrard et al., 2004). In addition, Ca²⁺ waves propagate through radial glial cells in the proliferative cortical ventricular zone (VZ) and require connexin hemichannels, P2Y1 ATP receptors, and intracellular InsP3-mediated Ca²⁺ release, suggesting critical roles for radial glial signaling mechanisms in cortical neuronal production (Weissman et al., 2004; Lim et al., 2021b). In this process, the G protein-coupled receptor GPR157, an orphan G protein-coupled receptor, is involved in regulating the neuronal differentiation of radial glial progenitors through Gq-InsP3-mediated Ca²⁺ cascades (Takeo et al., 2016). In mesenchymal stem cells, caffeine, an RyR agonist, induces an intracellular Ca²⁺ response that increases throughout neuronal differentiation (Resende et al., 2010). Specifically, RyR2 knockout decreases the neurogenesis of embryonic stem cells (Yu et al., 2008). Associated with the aforementioned mechanisms, the proliferation of embryonic and adult NPCs cultured as neurospheres and progenitors in the subventricular zone (SVZ) of adult mice in vivo was attenuated by depleting the expression of Stim1 and Orai1, suggesting pivotal roles for SOCE channel-mediated Ca²⁺ entry in mammalian neurogenesis (Somasundaram et al., 2014). In addition to Orai1, single knock down of Stim1, a Ca²⁺ sensor that mediates SOCE, impairs early and late embryonic stem cell differentiation into neural progenitors, neurons or astrocytes, increasing the cell death rate and suppressing the proliferation of neural progenitors (Hao et al., 2014; Deb et al., 2020). Similarly, pharmacological blockade of SOCE decreases the proliferation and self-renewal of NSCs, driving asymmetric division to the detriment of symmetric proliferative division, reducing the population of stem cells in the adult brain, and impairing the ability of SVZ cells to form neurospheres in culture (Domenichini et al., 2018). CRAC channels serve as a major route of Ca²⁺ entry in NSCs/NPCs and regulate key effector functions, including gene expression and proliferation, indicating that CRAC channels are important regulators of mammalian neurogenesis (Somasundaram et al., 2014). Similar to the ER, mitochondria are intracellular Ca²⁺ stores involved in regulating the neurogenesis of NPCs. For example, the inhibition of mPTPs and a selective reduction in mitochondrial superoxide spikes significantly ameliorates the negative effects of Aβ_1–42 on NPC proliferation and survival (Hou et al., 2014). Moreover, cyclosporin A inhibits neuronal differentiation by suppressing mPTP opening (Hou et al., 2013; Namba et al., 2020). All these observations confirm the involvement of Ca²⁺ and its transporters in regulating neurogenesis (Table 3).

The Effects of Ca²⁺ on Neurotoxicity

Ca²⁺ Induces Excitotoxicity via Its Transporters Located on Cell Membranes

Neurotoxicity might be the inherent cause of the Ca²⁺-mediated impairment of neuronal functions. In primary cultured cerebral cortical neurons, increased levels of Ca²⁺ induce excitotoxicity, whereas reduced Ca²⁺ release exerts neuroprotective effects (Frandsen and Schousboe, 1991). As the natural ligand of NMDAR, NMDA induces neurotoxicity by activating NMDAR in cerebellar granule cells (Xia et al., 1995). In addition to its natural ligand, the exposure of neurons to ethanol and glutamate also induces neurotoxicity by activating NMDARs (Thomas and Morrisett, 2000; Miao et al., 2012). Similar to its effect on the AD pathway, Aβ_25–35 induces neurotoxicity by deactivating the pCRMP2 and NMDAR2B signaling pathways in SH-SY5Y cells (Ji et al., 2019). However, the researchers did not extend their observations to the involvement of Ca²⁺ in neurotoxicity. In cultured cerebellar granule neurons, domoic acid induces neurotoxicity through NMDAR-mediated Ca²⁺ influx (Berman et al., 2002). By blocking NMDAR-mediated Ca²⁺ influx, dantrolene and ionomycin prevent neurotoxicity in cultured rat cortical and retinal ganglion cell neurons (Lei et al., 1992). Drug-induced inhibition of Glutamate ionotropic receptor NMDA type subunit 2A (GluN2A) NMDAR or deletion of the GluN2A subunit gene attenuates the effects of homocysteine on increasing intracellular Ca²⁺ concentrations, leading to neurotoxicity (Deep et al., 2019). In hippocampal neurons, Aβ-induced Ca²⁺ influx mediated by NMDARs leads to calpain-dependent neurotoxicity (Kelly and Ferreira, 2006; Deep et al., 2019). Based on these observations, NMDARs have the ability to mediate Aβ-induced neurotoxicity via Ca²⁺-dependent mechanisms. In addition, AMPAR was also reported to be involved in regulating neurotoxicity as another glutamate receptor type functioning as a Ca²⁺ transporter. For example, cannabinoid receptor activation attenuates the effects of TNF-α on the surface localization of AMPAR, which resulted in excitotoxicity in cultured hippocampal neurons (Zhao et al., 2010; Ganguly et al., 2019). AMPAR trafficking to the cell membrane of CNS neurons regulates excitotoxicity induced by TNF-α (Ferguson et al., 2008). TNF-α induces a rapid reduction in AMPAR-mediated Ca²⁺ entry by increasing the expression of the GluR2 subunit on the cell surface, which results in excitotoxicity during the progression of neurodegeneration (Rainey-Smith et al., 2010). Moreover, AMPAR mediated AMPA- and kainite-induced neurotoxicity via Ca²⁺ influx mechanisms in cultured rat hippocampal neurons (Ambrósio et al., 2000). In addition, ethanol induces neurotoxicity in hippocampal slices by activating AMPAR (Gerace et al., 2021). Of note, either Aβ or trimethyltin has the ability to induce neuronal death via activating L-VGCC, leading to the Ca²⁺ overload (Piacentini et al., 2008a, b). Therefore, NMDARs and AMPARs are critical for inducing neurotoxicity by triggering Ca²⁺ influx.

In the cell membrane, L-VGCC is also involved in mediating AMPA/Zn²⁺-induced neurotoxicity in primary cultured rat cortical neurons (Ambrósio et al., 2000; Lee et al., 2016). In these cells, L-VGCCs were further reported to be critical for iron-induced neurotoxicity (Xu Y. Y. et al., 2020). In cerebral cortical cells, CXCL12 induces neurotoxicity via NMDAR and L-VGCC-dependent p38 MAPK activation (Sanchez et al., 2016). By blocking the L/N-type Ca²⁺ channel, cilnidipine protects the retina from neurotoxicity in ischaemia-reperfusion-treated rats (Sakamoto et al., 2009).

Another family of Ca²⁺ transporters, TRPs, was also reported to be involved in regulating neurotoxicity. In primary cultures of mouse DRG neurons, the inhibition of TRPV1 with specific blockers, such as capsaicin or resiniferatoxin, reduces the prooxidant capacity of microglial neurotoxicity (Ma et al., 2009). In addition, TRPV1 mediates vanilloid- and low pH-induced neurotoxicity in cultured rat cortical neurons (Shirakawa et al., 2007; Ertilav et al., 2021). In contrast, the inhibition of TRPV1 by the antagonist capsazepine attenuates its neuroprotective effects, indicating that TRPV1 activation contributes to the survival of rat nigral neurons (Park et al., 2012). To the best of our knowledge, no report has reconciled these conflicting results. With respect to TRPC1, neurotoxicity in SH-SY5Y cells is markedly induced by treatment with 1-methyl-4-phenylpyridinium ion (MPP⁺) through TRPC1-deactivating Ca²⁺-dependent mechanisms (Bollimuntha et al., 2005). TRPC1 overexpression inhibits neurotoxicity by inhibiting the release of cytochrome c and the expression of the Bax and Apaf-1 proteins in SH-SY5Y cells (Morelli et al., 2013). In contrast to TRPC1, TRPC6 deletion attenuates the effects of NMDAR-mediated Ca²⁺ entry, resulting in a disruption of the effect of Ca²⁺ on neurotoxicity in primary cultured neurons (Chen J. et al., 2017). Blocking TRPV4-mediated Ca²⁺ influx reduces the neurotoxicity of paclitaxel to small and medium dorsal root ganglion neurons (Boehmerle et al., 2018). Regarding TRPM2, cisplatin-induced neurotoxicity in primary DRG cells is attenuated by treatment with its antagonist, 2-aminoethoxydiphenyl borate (Chen J. et al., 2017). TRPM2 knockout blocks Aβ oligomer-induced neurotoxicity, which results in impaired memory in APP/PS1 mice (Ostapchenko et al., 2015). In hippocampal neurons, Aβ_1–42 induces neurotoxicity by activating TRPM2 (Li and Jiang, 2018).

In addition to these canonical Ca²⁺ transporters, decreasing the expression of CALHM1 exerts neuroprotective effects on oxygen and glucose deprivation in hippocampal slices (Garrosa et al., 2020). On the other hand, APOE has been reported to be involved in regulating neurotoxicity. For example, APOE4 promotes the neurotoxicity induced by Aβ aggregation in AD (Ma et al., 1996). Extracellular APOE4 is cytotoxic to human neuroblastoma SK-N-SH cells, and Aβ_1–42 enhances the cytotoxicity of APOE4. The carboxyl terminal mutation of L279Q, K282A or Q284A decreases the ability of APOE4 to form SDS-stable oligomers and decreases its cytotoxicity. Structural and thermodynamic analyses showed that all three APOE4 mutants contain significantly increased α-helical and β-sheet structures, which resulted in reduced exposure of the hydrophobic surface to the solvent and reduced conformational stability during chemical denaturation (Dafnis et al., 2018). In N2a-APP₆₉₅ cells, APOE4 exacerbates the effects of ethanol on inducing neurotoxicity by increasing oxidative stress and apoptosis (Ji et al., 2019). In contrast, APOE1–3 has been shown to protect primary cultures of rat cortical neurons from the neurotoxic effects of the nonfibrillar C-terminal domain of Aβ (Drouet et al., 2001; Brookhouser et al., 2021). APOE isoforms play different roles in neurotoxicity by modulating Aβ deposition in the mouse brain (Drouet et al., 2001). Ca²⁺ mediates the effects of truncated APOE on neurotoxicity in cultured embryonic rat hippocampal neurons (Tolar et al., 1999). Through these mechanisms, APOE-related neurotoxicity might be a therapeutic target for AD (Marques and Crutcher, 2003; Figure 1).

The ER Mediates the Effects of Ca²⁺ on Inducing Neurotoxicity as an Intracellular Store

Since Ca²⁺ regulates neurotoxicity via transporters located in the cell membrane, the roles of Ca²⁺ derived from intracellular stores in neurotoxicity are further addressed in Table 4. For example, Aβ induces neurotoxicity in cortical neurons via an ER-mediated apoptotic pathway (Ferreiro et al., 2006; Goswami et al., 2020). In the spinal cord, Ca²⁺ mediates the effects of ER stress on neurotoxicity (Li et al., 2014). By alleviating ER stress, nicotine suppresses the activity of MPP ⁺ /MPTP associated with neurotoxicity in PC12 cells (Cai et al., 2017). Similar to its role in AD, Aβ induces neurotoxicity in cortical neurons by promoting ER stress (Song et al., 2008).

As Ca²⁺ mediates the effects of ER stress on neurotoxicity, Ca²⁺ transporters in ER membranes must be associated with neurotoxicity. For example, The generation of InsP3 by activated M3 muscarinic receptors contributes to increased Ca²⁺ influx and subsequent cytotoxicity in rat cerebellar granule cells (Limke et al., 2004). Furthermore, cyanide induces the formation of InsP3, which triggers intracellular neurotoxic signaling events in PC12 cells (Yang et al., 1996). In hippocampal neurons, Ca²⁺ was also found to be the critical cause of microcystin-LR-induced neurotoxicity through PLC- and InsP3-dependent pathways (Cai et al., 2015). Regarding the receptors of InsP3, InsP3R triggers Ca²⁺ influx to mediate isoflurane-induced neurotoxicity, which is facilitated by an APP mutant in SH-SY5Y cells (Liu et al., 2016). In primary cultures of cortical cells, Aβ induces neurotoxic effects by inducing Ca²⁺ release from the ER via InsP3R- and RyR-dependent mechanisms (Ferreiro et al., 2004). After inhibiting the activity of InsP3R and RyR, the cytotoxicity and increased Ca²⁺ levels are attenuated. More interestingly, the combined inhibition of both receptors paradoxically increases the amount of cytosolic Ca²⁺ entering PC12 cells from the extracellular space, increasing cytotoxicity (Yang et al., 2019). In addition to InsP3R, RyR alone might be critical for modulating neurotoxicity in human microglia and THP-1 cells (Klegeris et al., 2007; Holland and Pessah, 2021). In cultured mammalian neurons, Xbpls ameliorates Aβ-induced neurotoxicity through an RyR-dependent mechanism (Fernandez-Funez et al., 2010). Thus, the ER is an important intracellular Ca²⁺ store for regulating neurotoxicity in neurons (Figure 2).

Mitochondria Are Critical for Regulating Neurotoxicity Through a Ca²⁺-Dependent Mechanism

In addition to the ER, mitochondria are reported to be critical for regulating neurotoxicity through a Ca²⁺-dependent mechanism. In particular, VDAC1, a transporter located in mitochondria, mediates Aβ-induced neurotoxicity in PC12 and SH-SY5Y cells and thus represents a potential target for AD treatment (Smilansky et al., 2015). In addition, the dephosphorylation of VDAC1 by hesperidin blocks Aβ-induced neurotoxicity in PC12 cells through a mitochondria-dependent mechanism (Wang et al., 2013). Aβ directly induces neurotoxicity via the dephosphorylation of VDAC1 in murine septal SN56, SH-SY5Y and hippocampal HT22 cells (Fernandez-Echevarria et al., 2014; Shoshan-Barmatz et al., 2018). In these cells, the interaction between VDAC and mERα at the plasma membrane may lead to the modulation of Aβ-induced neurotoxicity (Marin et al., 2007). In addition to VDAC1, an anti-VDAC2 antibody reduces neurotoxicity by decreasing intracellular Ca²⁺ levels in SH-SY5Y cells (Marin et al., 2007; Nagakannan et al., 2019). By inhibiting the opening of the mPTP, cyclosporin A protects SH-SY5Y and PC12 cells from neurotoxicity (Ye et al., 2016). In primary cultures of rat cortical neurons, 4-hydroxy-2(E)-nonenal facilitates NMDA-induced neurotoxicity by opening the mPTP, which results in Ca²⁺ influx (Choi et al., 2013). This observation is further supported by a report showing that NMDA induced neurotoxicity via the mPTP in cultured murine cortical neurons (Kinjo et al., 2018). Based on this evidence, intracellular Ca²⁺ stores are involved in mediating the effects of Ca²⁺ on neurotoxicity, which potentially contributes to neuronal apoptosis or death (Table 4, Figure 3).

Ca²⁺ Disrupts The Autophagic Clearance of Aggregated Proteins

Ca²⁺ Transporters on the Cell Membranes Are Presumably Involved in Regulating Autophagy and Are Responsible for Clearing Aβ or Phosphorylated Tau

As a protein clearing function, autophagy deficiency might be the cause of the aggregation and deposition of Aβ or hyperphosphorylation of tau in APs and NFTs (Pickford et al., 2008; Heckmann et al., 2019). Ca²⁺ signaling plays a crucial role in autophagy in various experimental models (Shaikh et al., 2016; Zhang et al., 2016). Logically, Ca²⁺ transporters are proposed to be involved in regulating autophagy. According to preliminary evidence, NMDARs on the cell membrane contribute to autophagy and the membrane potential in leukaemic megakaryoblasts (Nursalim, 2016). Specifically, exposure to low-dosage NMDA increases LC3 II production, which results in the degradation of GluR1, a subunit of AMPAR, in cultured rat hippocampal neurons (Shehata et al., 2012). Treatment with an antagonist of NMDAR, memantine, induces the NMDAR1-mediated autophagic cell death of T-98G cells (Yoon et al., 2017). In cultured hippocampal neurons, the NR2B antagonist Ro25-6981 markedly attenuates NMDA- and global ischaemia-induced activation of the autophagy pathway by disrupting the association of NR2B and Beclin1, resulting in cell death (Borsello et al., 2003; Liu and Zhao, 2013). In contrast, autophagy upregulates the expression of AMPAR subunits, including GluR1, GluR2, and GluR3, in oxygen- and glucose-deprived and reoxygenated injured neurons (Bao et al., 2017). These observations indicate the involvement of Ca²⁺ transporters located in the cell membranes in regulating autophagy. Similarly, VGCC induces Ca²⁺ influx to inhibit autophagy by activating calpains that cleave ATG5, an important factor for elongating autophagosomes, in H4 cells (Williams et al., 2008). As an atypical Ca²⁺ transporter in the cell membrane, APOE4 potentiates the effects of Aβ on the destabilization and permeabilization of lysosomal membranes, which results in impaired autophagy and the degradation of lysosomes in N2a cells (Ji et al., 2006; Nasiri-Ansari et al., 2021). In addition, rapamycin, an autophagy inducer, enhances mitochondrial autophagy and restores mitochondrial function in APOE4-expressing astrocytes (Schmukler et al., 2020). In astrocytes, APOE4 also impairs autophagy, resulting in attenuated clearance of Aβ (Simonovitch et al., 2016; Figure 1).

ER Stress Induces Autophagy by Modulating the Dyshomeostasis of Ca²⁺

In terms of intracellular Ca²⁺ stores, ER stress induces autophagy in propofol-stimulated C2C12 myoblast cells (Chen et al., 2018). In SK-N-SH cells, ER stress activates autophagy in UPR-stimulated SK-N-SH cells, which indicates its roles in AD (Nijholt et al., 2011). Specifically, polyglutamine induces LC3 conversion via ER stress, which initiates the onset of autophagy in C2C5 myoblast cells (Kouroku et al., 2007). Similarly, inducers of ER stress, including tunicamycin, DTT and MG132, concurrently decrease the activity of mTOR and increase the conversion of LC3 I to LC3 II in MEFs (Qin et al., 2010). Lithium induces autophagy by suppressing inositol monophosphatase, leading to the depletion of free inositol and InsP3 in SK-N-SH and COS-7 cells (Sarkar et al., 2005). This observation was also confirmed in lithium-treated IMPA1 knockout mice (Sade et al., 2016). In another study, Ca²⁺ was reported to be located downstream of InsP3R and mediated 2-aminoethoxydiphenyl borate (2-APB)-induced autophagy flux in neonatal rat ventricular myocytes (NRVMs) and HeLa cells (Wong et al., 2013). In addition, by inhibiting InsP3-mediated Ca²⁺ signaling, glucocorticoids induce autophagy in T lymphocytes (Harr et al., 2010). Blockade of InsP3R, the receptor of InsP3, restores autophagy and mitochondrial function in muscle fibers from WT and MDX mice (Valladares et al., 2018). InsP3R knockout upregulates the expression of autophagy markers compared to the WT controls (Cárdenas et al., 2010; Khan and Joseph, 2010). Researchers further emphasized the involvement of Ca²⁺ in autophagy by inducing autophagy through starvation and the activation of the InsP3R-mediated Ca²⁺ signaling pathway, as evidenced by the abolishment of LC3 lipidation and the formation of GFP-LC3 puncta in HeLa cells; these changes were blocked by the Ca²⁺ chelator BAPTA-AM and the InsP3R inhibitor xestospongin B (Cárdenas et al., 2010). In PC12 cells, isoflurane induced autophagy-dependent cell death via InsP3R-Ca²⁺-dependent mechanisms (Peng et al., 2011). Moreover, InsP3R-mediated transfer of Ca²⁺ from the ER to mitochondria is required to maintain the proper production of ATP, and Ca²⁺ blockade inhibits AMPK activity, leading to the suppression of autophagy in DT40 cells (Cárdenas et al., 2010; Lim et al., 2021a). Regarding the other Ca²⁺ transporters in ER membranes, RyR mediates the effects of propofol on inducing autophagy in cortical neuronal progenitor cells (Qiao et al., 2017). In primary cultured cortical neurons, RyR1 and RyR3 upregulation induced by insulin deprivation increase Ca²⁺ release from the ER, which increases the production of LC3II, an important autophagy marker (Edinger and Thompson, 2004; Chung et al., 2016). As an antagonist of RyRs, ryanodine stimulates autophagy by decreasing the cytosolic levels of Ca²⁺, leading to neuroprotection in CBE-N2a cells (Liou et al., 2016). By blocking RyR activity, dantrolene and an inhibitory dose of ryanodine reduce the conversion of LC3I to LC3II in HEK293 and C2C12 cells (Vervliet et al., 2017). Similarly, the downregulation of RyR2-mediated Ca²⁺ release decreases ATP production by suppressing mitochondrial metabolism, resulting in an increase in the autophagy-dependent death of rat neonatal cardiomyocytes (Pedrozo et al., 2013; McDaid et al., 2020). By depleting Ca²⁺ from the ER, SOCE exerts a biological effect on Ca²⁺ influx. In PC3 and DU145 cells, autophagic cell death was induced by resveratrol, which downregulated the expression of Stim1 and disrupted its association with TRPC1 and Orai1 (Selvaraj et al., 2016). The overexpression of Stim1 and Orai1 inhibits the effects of starvation- and rapamycin-induced autophagy on A7R5 rat arterial smooth muscle cells (Michiels et al., 2015). Moreover, caerulein promotes the interaction between Stim1 and Orai1, which activates CaN by inducing Ca²⁺ overload, leading to the expression of autophagy-related genes in mice with acute pancreatitis (Zhu et al., 2018). These observations revealed the involvement of ER Ca²⁺ stores in regulating autophagy (Figure 2).

Based on the aforementioned observations, InsP3R was found to connect mitochondria, potentially contributing to apoptosis and autophagy (Decuypere et al., 2011b). In Aβ-treated PC12 cells, moderate activation of autophagy regulates intracellular Ca²⁺ levels and the mitochondrial membrane potential (Xue et al., 2016). Reciprocally, mitochondrial fission-mediated Ca²⁺ signaling induces the expression of Stim1 and subsequent SOCE, which promoted autophagy through Ca²⁺/CAMKK/AMPK signaling cascades (Huang et al., 2017). Regarding Ca²⁺ transporters in mitochondria, VDAC recruits Parkin to defective mitochondria, resulting in the induction of mitochondrial autophagy in HEK293 cells (Sun et al., 2012). In addition, p53 is actively recruited to the outer membrane of mitochondria during nutrient deprivation, resulting in opening of the mPTP, an increase in the conversion of LC3BII to LC3BI, and the formation of LC3-GFP puncta in ventricular myocytes (Eydelnant et al., 2009; Xu H. X. et al., 2020).

Ca²⁺ Transporters on the Lysosomal Membranes Are Responsible for Regulating the Degradation of Aggregated Proteins

As the lysosome is the organelle responsible for degrading proteins, studies aiming to elucidate the roles of Ca²⁺ transporters located in lysosomes in regulating autophagy would be interesting. For example, Ca²⁺ stimulates lysosomal v-ATPase and mTORC1 pathways, which potentially contribute to the effects of orexin and hypocretin on autophagy in HEK293T cells (Wang et al., 2014). Rapamycin treatment inhibits mTOR activity by decreasing phosphorylation at two serine residues, leading to the induction of autophagy via a Ca²⁺-dependent mechanism (Onyenwoke et al., 2015). Furthermore, v-ATPase deficiency in Presenilin 1 (PS1) loss-of-function states causes deficits in lysosomes and autophagy, which contributes to abnormal cellular Ca²⁺ homeostasis (Lee et al., 2015). In addition, accumulating evidence is showing that the functional regulation of TRP channels contributes to Ca²⁺ signaling and subsequent autophagy initiation (Sukumaran et al., 2016). Transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1) is a lysosomal Ca²⁺ channel, which can mediate the release of Ca²⁺ from lysosomes to cytoplasm. TRPML1 mutation increases the formation of autophagosomes, disrupts the fusion of autophagosomes and lysosomes, and induces the accumulation of p62 and insufficient removal of ubiquitinated proteins and/or defective mitochondria in fibroblasts from patients with mucolipidosis type IV (MLIV; Vergarajauregui et al., 2008; Nakamura et al., 2020). Under nutrient starvation conditions, TRPML1 upregulation is critical for increasing lysosomal proteolytic activity in COS-1 cells (Wang W. et al., 2015). Moreover, the overexpression of TRPML3/MCOLN3 induces autophagy in HeLa cells via a Ca²⁺-dependent mechanism (Kim et al., 2009). Similarly, both exogenous and endogenous Ca²⁺ modulate autophagy via different transporters (Table 5).

The Herbs Used as Food and Seasonings in Chinese Daily Life Potentially Contribute to AD Treatment by Restoring The Ca²⁺ Concentration Through Effects on Its Transporters

As discussed above, Ca²⁺ overload plays important roles in aggravating AD via its transporters. In particular, Ca²⁺ overload perturbs the activities of the brain network, which increases the risk of AD and contributes causally to synaptic and cognitive deficits in hAPP mice. Since Ca²⁺ homeostasis is regulated by different transporters, transporters might be potential therapeutic targets for treating AD by modulating Ca²⁺ homeostasis. However, the outcome is not always consistent with our expectation. For instance, memantine, a noncompetitive NMDA antagonist, is an effective drug approved by the FDA for the treatment of AD. The VGCC inhibitor levetiracetam, an antiepileptic drug, exerts positive effects on patients with AD (Cumbo and Ligori, 2010; Vogl et al., 2012), whereas no beneficial therapeutic effect on AD was observed for the VGCC antagonist nilvadipine (Lawlor et al., 2018).

Although several FDA-approved chemical drugs are currently available for treating AD, the identification of new compounds targeting Ca²⁺ transporters to prevent, halt and reverse the dyshomeostasis of Ca²⁺ is urgently needed. We thereby summarized the drug candidates derived from herbs used as food or seasonings in Chinese daily life used to restore Ca²⁺ homeostasis in animals (Table 6). For example, asiatic acid from Centella asiatica reduces intracellular Ca²⁺ levels by inhibiting N- and P/Q-type calcium channels in the rat hippocampus (Lu et al., 2019). In rat cerebrocortical synaptosomes, silymarin derived from Silybum marianum similarly reduces intracellular Ca²⁺ concentrations by inhibiting N- and P/Q-type Ca²⁺ channels (Lu et al., 2020a). In addition, the I3C derivative [1(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol (CIM) from broccoli, cauliflower, and brussels sprouts inhibits Ca²⁺ influx by suppressing the activities of P/Q-type Ca²⁺ channels in rats (Lu et al., 2020b). In addition, numerous active compounds, such as uncarialin A, emodin, flavones, aconitine, patchouli alcohol (PA), coutareagenin, neferine, salvianolic acid B (Sal B), danshensu, tetrandrine, osthole, and hydroxy-safflor yellow A, derived from herbs, including Uncaria rhynchophylla, rhubarb, Acanthopanax senticosus (AS), Aconitum, Cablin, dandelion and Astragalus, plantule of Nelumbo nucifera, Salvia miltiorrhiza, Radix Salvia miltiorrhiza, Stephania tetrandra, Cnidium monnieri, and Carthamus tinctorius L., respectively, inhibit Ca²⁺ influx by deactivating Ca²⁺ transporters on the cell membrane, such as L-type Ca²⁺ channels, VDCC, G protein-coupled receptors, TRPCs, and TRPVs in different animal and cell models (Sun G. B. et al., 2014; Vierling et al., 2014; Zhou et al., 2014; Guan et al., 2015; Meng et al., 2016; Yang et al., 2016; Chen R. C. et al., 2017; Li et al., 2018; Yang J. et al., 2020; Yeh et al., 2020; Yu et al., 2020; Yun et al., 2020). Moreover, active compounds, including homoharringtonine, magnolol, polydatin (PD), and Ginkgo biloba extracts (EGb), derived from herbs, such as Cephalotaxus fortunei, magnolia tree, Polygonum cuspidatum, and Ginkgo biloba, respectively, modulate Ca²⁺ homeostasis by regulating the activities of transporters located in the ER through mechanism partially dependent on SOCE or mitochondria (Matsubara et al., 2005; Yang et al., 2013; Guo et al., 2014; Hsieh et al., 2018; Li et al., 2019). Although these herbs have not been used in clinical trials, all this evidence suggests that the herbs used as food and seasonings in Chinese daily life potentially contribute to treating AD by targeting Ca²⁺ transporters to restore Ca²⁺ concentrations (Table 6).

Conclusions

During the development and progression of AD, Ca²⁺ concentrations are increased in the cytosol of neuronal cells via transportation from the extracellular space and intracellular stores through transporter-dependent mechanisms. Ca²⁺ accumulation in neuronal cells induces the production and deposition of Aβ and hyperphosphorylated tau in APs and NFTs, leading to impaired learning ability in patients with AD. Moreover, transporters in the cell membrane, endoplasmic reticulum, mitochondria, and lysosomal membranes are critical for mediating the effects of Ca²⁺ on neuroinflammation, neuronal injury, neurogenesis, neurotoxicity, neuroprotection, autophagy, and synaptic plasticity, which contribute to the cognitive decline associated with AD (Figure 4). Based on these theoretical investigations, some bioactive components from Chinese herbal medicines have the potential to treat AD by targeting Ca²⁺ transporters. Moreover, Ca²⁺ transporters are progressively becoming new therapeutic targets for treating AD.

Figure 4

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

• 1

  Ambrósio A. F. Silva A. P. Malva J. O. Mesquita J. F. Carvalho A. P. Carvalho C. M. (2000). Role of desensitization of AMPA receptors on the neuronal viability and on the [Ca²⁺]i changes in cultured rat hippocampal neurons. Eur. J. Neurosci.12, 2021–2031. 10.1046/j.1460-9568.2000.00091.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 2

  Arispe N. Diaz J. Durell S. R. Shafrir Y. Guy H. R. (2010). Polyhistidine peptide inhibitor of the Abeta calcium channel potently blocks the Abeta-induced calcium response in cells. Theoretical modeling suggests a cooperative binding process. Biochemistry49, 7847–7853. 10.1021/bi1006833

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3

  Bao L. Li R. H. Li M. Jin M. F. Li G. Han X. et al . (2017). Autophagy-regulated AMPAR subunit upregulation in in vitro oxygen glucose deprivation/reoxygenation-induced hippocampal injury. Brain Res.1668, 65–71. 10.1016/j.brainres.2017.05.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4

  Beattie M. S. Ferguson A. R. Bresnahan J. C. (2010). AMPA-receptor trafficking and injury-induced cell death. Eur. J. Neurosci.32, 290–297. 10.1111/j.1460-9568.2010.07343.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 5

  Ben-Hail D. Shoshan-Barmatz V. (2016). VDAC1-interacting anion transport inhibitors inhibit VDAC1 oligomerization and apoptosis. Biochim. Biophys. Acta1863, 1612–1623. 10.1016/j.bbamcr.2016.04.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 6

  Berman F. W. LePage K. T. Murray T. F. (2002). Domoic acid neurotoxicity in cultured cerebellar granule neurons is controlled preferentially by the NMDA receptor Ca²⁺ influx pathway. Brain Res.924, 20–29. 10.1016/s0006-8993(01)03221-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 7

  Bessou M. Lopez J. Gadet R. Deygas M. Popgeorgiev N. Poncet D. et al . (2020). The apoptosis inhibitor Bcl-xL controls breast cancer cell migration through mitochondria-dependent reactive oxygen species production. Oncogene39, 3056–3074. 10.1038/s41388-020-1212-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8

  Blackshaw S. Sawa A. Sharp A. H. Ross C. A. Snyder S. H. Khan A. A. (2000). Type 3 inositol 1,4,5-trisphosphate receptor modulates cell death. FASEB J.14, 1375–1379. 10.1096/fj.14.10.1375

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 9

  Boehmerle W. Huehnchen P. Lee S. L. L. Harms C. Endres M. (2018). TRPV4 inhibition prevents paclitaxel-induced neurotoxicity in preclinical models. Exp. Neurol.306, 64–75. 10.1016/j.expneurol.2018.04.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 10

  Bollimuntha S. Singh B. B. Shavali S. Sharma S. K. Ebadi M. (2005). TRPC1-mediated inhibition of 1-methyl-4-phenylpyridinium ion neurotoxicity in human SH-SY5Y neuroblastoma cells. J. Biol. Chem.280, 2132–2140. 10.1074/jbc.M407384200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 11

  Borsello T. Croquelois K. Hornung J. P. Clarke P. G. (2003). N-methyl-d-aspartate-triggered neuronal death in organotypic hippocampal cultures is endocytic, autophagic and mediated by the c-Jun N-terminal kinase pathway. Eur. J. Neurosci.18, 473–485. 10.1046/j.1460-9568.2003.02757.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 12

  Brand-Schieber E. Werner P. (2004). Calcium channel blockers ameliorate disease in a mouse model of multiple sclerosis. Exp. Neurol.189, 5–9. 10.1016/j.expneurol.2004.05.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 13

  Brookhouser N. Raman S. Frisch C. Srinivasan G. Brafman D. A. (2021). APOE2 mitigates disease-related phenotypes in an isogenic hiPSC-based model of Alzheimer’s disease. Mol. Psychiatry [Online ahead of print]. 10.1038/s41380-021-01076-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14

  Brown G. C. Neher J. J. (2014). Microglial phagocytosis of live neurons. Nat. Rev. Neurosci.15, 209–216. 10.1038/nrn3710

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15

  Brustein E. Côté S. Ghislain J. Drapeau P. (2013). Spontaneous glycine-induced calcium transients in spinal cord progenitors promote neurogenesis. Dev. Neurobiol.73, 168–175. 10.1002/dneu.22050

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 16

  Bull R. Finkelstein J. P. Gálvez J. Sánchez G. Donoso P. Behrens M. I. et al . (2008). Ischemia enhances activation by Ca²⁺ and redox modification of ryanodine receptor channels from rat brain cortex. J. Neurosci.28, 9463–9472. 10.1523/JNEUROSCI.2286-08.2008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 17

  Bullock R. (2006). Efficacy and safety of memantine in moderate-to-severe Alzheimer disease: the evidence to date. Alzheimer Dis. Assoc. Disord.20, 23–29. 10.1097/01.wad.0000201847.29836.a5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 18

  Bursztajn S. Falls W. A. Berman S. A. Friedman M. J. (2007). Cell proliferation in the brains of NMDAR NR1 transgenic mice. Brain Res.1172, 10–20. 10.1016/j.brainres.2007.07.045

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 19

  Cai F. Liu J. Li C. Wang J. (2015). Intracellular calcium plays a critical role in the microcystin-LR-elicited neurotoxicity through PLC/IP3 pathway. Int. J. Toxicol.34, 551–558. 10.1177/1091581815606352

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20

  Cai Y. Zhang X. Zhou X. Wu X. Li Y. Yao J. et al . (2017). Nicotine suppresses the neurotoxicity by MPP(+)/MPTP through activating α7nAChR/PI3K/Trx-1 and suppressing ER stress. Neurotoxicology59, 49–55. 10.1016/j.neuro.2017.01.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21

  Calvo-Rodriguez M. Hernando-Pérez E. López-Vázquez S. Núñez J. Villalobos C. Núñez L. (2020). Remodeling of intracellular Ca(2+) homeostasis in rat hippocampal neurons aged in vitro. Int. J. Mol. Sci.21:1549. 10.3390/ijms21041549

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22

  Cao L. L. Guan P. P. Liang Y. Y. Huang X. S. Wang P. (2019). Calcium ions stimulate the hyperphosphorylation of tau by activating microsomal prostaglandin E synthase 1. Front. Aging Neurosci.11:108. 10.3389/fnagi.2019.00108

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 23

  Cao X. Südhof T. C. (2001). A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science293, 115–120. 10.1126/science.1058783

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 24

  Cárdenas C. Miller R. A. Smith I. Bui T. Molgó J. Müller M. et al . (2010). Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell142, 270–283. 10.1016/j.cell.2010.06.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 25

  Cardozo A. K. Ortis F. Storling J. Feng Y. M. Rasschaert J. Tonnesen M. et al . (2005). Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic beta-cells. Diabetes54, 452–461. 10.2337/diabetes.54.2.452

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 26

  Chao C. C. Huang C. C. Lu D. Y. Wong K. L. Chen Y. R. Cheng T. H. et al . (2012). Ca2+ store depletion and endoplasmic reticulum stress are involved in P2X7 receptor-mediated neurotoxicity in differentiated NG108–15 cells. J. Cell. Biochem.113, 1377–1385. 10.1002/jcb.24010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 27

  Chen S. Averett N. T. Manelli A. Ladu M. J. May W. Ard M. D. (2005). Isoform-specific effects of apolipoprotein E on secretion of inflammatory mediators in adult rat microglia. J. Alzheimers Dis.7, 25–35. 10.3233/jad-2005-7104

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 28

  Chen T. Dai S. H. Jiang Z. Q. Luo P. Jiang X. F. Fei Z. et al . (2017). The AMPAR antagonist perampanel attenuates traumatic brain injury through anti-oxidative and anti-inflammatory activity. Cell. Mol. Neurobiol.37, 43–52. 10.1007/s10571-016-0341-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 29

  Chen H. Gao W. Yang Y. Guo S. Wang H. Wang W. et al . (2014). Inhibition of VDAC1 prevents Ca²-mediated oxidative stress and apoptosis induced by 5-aminolevulinic acid mediated sonodynamic therapy in THP-1 macrophages. Apoptosis19, 1712–1726. 10.1007/s10495-014-1045-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 30

  Chen J. Li Z. Hatcher J. T. Chen Q. H. Chen L. Wurster R. D. et al . (2017). Deletion of TRPC6 attenuates NMDA receptor-mediated Ca(2+) entry and Ca(2+)-induced neurotoxicity following cerebral ischemia and oxygen-glucose deprivation. Front. Neurosci.11:138. 10.3389/fnins.2017.00138

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 31

  Chen X. Li L. Y. Jiang J. L. Li K. Su Z. B. Zhang F. Q. et al . (2018). Propofol elicits autophagy via endoplasmic reticulum stress and calcium exchange in C2C12 myoblast cell line. PLoS One13:e0197934. 10.1371/journal.pone.0197934

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32

  Chen R. C. Sun G. B. Ye J. X. Wang J. Zhang M. D. Sun X. B. (2017). Salvianolic acid B attenuates doxorubicin-induced ER stress by inhibiting TRPC3 and TRPC6 mediated Ca(2+) overload in rat cardiomyocytes. Toxicol. Lett.276, 21–30. 10.1016/j.toxlet.2017.04.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33

  Cheng A. Kawahata I. Fukunaga K. (2020). Fatty acid binding protein 5 mediates cell death by psychosine exposure through mitochondrial macropores formation in oligodendrocytes. Biomedicines8:635. 10.3390/biomedicines8120635

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34

  Cheng L. Muroi M. Cao S. Bian L. Osada H. Xiang L. et al . (2019). 3β,23,28-Trihydroxy-12-oleanene 3β-caffeate from desmodium sambuense-induced neurogenesis in PC12 cells mediated by ER stress and BDNF-TrkB signaling pathways. Mol. Pharm.16, 1423–1432. 10.1021/acs.molpharmaceut.8b00939

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35

  Choi I. Y. Lim J. H. Kim C. Song H. Y. Ju C. Kim W. K. (2013). 4-hydroxy-2(E)-nonenal facilitates nmda-induced neurotoxicity via triggering mitochondrial permeability transition pore opening and mitochondrial calcium overload. Exp. Neurobiol.22, 200–207. 10.5607/en.2013.22.3.200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 36

  Chung K. M. Jeong E. J. Park H. An H. K. Yu S. W. (2016). Mediation of autophagic cell death by type 3 ryanodine receptor (RyR3) in adult hippocampal neural stem cells. Front. Cell. Neurosci.10:116. 10.3389/fncel.2016.00116

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 37

  Coen K. Flannagan R. S. Baron S. Carraro-Lacroix L. R. Wang D. Vermeire W. et al . (2012). Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells. J. Cell. Biol.198, 23–35. 10.1083/jcb.201201076

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38

  Cui R. Yan L. Luo Z. Guo X. Yan M. (2015). Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis. Toxicol. Appl. Pharmacol.287, 52–66. 10.1016/j.taap.2015.05.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 39

  Cumbo E. Ligori L. D. (2010). Levetiracetam, lamotrigine and phenobarbital in patients with epileptic seizures and Alzheimer’s disease. Epilepsy Behav.17, 461–466. 10.1016/j.yebeh.2010.01.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40

  Dafnis I. Argyri L. Chroni A. (2018). Amyloid-peptide β 42 enhances the oligomerization and neurotoxicity of apoE4: The C-terminal residues Leu279, Lys282 and Gln284 modulate the structural and functional properties of apoE4. Neuroscience394, 144–155. 10.1016/j.neuroscience.2018.10.026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41

  D’Ascenzo M. Piacentini R. Casalbore P. Budoni M. Pallini R. Azzena G. B. et al . (2006). Role of L-type Ca2+ channels in neural stem/progenitor cell differentiation. Eur. J. Neurosci.23, 935–944. 10.1111/j.1460-9568.2006.04628.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42

  Daschil N. Obermair G. J. Flucher B. E. Stefanova N. Hutter-Paier B. Windisch M. et al . (2013). CaV1.2 calcium channel expression in reactive astrocytes is associated with the formation of amyloid-β plaques in an Alzheimer’s disease mouse model. J. Alzheimers Dis.37, 439–451. 10.3233/JAD-130560

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43

  Deb B. K. Chakraborty P. Gopurappilly R. Hasan G. (2020). SEPT7 regulates Ca(2+) entry through Orai channels in human neural progenitor cells and neurons. Cell Calcium90:102252. 10.1016/j.ceca.2020.102252

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44

  Decuypere J. P. Bultynck G. Parys J. B. (2011a). A dual role for Ca(2+) in autophagy regulation. Cell Calcium50, 242–250. 10.1016/j.ceca.2011.04.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 45

  Decuypere J. P. Monaco G. Bultynck G. Missiaen L. De Smedt H. Parys J. B. (2011b). The IP(3) receptor-mitochondria connection in apoptosis and autophagy. Biochim. Biophys. Acta1813, 1003–1013. 10.1016/j.bbamcr.2010.11.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 46

  Deep S. N. Mitra S. Rajagopal S. Paul S. Poddar R. (2019). GluN2A-NMDA receptor-mediated sustained Ca(2+) influx leads to homocysteine-induced neuronal cell death. J. Biol. Chem.294, 11154–11165. 10.1074/jbc.RA119.008820

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 47

  Dolga A. M. Letsche T. Gold M. Doti N. Bacher M. Chiamvimonvat N. et al . (2012). Activation of KCNN3/SK3/K(Ca)2.3 channels attenuates enhanced calcium influx and inflammatory cytokine production in activated microglia. Glia60, 2050–2064. 10.1002/glia.22419

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48

  Domenichini F. Terrié E. Arnault P. Harnois T. Magaud C. Bois P. et al . (2018). Store-operated calcium entries control neural stem cell self-renewal in the adult brain subventricular zone. Stem Cells36, 761–774. 10.1002/stem.2786

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 49

  Dong Y. Kalueff A. V. Song C. (2017). N-methyl-d-aspartate receptor-mediated calcium overload and endoplasmic reticulum stress are involved in interleukin-1beta-induced neuronal apoptosis in rat hippocampus. J. Neuroimmunol.307, 7–13. 10.1016/j.jneuroim.2017.03.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50

  Drouet B. Fifre A. Pinçon-Raymond M. Vandekerckhove J. Rosseneu M. Guéant J. L. et al . (2001). ApoE protects cortical neurones against neurotoxicity induced by the non-fibrillar C-terminal domain of the amyloid-beta peptide. J. Neurochem.76, 117–127. 10.1046/j.1471-4159.2001.00047.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 51

  Du H. Guo L. Fang F. Chen D. Sosunov A. A. McKhann G. M. et al . (2008). Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat. Med.14, 1097–1105. 10.1038/nm.1868

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52

  Du L. L. Wang L. Yang X. F. Wang P. Li X. H. Chai D. M. et al . (2017). Transient receptor potential-canonical 1 is essential for environmental enrichment-induced cognitive enhancement and neurogenesis. Mol. Neurobiol.54, 1992–2002. 10.1007/s12035-016-9758-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53

  Durell S. R. Guy H. R. Arispe N. Rojas E. Pollard H. B. (1994). Theoretical models of the ion channel structure of amyloid beta-protein. Biophys. J.67, 2137–2145. 10.1016/S0006-3495(94)80717-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54

  Edinger A. L. Thompson C. B. (2004). Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol16, 663–669. 10.1016/j.ceb.2004.09.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55

  Elgh E. Lindqvist Astot A. Fagerlund M. Eriksson S. Olsson T. Näsman B. (2006). Cognitive dysfunction, hippocampal atrophy and glucocorticoid feedback in Alzheimer’s disease. Biol. Psychiatry59, 155–161. 10.1016/j.biopsych.2005.06.017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 56

  Ertilav K. Nazıroğlu M. Ataizi Z. S. Yıldızhan K. (2021). Melatonin and selenium suppress docetaxel-induced TRPV1 activation, neuropathic pain and oxidative neurotoxicity in mice. Biol. Trace Elem. Res.199, 1469–1487. 10.1007/s12011-020-02250-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  Espinosa-Parrilla J. F. Martínez-Moreno M. Gasull X. Mahy N. Rodríguez M. J. (2015). The L-type voltage-gated calcium channel modulates microglial pro-inflammatory activity. Mol. Cell. Neurosci.64, 104–115. 10.1016/j.mcn.2014.12.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 58

  Etcheberrigaray R. Hirashima N. Nee L. Prince J. Govoni S. Racchi M. et al . (1998). Calcium responses in fibroblasts from asymptomatic members of Alzheimer’s disease families. Neurobiol. Dis.5, 37–45. 10.1006/nbdi.1998.0176

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59

  Evrard Y. A. Mohammad-Zadeh L. Holton B. (2004). Alterations in Ca2+-dependent and cAMP-dependent signaling pathways affect neurogenesis and melanogenesis of quail neural crest cells in vitro. Dev. Genes Evol.214, 193–199. 10.1007/s00427-004-0395-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60

  Eydelnant I. A. Zhang T. Bednarczyk J. Gang H. Y. (2009). Abstract 3994: recruitment of p53 to mitochondrial VDAC1 triggers autophagy of ventricular myocytes during metabolic stress. Circulation120:S902.

  • Google Scholar

• 61

  Fan H. Gao J. Wang W. Li X. Xu T. Yin X. (2012). Expression of NMDA receptor and its effect on cell proliferation in the subventricular zone of neonatal rat brain. Cell Biochem. Biophys.62, 305–316. 10.1007/s12013-011-9302-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  Faure A. V. Grunwald D. Moutin M. J. Hilly M. Mauger J. P. Marty I. et al . (2001). Developmental expression of the calcium release channels during early neurogenesis of the mouse cerebral cortex. Eur. J. Neurosci.14, 1613–1622. 10.1046/j.0953-816x.2001.01786.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63

  Ferguson A. R. Christensen R. N. Gensel J. C. Miller B. A. Sun F. Beattie E. C. et al . (2008). Cell death after spinal cord injury is exacerbated by rapid TNF alpha-induced trafficking of GluR2-lacking AMPARs to the plasma membrane. J. Neurosci.28, 11391–11400. 10.1523/JNEUROSCI.3708-08.2008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64

  Fernandez A. M. Fernandez S. Carrero P. Garcia-Garcia M. Torres-Aleman I. (2007). Calcineurin in reactive astrocytes plays a key role in the interplay between proinflammatory and anti-inflammatory signals. J. Neurosci.27, 8745–8756. 10.1523/JNEUROSCI.1002-07.2007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65

  Fernandez-Echevarria C. Díaz M. Ferrer I. Canerina-Amaro A. Marin R. (2014). Aβ promotes VDAC1 channel dephosphorylation in neuronal lipid rafts. Relevance to the mechanisms of neurotoxicity in Alzheimer’s disease. Neuroscience278, 354–366. 10.1016/j.neuroscience.2014.07.079

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66

  Fernandez-Funez P. Casas-Tinto S. Zhang Y. Rincon-Limas D. (2010). P4-078: Xbp1s prevents amyloid-β neurotoxicity by regulating ryanodine Ca2+ channels. Alzheimer’s Dement.6, e45–e45. 10.1016/j.jalz.2010.08.139

  • CrossRef
  • Google Scholar

• 67

  Ferreiro E. Oliveira C. R. Pereira C. (2004). Involvement of endoplasmic reticulum Ca2+ release through ryanodine and inositol 1,4,5-triphosphate receptors in the neurotoxic effects induced by the amyloid-beta peptide. J. Neurosci. Res.76, 872–880. 10.1002/jnr.20135

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68

  Ferreiro E. Resende R. Costa R. Oliveira C. R. Pereira C. M. (2006). An endoplasmic-reticulum-specific apoptotic pathway is involved in prion and amyloid-beta peptides neurotoxicity. Neurobiol. Dis.23, 669–678. 10.1016/j.nbd.2006.05.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69

  Fiorio Pla A. Maric D. Brazer S. C. Giacobini P. Liu X. Chang Y. H. et al . (2005). Canonical transient receptor potential 1 plays a role in basic fibroblast growth factor (bFGF)/FGF receptor-1-induced Ca2+ entry and embryonic rat neural stem cell proliferation. J. Neurosci.25, 2687–2701. 10.1523/JNEUROSCI.0951-04.2005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70

  Flourakis M. Lehen’kyi V. Beck B. Raphaël M. Vandenberghe M. Abeele F. V. et al . (2010). Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells. Cell Death Dis.1:e75. 10.1038/cddis.2010.52

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 71

  Fonfria E. Marshall I. C. Boyfield I. Skaper S. D. Hughes J. P. Owen D. E. et al . (2005). Amyloid beta-peptide(1–42) and hydrogen peroxide-induced toxicity are mediated by TRPM2 in rat primary striatal cultures. J. Neurochem.95, 715–723. 10.1111/j.1471-4159.2005.03396.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  Fonfria E. Mattei C. Hill K. Brown J. T. Randall A. Benham C. D. et al . (2006). TRPM2 is elevated in the tMCAO stroke model, transcriptionally regulated and functionally expressed in C13 microglia. J. Recept. Signal Transduct. Res.26, 179–198. 10.1080/10799890600637522

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  Franciosi S. Choi H. B. Kim S. U. McLarnon J. G. (2002). Interferon-gamma acutely induces calcium influx in human microglia. J. Neurosci. Res.69, 607–613. 10.1002/jnr.10331

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 74

  Frandsen A. Schousboe A. (1991). Dantrolene prevents glutamate cytotoxicity and Ca2+ release from intracellular stores in cultured cerebral cortical neurons. J. Neurochem.56, 1075–1078. 10.1111/j.1471-4159.1991.tb02031.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75

  Furman J. L. Sama D. M. Gant J. C. Beckett T. L. Murphy M. P. Bachstetter A. D. et al . (2012). Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer’s disease. J. Neurosci.32, 16129–16140. 10.1523/JNEUROSCI.2323-12.2012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  Furukawa K. Mattson M. P. (1998). The transcription factor NF-kappaB mediates increases in calcium currents and decreases in NMDA- and AMPA/kainate-induced currents induced by tumor necrosis factor-alpha in hippocampal neurons. J. Neurochem.70, 1876–1886. 10.1046/j.1471-4159.1998.70051876.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  Ganguly P. Honeycutt J. A. Rowe J. R. Demaestri C. Brenhouse H. C. (2019). Effects of early life stress on cocaine conditioning and AMPA receptor composition are sex-specific and driven by TNF. Brain Behav. Immun.78, 41–51. 10.1016/j.bbi.2019.01.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  Garrosa J. Paredes I. Marambaud P. López M. G. Cano-Abad M. F. (2020). Molecular and pharmacological modulation of CALHM1 promote neuroprotection against oxygen and glucose deprivation in a model of hippocampal slices. Cells9:664. 10.3390/cells9030664

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79

  Geffin R. Martinez R. de Las Pozas A. Issac B. McCarthy M. (2017). Apolipoprotein E4 suppresses neuronal-specific gene expression in maturing neuronal progenitor cells exposed to HIV. J. Neuroimmune. Pharmacol.12, 462–483. 10.1007/s11481-017-9734-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80

  Gerace E. Ilari A. Caffino L. Buonvicino D. Lana D. Ugolini F. et al . (2021). Ethanol neurotoxicity is mediated by changes in expression, surface localization and functional properties of glutamate AMPA receptors. J. Neurochem.157, 2106–2118. 10.1111/jnc.15223

  • CrossRef
  • Google Scholar

• 81

  Giarratana A. O. Zheng C. Reddi S. Teng S. L. Berger D. Adler D. et al . (2020). APOE4 genetic polymorphism results in impaired recovery in a repeated mild traumatic brain injury model and treatment with Bryostatin-1 improves outcomes. Sci. Rep.10:19919. 10.1038/s41598-020-76849-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82

  Gkouveris I. Nikitakis N. G. Aseervatham J. Ogbureke K. U. E. (2018). Interferon γ suppresses dentin sialophosphoprotein in oral squamous cell carcinoma cells resulting in antitumor effects, via modulation of the endoplasmic reticulum response. Int. J. Oncol.53, 2423–2432. 10.3892/ijo.2018.4590

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83

  Goghari V. Franciosi S. Kim S. U. Lee Y. B. McLarnon J. G. (2000). Acute application of interleukin-1beta induces Ca(2+) responses in human microglia. Neurosci. Lett.281, 83–86. 10.1016/s0304-3940(00)00824-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84

  Goswami P. Afjal M. A. Akhter J. Mangla A. Khan J. Parvez S. et al . (2020). Involvement of endoplasmic reticulum stress in amyloid β ((1–42))-induced Alzheimer’s like neuropathological process in rat brain. Brain Res. Bull.165, 108–117. 10.1016/j.brainresbull.2020.09.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85

  Grotemeier A. Alers S. Pfisterer S. G. Paasch F. Daubrawa M. Dieterle A. et al . (2010). AMPK-independent induction of autophagy by cytosolic Ca2+ increase. Cell. Signal.22, 914–925. 10.1016/j.cellsig.2010.01.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86

  Gu C. Li L. Huang Y. Q25an D. Liu W. Zhang C. et al . (2020). Salidroside ameliorates mitochondria-dependent neuronal apoptosis after spinal cord ischemia-reperfusion injury partially through inhibiting oxidative stress and promoting mitophagy. Oxid. Med. Cell. Longev.2020:3549704. 10.1155/2020/3549704

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87

  Guan P. P. Cao L. L. Wang P. (2021). Elevating the levels of calcium ions exacerbate Alzheimer’s disease via inducing the production and aggregation of β-amyloid protein and phosphorylated Tau. Int. J. Mol. Sci.22:5900. 10.3390/ijms22115900

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88

  Guan S. Ma J. Chu X. Gao Y. Zhang Y. Zhang X. et al . (2015). Effects of total flavones from Acanthopanax senticosus on L-type calcium channels, calcium transient and contractility in rat ventricular myocytes. Phytother. Res.29, 533–539. 10.1002/ptr.5278

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89

  Guo Y. Han S. Cao J. Liu Q. Zhang T. (2014). Screening of allergic components mediated by H(1)R in homoharringtonine injection through H(1)R/CMC-HPLC/MS. Biomed. Chromatogr.28, 1607–1614. 10.1002/bmc.3188

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  Güzel M. Nazıroğlu M. Akpınar O. Çınar R. (2021). Interferon gamma-mediated oxidative stress induces apoptosis, neuroinflammation, zinc ion influx, and TRPM2 channel activation in neuronal cell line: modulator role of curcumin. Inflammation44, 1878–1894. 10.1007/s10753-021-01465-4

  • CrossRef
  • Google Scholar

• 91

  Han X. J. Hu Y. Y. Yang Z. J. Jiang L. P. Shi S. L. Li Y. R. et al . (2017). Amyloid β-42 induces neuronal apoptosis by targeting mitochondria. Mol. Med. Rep.16, 4521–4528. 10.3892/mmr.2017.7203

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  Hao B. Lu Y. Wang Q. Guo W. Cheung K. H. Yue J. (2014). Role of STIM1 in survival and neural differentiation of mouse embryonic stem cells independent of Orai1-mediated Ca2+ entry. Stem Cell Res.12, 452–466. 10.1016/j.scr.2013.12.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  Harr M. W. McColl K. S. Zhong F. Molitoris J. K. Distelhorst C. W. (2010). Glucocorticoids downregulate Fyn and inhibit IP(3)-mediated calcium signaling to promote autophagy in T lymphocytes. Autophagy6, 912–921. 10.4161/auto.6.7.13290

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  Heckmann B. L. Teubner B. J. W. Tummers B. Boada-Romero E. Harris L. Yang M. et al . (2019). LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s disease. Cell178, 536–551.e514. 10.1016/j.cell.2019.05.056

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95

  Holland E. B. Pessah I. N. (2021). Non-dioxin-like polychlorinated biphenyl neurotoxic equivalents found in environmental and human samples. Regul. Toxicol. Pharmacol.120:104842. 10.1016/j.yrtph.2020.104842

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96

  Hong S. H. Choi H. B. Kim S. U. McLarnon J. G. (2006). Mitochondrial ligand inhibits store-operated calcium influx and COX-2 production in human microglia. J. Neurosci. Res.83, 1293–1298. 10.1002/jnr.20829

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 97

  Hong S. Kim A. Kernie S. (2013). Apoe4 impairs injury-induced neurogenesis. Critical Care Med.41, A39–A40. 10.1097/01.ccm.0000439329.97813.61

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98

  Hopp S. C. Royer S. E. D’Angelo H. M. Kaercher R. M. Fisher D. A. Wenk G. L. (2015). Differential neuroprotective and anti-inflammatory effects of L-type voltage dependent calcium channel and ryanodine receptor antagonists in the substantia nigra and locus coeruleus. J. Neuroimmune Pharmacol.10, 35–44. 10.1007/s11481-014-9568-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99

  Hou Y. Ghosh P. Wan R. Ouyang X. Cheng H. Mattson M. P. et al . (2014). Permeability transition pore-mediated mitochondrial superoxide flashes mediate an early inhibitory effect of amyloid beta1–42 on neural progenitor cell proliferation. Neurobiol. Aging35, 975–989. 10.1016/j.neurobiolaging.2013.11.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100

  Hou P. F. Liu Z. H. Li N. Cheng W. J. Guo S. W. (2015). Knockdown of STIM1 improves neuronal survival after traumatic neuronal injury through regulating mGluR1-dependent Ca(2+) signaling in mouse cortical neurons. Cell. Mol. Neurobiol.35, 283–292. 10.1007/s10571-014-0123-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101

  Hou Y. Mattson M. P. Cheng A. (2013). Permeability transition pore-mediated mitochondrial superoxide flashes regulate cortical neural progenitor differentiation. PLoS One8:e76721. 10.1371/journal.pone.0076721

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102

  Høyer-Hansen M. Bastholm L. Szyniarowski P. Campanella M. Szabadkai G. Farkas T. et al . (2007). Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta and Bcl-2. Mol. Cell25, 193–205. 10.1016/j.molcel.2006.12.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 103

  Hsieh S. F. Chou C. T. Liang W. Z. Kuo C. C. Wang J. L. Hao L. J. et al . (2018). The effect of magnolol on Ca(2+) homeostasis and its related physiology in human oral cancer cells. Arch. Oral Biol.89, 49–54. 10.1016/j.archoralbio.2018.02.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104

  Huang Q. Cao H. Zhan L. Sun X. Wang G. Li J. et al . (2017). Mitochondrial fission forms a positive feedback loop with cytosolic calcium signaling pathway to promote autophagy in hepatocellular carcinoma cells. Cancer Lett403, 108–118. 10.1016/j.canlet.2017.05.034

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105

  Huang Y. Smith D. E. Ibáñez-Sandoval O. Sims J. E. Friedman W. J. (2011). Neuron-specific effects of interleukin-1β are mediated by a novel isoform of the IL-1 receptor accessory protein. J. Neurosci.31, 18048–18059. 10.1523/JNEUROSCI.4067-11.2011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106

  Hudecova S. Markova J. Simko V. Csaderova L. Stracina T. Sirova M. et al . (2016). Sulforaphane-induced apoptosis involves the type 1 IP3 receptor. Oncotarget7, 61403–61418. 10.18632/oncotarget.8968

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  Hudry E. Dashkoff J. Roe A. D. Takeda S. Koffie R. M. Hashimoto T. et al . (2013). Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain. Sci. Transl. Med.5:212ra161. 10.1126/scitranslmed.3007000

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108

  Jang H. Ma B. Lal R. Nussinov R. (2008). Models of toxic beta-sheet channels of protegrin-1 suggest a common subunit organization motif shared with toxic alzheimer beta-amyloid ion channels. Biophys. J.95, 4631–4642. 10.1529/biophysj.108.134551

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 109

  Ji Y. Hu Y. Ren J. Khanna R. Yao Y. Chen Y. et al . (2019). CRMP2-derived peptide ST2–104 (R9-CBD3) protects SH-SY5Y neuroblastoma cells against Aβ(25–35)-induced neurotoxicity by inhibiting the pCRMP2/NMDAR2B signaling pathway. Chem. Biol. Interact305, 28–39. 10.1016/j.cbi.2019.03.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110

  Ji Z. S. Müllendorff K. Cheng I. H. Miranda R. D. Huang Y. Mahley R. W. (2006). Reactivity of apolipoprotein E4 and amyloid beta peptide: lysosomal stability and neurodegeneration. J. Biol. Chem.281, 2683–2692. 10.1074/jbc.M506646200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111

  Jiang L. Zhong J. Dou X. Cheng C. Huang Z. Sun X. (2015). Effects of ApoE on intracellular calcium levels and apoptosis of neurons after mechanical injury. Neuroscience301, 375–383. 10.1016/j.neuroscience.2015.06.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  Joseph J. D. Peng Y. Mak D. O. Cheung K. H. Vais H. Foskett J. K. et al . (2014). General anesthetic isoflurane modulates inositol 1,4,5-trisphosphate receptor calcium channel opening. Anesthesiology121, 528–537. 10.1097/ALN.0000000000000316

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113

  Ju Y. Ge J. Ren X. Zhu X. Xue Z. Feng Y. et al . (2015). Cav1.2 of L-type calcium channel is a key factor for the differentiation of dental pulp stem cells. J. Endod.41, 1048–1055. 10.1016/j.joen.2015.01.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 114

  Kakae M. Miyanohara J. Morishima M. Nagayasu K. Mori Y. Shirakawa H. et al . (2019). Pathophysiological role of TRPM2 in age-related cognitive impairment in mice. Neuroscience408, 204–213. 10.1016/j.neuroscience.2019.04.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  Kaneko S. Kawakami S. Hara Y. Wakamori M. Itoh E. Minami T. et al . (2006). A critical role of TRPM2 in neuronal cell death by hydrogen peroxide. J. Pharmacol. Sci.101, 66–76. 10.1254/jphs.fp0060128

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116

  Kawada K. Iekumo T. Saito R. Kaneko M. Mimori S. Nomura Y. et al . (2014). Aberrant neuronal differentiation and inhibition of dendrite outgrowth resulting from endoplasmic reticulum stress. J. Neurosci. Res.92, 1122–1133. 10.1002/jnr.23389

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117

  Kawasaki Y. Zhang L. Cheng J. K. Ji R. R. (2008). Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J. Neurosci.28, 5189–5194. 10.1523/JNEUROSCI.3338-07.2008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118

  Keinan N. Pahima H. Ben-Hail D. Shoshan-Barmatz V. (2013). The role of calcium in VDAC1 oligomerization and mitochondria-mediated apoptosis. Biochim. Biophys. Acta1833, 1745–1754. 10.1016/j.bbamcr.2013.03.017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119

  Kelly B. L. Ferreira A. (2006). beta-Amyloid-induced dynamin 1 degradation is mediated by N-methyl-D-aspartate receptors in hippocampal neurons. J. Biol. Chem.281, 28079–28089. 10.1074/jbc.M605081200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  Khan M. T. Joseph S. K. (2010). Role of inositol trisphosphate receptors in autophagy in DT40 cells. J. Biol. Chem.285, 16912–16920. 10.1074/jbc.M110.114207

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  Kim S. R. Kim S. U. Oh U. Jin B. K. (2006). Transient receptor potential vanilloid subtype 1 mediates microglial cell death in vivo and in vitro via Ca2+-mediated mitochondrial damage and cytochrome c release. J. Immunol.177, 4322–4329. 10.4049/jimmunol.177.7.4322

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122

  Kim H. J. Soyombo A. A. Tjon-Kon-Sang S. So I. Muallem S. (2009). The Ca(2+) channel TRPML3 regulates membrane trafficking and autophagy. Traffic10, 1157–1167. 10.1111/j.1600-0854.2009.00924.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123

  Kinjo T. Ashida Y. Higashi H. Sugimura S. Washida M. Niihara H. et al . (2018). Alleviation by GABA(B) receptors of neurotoxicity mediated by mitochondrial permeability transition pore in cultured murine cortical neurons exposed to N-Methyl-D-aspartate. Neurochem. Res.43, 79–88. 10.1007/s11064-017-2311-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124

  Klegeris A. Choi H. B. McLarnon J. G. McGeer P. L. (2007). Functional ryanodine receptors are expressed by human microglia and THP-1 cells: their possible involvement in modulation of neurotoxicity. J. Neurosci. Res.85, 2207–2215. 10.1002/jnr.21361

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 125

  Komita M. Jin H. Aoe T. (2013). The effect of endoplasmic reticulum stress on neurotoxicity caused by inhaled anesthetics. Anesth. Analg.117, 1197–1204. 10.1213/ANE.0b013e3182a74773

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126

  Komuro H. Rakic P. (1992). Selective role of N-type calcium channels in neuronal migration. Science257, 806–809. 10.1126/science.1323145

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  Konno M. Shirakawa H. Iida S. Sakimoto S. Matsutani I. Miyake T. et al . (2012). Stimulation of transient receptor potential vanilloid 4 channel suppresses abnormal activation of microglia induced by lipopolysaccharide. Glia60, 761–770. 10.1002/glia.22306

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 128

  Kouroku Y. Fujita E. Tanida I. Ueno T. Isoai A. Kumagai H. et al . (2007). ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ.14, 230–239. 10.1038/sj.cdd.4401984

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 129

  Kraft R. Grimm C. Grosse K. Hoffmann A. Sauerbruch S. Kettenmann H. et al . (2004). Hydrogen peroxide and ADP-ribose induce TRPM2-mediated calcium influx and cation currents in microglia. Am. J. Physiol. Cell Physiol.286, C129–137. 10.1152/ajpcell.00331.2003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130

  Kraft A. Jubal E. R. von Laer R. Döring C. Rocha A. Grebbin M. et al . (2017). Astrocytic calcium waves signal brain injury to neural stem and progenitor cells. Stem Cell Rep.8, 701–714. 10.1016/j.stemcr.2017.01.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 131

  Lashuel H. A. Hartley D. M. Petre B. M. Wall J. S. Simon M. N. Walz T. et al . (2003). Mixtures of wild-type and a pathogenic (E22G) form of Abeta40 in vitro accumulate protofibrils, including amyloid pores. J. Mol. Biol.332, 795–808. 10.1016/s0022-2836(03)00927-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132

  Lashuel H. A. Hartley D. Petre B. M. Walz T. Lansbury P. T. Jr. (2002). Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature418:291. 10.1038/418291a

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133

  Lawlor B. Segurado R. Kennelly S. Olde Rikkert M. G. M. Howard R. Pasquier F. et al . (2018). Nilvadipine in mild to moderate Alzheimer disease: a randomised controlled trial. PLoS Med.15:e1002660. 10.1371/journal.pmed.1002660

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 134

  Lee Y. J. Choi S. Y. Yang J. H. (2016). AMP-activated protein kinase is involved in perfluorohexanesulfonate-induced apoptosis of neuronal cells. Chemosphere149, 1–7. 10.1016/j.chemosphere.2016.01.073

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 135

  Lee J. H. McBrayer M. K. Wolfe D. M. Haslett L. J. Kumar A. Sato Y. et al . (2015). Presenilin 1 maintains lysosomal Ca(2+) homeostasis via TRPML1 by regulating vATPase-mediated lysosome acidification. Cell Rep.12, 1430–1444. 10.1016/j.celrep.2015.07.050

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136

  Lei S. Z. Zhang D. Abele A. E. Lipton S. A. (1992). Blockade of NMDA receptor-mediated mobilization of intracellular Ca2+ prevents neurotoxicity. Brain Res.598, 196–202. 10.1016/0006-8993(92)90183-a

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 137

  Leissring M. A. Murphy M. P. Mead T. R. Akbari Y. Sugarman M. C. Jannatipour M. et al . (2002). A physiologic signaling role for the gamma -secretase-derived intracellular fragment of APP. Proc. Natl. Acad. Sci. U S A99, 4697–4702. 10.1073/pnas.072033799

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 138

  Li X. Jiang L. H. (2018). Multiple molecular mechanisms form a positive feedback loop driving amyloid β42 peptide-induced neurotoxicity via activation of the TRPM2 channel in hippocampal neurons. Cell Death Dis.9:195. 10.1038/s41419-018-0270-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139

  Li Y. Jiao J. (2020). Deficiency of TRPM2 leads to embryonic neurogenesis defects in hyperthermia. Sci. Adv.6:eaay6350. 10.1126/sciadv.aay6350

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 140

  Li R. Jin Y. Li Q. Sun X. Zhu H. Cui H. (2018). MiR-93–5p targeting PTEN regulates the NMDA-induced autophagy of retinal ganglion cells via AKT/mTOR pathway in glaucoma. Biomed. Pharmacother.100, 1–7. 10.1016/j.biopha.2018.01.044

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 141

  Li Y. Lin X. Zhao X. Xie J. JunNan W. Sun T. et al . (2014). Ozone (O3) elicits neurotoxicity in spinal cord neurons (SCNs) by inducing ER Ca(2+) release and activating the CaMKII/MAPK signaling pathway. Toxicol. Appl. Pharmacol.280, 493–501. 10.1016/j.taap.2014.08.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142

  Li L. Tsai H. J. Li L. Wang X. M. (2010). Icariin inhibits the increased inward calcium currents induced by amyloid-beta(25–35) peptide in CA1 pyramidal neurons of neonatal rat hippocampal slice. Am. J. Chin. Med.38, 113–125. 10.1142/S0192415X10007701

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 143

  Li T. Zhang Y. Tian J. Yang L. Wang J. (2019). Ginkgo biloba pretreatment attenuates myocardial ischemia-reperfusion injury via mitoBK(Ca). Am. J. Chin. Med.47, 1057–1073. 10.1142/S0192415X1950054X

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144

  Lim D. Dematteis G. Tapella L. Genazzani A. A. Calì T. Brini M. et al . (2021a). Ca(2+) handling at the mitochondria-ER contact sites in neurodegeneration. Cell Calcium98:102453. 10.1016/j.ceca.2021.102453

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145

  Lim D. Semyanov A. Genazzani A. Verkhratsky A. (2021b). Calcium signaling in neuroglia. Int. Rev. Cell Mol. Biol.362, 1–53. 10.1016/bs.ircmb.2021.01.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 146

  Limke T. L. Bearss J. J. Atchison W. D. (2004). Acute exposure to methylmercury causes Ca2+ dysregulation and neuronal death in rat cerebellar granule cells through an M3 muscarinic receptor-linked pathway. Toxicol. Sci.80, 60–68. 10.1093/toxsci/kfh131

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 147

  Lin H. Bhatia R. Lal R. (2001). Amyloid beta protein forms ion channels: implications for Alzheimer’s disease pathophysiology. FASEB J15, 2433–2444. 10.1096/fj.01-0377com

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 148

  Liou B. Peng Y. Li R. Inskeep V. Zhang W. Quinn B. et al . (2016). Modulating ryanodine receptors with dantrolene attenuates neuronopathic phenotype in Gaucher disease mice. Hum. Mol. Genet.25, 5126–5141. 10.1093/hmg/ddw322

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 149

  Liu X. Du H. Chen D. Yuan H. Chen W. Jia W. et al . (2019). Cyclophilin D deficiency protects against the development of mitochondrial ROS and cellular inflammation in aorta. Biochem. Biophys. Res. Commun.508, 1202–1208. 10.1016/j.bbrc.2018.12.064

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150

  Liu H. Jia X. Luo Z. Guan H. Jiang H. Li X. et al . (2012). Inhibition of store-operated Ca(2+) channels prevent ethanol-induced intracellular Ca(2+) increase and cell injury in a human hepatoma cell line. Toxicol. Lett208, 254–261. 10.1016/j.toxlet.2011.11.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151

  Liu T. Jiang C. Y. Fujita T. Luo S. W. Kumamoto E. (2013). Enhancement by interleukin-1β of AMPA and NMDA receptor-mediated currents in adult rat spinal superficial dorsal horn neurons. Mol. Pain9:16. 10.1186/1744-8069-9-16

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152

  Liu X. Song S. Wang Q. Yuan T. He J. (2016). A mutation in β-amyloid precursor protein renders SH-SY5Y cells vulnerable to isoflurane toxicity: the role of inositol 1,4,5-trisphosphate receptors. Mol. Med. Rep.14, 5435–5442. 10.3892/mmr.2016.5930

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153

  Liu S. B. Zhao M. G. (2013). Neuroprotective effect of estrogen: role of nonsynaptic NR2B-containing NMDA receptors. Brain Res. Bull.93, 27–31. 10.1016/j.brainresbull.2012.10.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 154

  Liu S. J. Zukin R. S. (2007). Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death. Trends Neurosci.30, 126–134. 10.1016/j.tins.2007.01.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155

  Louhivuori L. M. Jansson L. Turunen P. M. Jäntti M. H. Nordström T. Louhivuori V. et al . (2015). Transient receptor potential channels and their role in modulating radial glial-neuronal interaction: a signaling pathway involving mGluR5. Stem Cells Dev.24, 701–713. 10.1089/scd.2014.0209

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 156

  Louhivuori L. M. Louhivuori V. Wigren H. K. Hakala E. Jansson L. C. Nordström T. et al . (2013). Role of low voltage activated calcium channels in neuritogenesis and active migration of embryonic neural progenitor cells. Stem Cells Dev.22, 1206–1219. 10.1089/scd.2012.0234

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 157

  Lu C. W. Lin T. Y. Chiu K. M. Lee M. Y. Huang J. H. Wang S. J. (2020a). Silymarin inhibits glutamate release and prevents against kainic acid-induced excitotoxic injury in rats. Biomedicines8:486. 10.3390/biomedicines8110486

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 158

  Lu C. W. Lin T. Y. Yang H. C. Hung C. F. Weng J. R. Chang C. et al . (2020b). [1–(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol, an indole-3-carbinol derivative, inhibits glutamate release in rat cerebrocortical nerve terminals by suppressing the P/Q-type Ca(2+) channels and Ca(2+)/calmodulin/protein kinase a pathway. Neurochem. Int.140:104845. 10.1016/j.neuint.2020.104845

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 159

  Lu C. W. Lin T. Y. Wang S. J. Huang S. K. (2019). Asiatic acid, an active substance of Centella asiatica, presynaptically depresses glutamate release in the rat hippocampus. Eur. J. Pharmacol.865:172781. 10.1016/j.ejphar.2019.172781

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 160

  Ma J. Brewer H. B. Jr. Potter H. (1996). Alzheimer A beta neurotoxicity: promotion by antichymotrypsin, ApoE4; inhibition by A beta-related peptides. Neurobiol. Aging17, 773–780. 10.1016/0197-4580(96)00112-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161

  Ma F. Zhang L. Westlund K. N. (2009). Reactive oxygen species mediate TNFR1 increase after TRPV1 activation in mouse DRG neurons. Mol. Pain5:31. 10.1186/1744-8069-5-31

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 162

  Ma S. H. Zhuang Q. X. Shen W. X. Peng Y. P. Q25u Y. H. (2015). Interleukin-6 reduces NMDAR-mediated cytosolic Ca² overload and neuronal death via JAK/CaN signaling. Cell Calcium58, 286–295. 10.1016/j.ceca.2015.06.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 163

  MacManus A. Ramsden M. Murray M. Henderson Z. Pearson H. A. Campbell V. A. (2000). Enhancement of (45)Ca(2+) influx and voltage-dependent Ca(2+) channel activity by beta-amyloid-(1–40) in rat cortical synaptosomes and cultured cortical neurons. Modulation by the proinflammatory cytokine interleukin-1beta. J. Biol. Chem.275, 4713–4718. 10.1074/jbc.275.7.4713

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 164

  Marcantoni A. Cerullo M. S. Buxeda P. Tomagra G. Giustetto M. Chiantia G. et al . (2020). Amyloid Beta42 oligomers up-regulate the excitatory synapses by potentiating presynaptic release while impairing postsynaptic NMDA receptors. J. Physiol.598, 2183–2197. 10.1113/JP279345

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 165

  Marin R. Ramírez C. M. González M. González-Muñoz E. Zorzano A. Camps M. et al . (2007). Voltage-dependent anion channel (VDAC) participates in amyloid beta-induced toxicity and interacts with plasma membrane estrogen receptor alpha in septal and hippocampal neurons. Mol. Membr. Biol.24, 148–160. 10.1080/09687860601055559

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 166

  Marques M. A. Crutcher K. A. (2003). Apolipoprotein E-related neurotoxicity as a therapeutic target for Alzheimer’s disease. J. Mol. Neurosci.20, 327–337. 10.1385/JMN:20:3:327

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 167

  Marschallinger J. Sah A. Schmuckermair C. Unger M. Rotheneichner P. Kharitonova M. et al . (2015). The L-type calcium channel Cav1.3 is required for proper hippocampal neurogenesis and cognitive functions. Cell Calcium58, 606–616. 10.1016/j.ceca.2015.09.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 168

  Matsubara M. Tamura T. Ohmori K. Hasegawa K. (2005). Histamine H1 receptor antagonist blocks histamine-induced proinflammatory cytokine production through inhibition of Ca2+-dependent protein kinase C, Raf/MEK/ERK and IKK/I kappa B/NF-kappa B signal cascades. Biochem. Pharmacol.69, 433–449. 10.1016/j.bcp.2004.10.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 169

  Mattson M. P. Furukawa K. (1997). Anti-apoptotic actions of cycloheximide: blockade of programmed cell death or induction of programmed cell life?Apoptosis2, 257–264. 10.1023/a:1026433019210

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 170

  McBrayer M. Nixon R. A. (2013). Lysosome and calcium dysregulation in Alzheimer’s disease: partners in crime. Biochem. Soc. Trans.41, 1495–1502. 10.1042/BST20130201

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 171

  McDaid J. Mustaly-Kalimi S. Stutzmann G. E. (2020). Ca(2+) dyshomeostasis disrupts neuronal and synaptic function in Alzheimer’s disease. Cells9:2655. 10.3390/cells9122655

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 172

  McLarnon J. G. Franciosi S. Wang X. Bae J. H. Choi H. B. Kim S. U. (2001). Acute actions of tumor necrosis factor-alpha on intracellular Ca(2+) and K(+) currents in human microglia. Neuroscience104, 1175–1184. 10.1016/s0306-4522(01)00119-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 173

  Mendez-David I. Guilloux J. P. Papp M. Tritschler L. Mocaer E. Gardier A.M. et al . (2017). S 47445 produces antidepressant- and anxiolytic-like effects through neurogenesis dependent and independent mechanisms. Front. Pharmacol.8:462. 10.3389/fphar.2017.00462

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 174

  Meng Y. Li W. Z. Shi Y. W. Zhou B. F. Ma R. Li W. P. (2016). Danshensu protects against ischemia/reperfusion injury and inhibits the apoptosis of H9c2 cells by reducing the calcium overload through the p-JNK-NF-κB-TRPC6 pathway. Int. J. Mol. Med.37, 258–266. 10.3892/ijmm.2015.2419

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 175

  Miao Y. Dong L. D. Chen J. Hu X. C. Yang X. L. Wang Z. (2012). Involvement of calpain/p35–p25/Cdk5/NMDAR signaling pathway in glutamate-induced neurotoxicity in cultured rat retinal neurons. PLoS One7:e42318. 10.1371/journal.pone.0042318

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 176

  Michiels C. F. Fransen P. De Munck D. G. De Meyer G. R. Martinet W. (2015). Defective autophagy in vascular smooth muscle cells alters contractility and Ca² homeostasis in mice. Am. J. Physiol. Heart Circ. Physiol.308, H557–567. 10.1152/ajpheart.00659.2014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 177

  Miyake T. Shirakawa H. Kusano A. Sakimoto S. Konno M. Nakagawa T. et al . (2014). TRPM2 contributes to LPS/IFNγ-induced production of nitric oxide via the p38/JNK pathway in microglia. Biochem. Biophys. Res. Commun.444, 212–217. 10.1016/j.bbrc.2014.01.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 178

  Miyanohara J. Kakae M. Nagayasu K. Nakagawa T. Mori Y. Arai K. et al . (2018). TRPM2 channel aggravates CNS inflammation and cognitive impairment via activation of microglia in chronic cerebral hypoperfusion. J. Neurosci.38, 3520–3533. 10.1523/JNEUROSCI.2451-17.2018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 179

  Morais Cardoso S. Swerdlow R. H. Oliveira C. R. (2002). Induction of cytochrome c-mediated apoptosis by amyloid beta 25–35 requires functional mitochondria. Brain Res.931, 117–125. 10.1016/s0006-8993(02)02256-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 180

  Morelli M. B. Amantini C. Liberati S. Santoni M. Nabissi M. (2013). TRP channels: new potential therapeutic approaches in CNS neuropathies. CNS Neurol. Disord. Drug Targets12, 274–293. 10.2174/18715273113129990056

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 181

  Moreno J.A. Halliday M. Molloy C. Radford H. Verity N. Axten J. M. et al . (2013). Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci. Transl. Med.5:206ra138. 10.1126/scitranslmed.3006767

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 182

  Murugan M. Sivakumar V. Lu J. Ling E. A. Kaur C. (2011). Expression of N-methyl D-aspartate receptor subunits in amoeboid microglia mediates production of nitric oxide via NF-κB signaling pathway and oligodendrocyte cell death in hypoxic postnatal rats. Glia59, 521–539. 10.1002/glia.21121

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 183

  Muth-Köhne E. Pachernegg S. Karus M. Faissner A. Hollmann M. (2010). Expression of NMDA receptors and Ca2+-impermeable AMPA receptors requires neuronal differentiation and allows discrimination between two different types of neural stem cells. Cell Physiol. Biochem.26, 935–946. 10.1159/000324002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 184

  Nagakannan P. Islam M. I. Karimi-Abdolrezaee S. Eftekharpour E. (2019). Inhibition of VDAC1 protects against glutamate-induced oxytosis and mitochondrial fragmentation in hippocampal HT22 cells. Cell Mol. Neurobiol.39, 73–85. 10.1007/s10571-018-0634-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 185

  Nakamura S. Shigeyama S. Minami S. Shima T. Akayama S. Matsuda T. et al . (2020). LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury. Nat. Cell Biol.22, 1252–1263. 10.1038/s41556-020-00583-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 186

  Namba T. Dóczi J. Pinson A. Xing L. Kalebic N. Wilsch-Bräuninger M. et al . (2020). Human-specific ARHGAP11B acts in mitochondria to expand neocortical progenitors by glutaminolysis. Neuron105, 867–881.e9. 10.1016/j.neuron.2019.11.027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 187

  Nasiri-Ansari N. Nikolopoulou C. Papoutsi K. Kyrou I. Mantzoros C. S. Kyriakopoulos G. et al . (2021). Empagliflozin attenuates non-alcoholic fatty liver disease (NAFLD) in high fat diet fed ApoE((−/−)) mice by activating autophagy and reducing ER stress and apoptosis. Int. J. Mol. Sci.22:818. 10.3390/ijms22020818

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 188

  Neumann J. Sauerzweig S. Rönicke R. Gunzer F. Dinkel K. Ullrich O. et al . (2008). Microglia cells protect neurons by direct engulfment of invading neutrophil granulocytes: a new mechanism of CNS immune privilege. J. Neurosci.28, 5965–5975. 10.1523/JNEUROSCI.0060-08.2008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 189

  Nijholt D. A. de Graaf T. R. van Haastert E. S. Oliveira A. O. Berkers C. R. Zwart R. et al . (2011). Endoplasmic reticulum stress activates autophagy but not the proteasome in neuronal cells: implications for Alzheimer’s disease. Cell Death Differ.18, 1071–1081. 10.1038/cdd.2010.176

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 190

  Nishitoh H. Kadowaki H. Takeda K. Ichijo H. (2009). ER quality control, ER stress-induced apoptosis and neurodegenerative diseases. Protein Misfolding Disord. Trip ER94–102. 10.2174/978160805013010901010094

  • CrossRef
  • Google Scholar

• 191

  Nursalim Y. (2016). Preliminary Evidence for NMDAR Contribution Towards Autophagy and Membrane Potential in Leukaemic Megakaryoblasts. Masters Thesis. University of Auckland.

  • Google Scholar

• 192

  Ogoshi F. Yin H. Z. Kuppumbatti Y. Song B. Amindari S. Weiss J. H. (2005). Tumor necrosis-factor-alpha (TNF-alpha) induces rapid insertion of Ca2+-permeable alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate (Ca-A/K) channels in a subset of hippocampal pyramidal neurons. Exp. Neurol.193, 384–393. 10.1016/j.expneurol.2004.12.026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 193

  Onyenwoke R. U. Sexton J. Z. Yan F. Díaz M. C. Forsberg L. J. Major M. B. et al . (2015). The mucolipidosis IV Ca2+ channel TRPML1 (MCOLN1) is regulated by the TOR kinase. Biochem. J.470, 331–342. 10.1042/BJ20150219

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 194

  Orellana D. I. Quintanilla R. A. Gonzalez-Billault C. Maccioni R. B. (2005). Role of the JAKs/STATs pathway in the intracellular calcium changes induced by interleukin-6 in hippocampal neurons. Neurotox. Res.8, 295–304. 10.1007/BF03033983

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 195

  Oseki K. T. Monteforte P. T. Pereira G. J. Hirata H. Ureshino R. P. Bincoletto C. et al . (2014). Apoptosis induced by Aβ25–35 peptide is Ca(2+) -IP3 signaling-dependent in murine astrocytes. Eur. J. Neurosci.40, 2471–2478. 10.1111/ejn.12599

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 196

  Ostapchenko V. G. Chen M. Guzman M. S. Xie Y. F. Lavine N. Fan J. et al . (2015). The transient receptor potential melastatin 2 (TRPM2) channel contributes to β-Amyloid oligomer-related neurotoxicity and memory impairment. J. Neurosci.35, 15157–15169. 10.1523/JNEUROSCI.4081-14.2015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 197

  Pahl H. L. Baeuerle P. A. (1996). Activation of NF-kappa B by ER stress requires both Ca2+ and reactive oxygen intermediates as messengers. FEBS Lett392, 129–136. 10.1016/0014-5793(96)00800-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 198

  Pahrudin Arrozi A. Shukri S. N. S. Wan Ngah W. Z. Mohd Yusof Y. A. Ahmad Damanhuri M. H. Jaafar F. et al . (2020). Comparative effects of alpha- and gamma-tocopherol on mitochondrial functions in Alzheimer’s disease in vitro model. Sci. Rep.10:8962. 10.1038/s41598-020-65570-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 199

  Park E. S. Kim S. R. Jin B. K. (2012). Transient receptor potential vanilloid subtype 1 contributes to mesencephalic dopaminergic neuronal survival by inhibiting microglia-originated oxidative stress. Brain Res. Bull.89, 92–96. 10.1016/j.brainresbull.2012.07.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 200

  Park K. M. Yule D. I. Bowers W. J. (2008). Tumor necrosis factor-alpha potentiates intraneuronal Ca²⁺ signaling via regulation of the inositol 1,4,5-trisphosphate receptor. J. Biol. Chem.283, 33069–33079. 10.1074/jbc.M802209200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 201

  Park K. M. Yule D. I. Bowers W. J. (2010). Impaired TNF-alpha control of IP3R-mediated Ca²⁺ release in Alzheimer’s disease mouse neurons. Cell Signal22, 519–526. 10.1016/j.cellsig.2009.11.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 202

  Pedrozo Z. Torrealba N. Fernández C. Gatica D. Toro B. Quiroga C. et al . (2013). Cardiomyocyte ryanodine receptor degradation by chaperone-mediated autophagy. Cardiovasc. Res.98, 277–285. 10.1093/cvr/cvt029

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 203

  Peng Y. Cheung K. H. Liang G. Inan S. Vais H. Joseph D. et al . (2011). General anesthetics influence autophagy and neurodegeneration through actions on the inositol 1,4,5-trisphosphate receptor calcium channel. Alzheimer’s Demen.7:S573. 10.1016/j.jalz.2011.05.1618

  • CrossRef
  • Google Scholar

• 204

  Piacentini R. Gangitano C. Ceccariglia S. Del Fà A. Azzena G. B. Michetti F. et al . (2008a). Dysregulation of intracellular calcium homeostasis is responsible for neuronal death in an experimental model of selective hippocampal degeneration induced by trimethyltin. J. Neurochem.105, 2109–2121. 10.1111/j.1471-4159.2008.05297.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 205

  Piacentini R. Ripoli C. Leone L. Misiti F. Clementi M. E. D’Ascenzo M. et al . (2008b). Role of methionine 35 in the intracellular Ca2+ homeostasis dysregulation and Ca2+-dependent apoptosis induced by amyloid beta-peptide in human neuroblastoma IMR32 cells. J. Neurochem.107, 1070–1082. 10.1111/j.1471-4159.2008.05680.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 206

  Piacentini R. Ripoli C. Mezzogori D. Azzena G. B. Grassi C. (2008c). Extremely low-frequency electromagnetic fields promote in vitro neurogenesis via upregulation of Ca(v)1-channel activity. J. Cell Physiol.215, 129–139. 10.1002/jcp.21293

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 207

  Pickford F. Masliah E. Britschgi M. Lucin K. Narasimhan R. Jaeger P. A. et al . (2008). The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J. Clin. Invest.118, 2190–2199. 10.1172/JCI33585

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 208

  Pierrot N. Ghisdal P. Caumont A. S. Octave J. N. (2004). Intraneuronal amyloid-beta1–42 production triggered by sustained increase of cytosolic calcium concentration induces neuronal death. J. Neurochem.88, 1140–1150. 10.1046/j.1471-4159.2003.02227.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 209

  Pitt D. Werner P. Raine C. S. (2000). Glutamate excitotoxicity in a model of multiple sclerosis. Nat. Med.6, 67–70. 10.1038/71555

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 210

  Pollock J. McFarlane S. M. Connell M. C. Zehavi U. Vandenabeele P. MacEwan D. J. et al . (2002). TNF-alpha receptors simultaneously activate Ca2+ mobilisation and stress kinases in cultured sensory neurones. Neuropharmacology42, 93–106. 10.1016/s0028-3908(01)00163-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 211

  Qiao H. Li Y. Xu Z. Li W. Fu Z. Wang Y. et al . (2017). Propofol affects neurodegeneration and neurogenesis by regulation of autophagy via effects on intracellular calcium homeostasis. Anesthesiology127, 490–501. 10.1097/ALN.0000000000001730

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 212

  Qin L. Wang Z. Tao L. Wang Y. (2010). ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy. Autophagy6, 239–247. 10.4161/auto.6.2.11062

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 213

  Qu M. Zhou Z. Chen C. Li M. Pei L. Yang J. et al . (2012). Inhibition of mitochondrial permeability transition pore opening is involved in the protective effects of mortalin overexpression against beta-amyloid-induced apoptosis in SH-SY5Y cells. Neurosci. Res.72, 94–102. 10.1016/j.neures.2011.09.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 214

  Raghunatha P. Vosoughi A. Kauppinen T. M. Jackson M. F. (2020). Microglial NMDA receptors drive pro-inflammatory responses via PARP-1/TRMP2 signaling. Glia68, 1421–1434. 10.1002/glia.23790

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 215

  Rainey-Smith S. R. Andersson D. A. Williams R. J. Rattray M. (2010). Tumour necrosis factor alpha induces rapid reduction in AMPA receptor-mediated calcium entry in motor neurones by increasing cell surface expression of the GluR2 subunit: relevance to neurodegeneration. J. Neurochem.113, 692–703. 10.1111/j.1471-4159.2010.06634.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 216

  Rash B. G. Ackman J. B. Rakic P. (2016). Bidirectional radial Ca(2+) activity regulates neurogenesis and migration during early cortical column formation. Sci. Adv.2:e1501733. 10.1126/sciadv.1501733

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 217

  Resende R. R. da Costa J. L. Kihara A. H. Adhikari A. Lorençon E. (2010). Intracellular Ca2+ regulation during neuronal differentiation of murine embryonal carcinoma and mesenchymal stem cells. Stem Cells Dev.19, 379–394. 10.1089/scd.2008.0289

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 218

  Rijpma A. Jansen D. Arnoldussen I. A. Fang X. T. Wiesmann M. Mutsaers M. P. et al . (2013). Sex differences in presynaptic density and neurogenesis in middle-aged ApoE4 and ApoE knockout mice. J. Neurodegener. Dis.2013:531326. 10.1155/2013/531326

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 219

  Rodriguez G. A. Tai L. M. LaDu M. J. Rebeck G. W. (2014). Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition. J. Neuroinflammation11:111. 10.1186/1742-2094-11-111

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 220

  Rostovtseva T. K. Antonsson B. Suzuki M. Youle R. J. Colombini M. Bezrukov S. M. (2004). Bid, but not bax, regulates VDAC channels. J. Biol. Chem.279, 13575–13583. 10.1074/jbc.M310593200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 221

  Sade Y. Toker L. Kara N.Z. Einat H. Rapoport S. Moechars D. et al . (2016). IP3 accumulation and/or inositol depletion: two downstream lithium’s effects that may mediate its behavioral and cellular changes. Transl. Psychiatry6:e968. 10.1038/tp.2016.217

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 222

  Sakamoto K. Kawakami T. Shimada M. Yamaguchi A. Kuwagata M. Saito M. et al . (2009). Histological protection by cilnidipine, a dual L/N-type Ca(2+) channel blocker, against neurotoxicity induced by ischemia-reperfusion in rat retina. Exp. Eye Res.88, 974–982. 10.1016/j.exer.2008.12.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 223

  Sama M. A. Mathis D. M. Furman J. L. Abdul H. M. Artiushin I. A. Kraner S. D. et al . (2008). Interleukin-1beta-dependent signaling between astrocytes and neurons depends critically on astrocytic calcineurin/NFAT activity. J. Biol. Chem.283, 21953–21964. 10.1074/jbc.M800148200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 224

  Sama D. M. Mohmmad Abdul H. Furman J. L. Artiushin I. A. Szymkowski D. E. Scheff S. W. et al . (2012). Inhibition of soluble tumor necrosis factor ameliorates synaptic alterations and Ca2+ dysregulation in aged rats. PLoS One7:e38170. 10.1371/journal.pone.0038170

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 225

  Sama D. M. Norris C. M. (2013). Calcium dysregulation and neuroinflammation: discrete and integrated mechanisms for age-related synaptic dysfunction. Ageing Res. Rev.12, 982–995. 10.1016/j.arr.2013.05.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 226

  Sanchez A. B. Medders K. E. Maung R. Sánchez-Pavón P. Ojeda-Juárez D. Kaul M. (2016). CXCL12-induced neurotoxicity critically depends on NMDA receptor-gated and L-type Ca(2+) channels upstream of p38 MAPK. J. Neuroinflammation13:252. 10.1186/s12974-016-0724-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 227

  Santoro M. Piacentini R. Perna A. Pisano E. Silvestri G. (2020). Resveratrol corrects aberrant splicing of RYR1 pre-mRNA and Ca 2+ signal in myotonic dystrophy type 1 myotubes. Neural Regen. Res.15, 1757–1766. 10.4103/1673-5374.276336

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 228

  Sappington R. M. Calkins D. J. (2008). Contribution of TRPV1 to microglia-derived IL-6 and NFkappaB translocation with elevated hydrostatic pressure. Invest. Ophthalmol. Vis. Sci.49, 3004–3017. 10.1167/iovs.07-1355

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 229

  Sarkar S. Floto R. A. Berger Z. Imarisio S. Cordenier A. Pasco M. et al . (2005). Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol.170, 1101–1111. 10.1083/jcb.200504035

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 230

  Schmukler E. Solomon S. Simonovitch S. Goldshmit Y. Wolfson E. Michaelson D. M. et al . (2020). Altered mitochondrial dynamics and function in APOE4-expressing astrocytes. Cell Death Dis.11:578. 10.1038/s41419-020-02776-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 231

  Selvaraj S. Sun Y. Sukumaran P. Singh B. B. (2016). Resveratrol activates autophagic cell death in prostate cancer cells via downregulation of STIM1 and the mTOR pathway. Mol. Carcinog.55, 818–831. 10.1002/mc.22324

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 232

  Seo H. Lee K. (2016). Epac2 contributes to PACAP-induced astrocytic differentiation through calcium ion influx in neural precursor cells. BMB Rep.49, 128–133. 10.5483/bmbrep.2016.49.2.202

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 233

  Shaikh S. Troncoso R. Criollo A. Bravo-Sagua R. García L. Morselli E. et al . (2016). Regulation of cardiomyocyte autophagy by calcium. Am. J. Physiol. Endocrinol. Metab.310, E587–E596. 10.1152/ajpendo.00374.2015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 234

  Shehata M. Matsumura H. Okubo-Suzuki R. Ohkawa N. Inokuchi K. (2012). Neuronal stimulation induces autophagy in hippocampal neurons that is involved in AMPA receptor degradation after chemical long-term depression. J. Neurosci.32, 10413–10422. 10.1523/JNEUROSCI.4533-11.2012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 235

  Shi M. Du F. Liu Y. Li L. Cai J. Zhang G. F. et al . (2013). Glial cell-expressed mechanosensitive channel TRPV4 mediates infrasound-induced neuronal impairment. Acta Neuropathol.126, 725–739. 10.1007/s00401-013-1166-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 236

  Shimizu S. Narita M. Tsujimoto Y. (1999). Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature399, 483–487. 10.1038/20959

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 237

  Shirakawa H. Yamaoka T. Sanpei K. Nakagawa T. Kaneko S. (2007). TRPV1 mediates vanilloids and low pH-induced neurotoxicity in rat cortical cultures. Neurosci. Res.58, S207–S207. 10.1016/j.neures.2007.06.946

  • CrossRef
  • Google Scholar

• 238

  Shoshan-Barmatz V. Nahon-Crystal E. Shteinfer-Kuzmine A. Gupta R. (2018). VDAC1, mitochondrial dysfunction and Alzheimer’s disease. Pharmacol. Res.131, 87–101. 10.1016/j.phrs.2018.03.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 239

  Shtaya A. Sadek A. R. Zaben M. Seifert G. Pringle A. Steinhäuser C. et al . (2018). AMPA receptors and seizures mediate hippocampal radial glia-like stem cell proliferation. Glia66, 2397–2413. 10.1002/glia.23479

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 240

  Simões A.P. Duarte J.A. Agasse F. Canas P.M. Tomé A.R. Agostinho P. et al . (2012). Blockade of adenosine A2A receptors prevents interleukin-1β-induced exacerbation of neuronal toxicity through a p38 mitogen-activated protein kinase pathway. J. Neuroinflammation9:204. 10.1177/00031348211048845

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 241

  Simonovitch S. Schmukler E. Bespalko A. Iram T. Frenkel D. Holtzman D. M. et al . (2016). Impaired autophagy in APOE4 astrocytes. J. Alzheimers Dis.51, 915–927. 10.3233/JAD-151101

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 242

  Smilansky A. Dangoor L. Nakdimon I. Ben-Hail D. Mizrachi D. Shoshan-Barmatz V. (2015). The voltage-dependent anion channel 1 mediates amyloid β toxicity and represents a potential target for alzheimer disease therapy. J. Biol. Chem.290, 30670–30683. 10.1074/jbc.M115.691493

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 243

  Smith T. Groom A. Zhu B. Turski L. (2000). Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat. Med.6, 62–66. 10.1038/71548

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 244

  Soboloff J. Berger S. A. (2002). Sustained ER Ca2+ depletion suppresses protein synthesis and induces activation-enhanced cell death in mast cells. J. Biol. Chem.277, 13812–13820. 10.1074/jbc.M112129200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 245

  Somasundaram A. Shum A. K. McBride H. J. Kessler J. A. Feske S. Miller R. J. et al . (2014). Store-operated CRAC channels regulate gene expression and proliferation in neural progenitor cells. J. Neurosci.34, 9107–9123. 10.1523/JNEUROSCI.0263-14.2014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 246

  Song S. Lee H. Kam T. I. Tai M. L. Lee J. Y. Noh J. Y. et al . (2008). E2–25K/Hip-2 regulates caspase-12 in ER stress-mediated Abeta neurotoxicity. J. Cell Biol.182, 675–684. 10.1083/jcb.200711066

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 247

  Song Y. Li D. Farrelly O. Miles L. Li F. Kim S. E. et al . (2019). The mechanosensitive ion channel piezo inhibits axon regeneration. Neuron102, 373–389.e376. 10.1016/j.neuron.2019.01.050

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 248

  Staats K. A. Humblet-Baron S. Bento-Abreu A. Scheveneels W. Nikolaou A. Deckers K. et al . (2016). Genetic ablation of IP3 receptor 2 increases cytokines and decreases survival of SOD1G93A mice. Hum. Mol. Genet.25, 3491–3499. 10.1093/hmg/ddw190

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 249

  Sukumaran P. Schaar A. Sun Y. Singh B. B. (2016). Functional role of TRP channels in modulating ER stress and Autophagy. Cell Calcium60, 123–132. 10.1016/j.ceca.2016.02.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 250

  Sun G. B. Sun H. Meng X. B. Hu J. Zhang Q. Liu B. et al . (2014). Aconitine-induced Ca2+ overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats. Toxicol. Appl. Pharmacol.279, 8–22. 10.1016/j.taap.2014.05.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 251

  Sun Y. Chauhan A. Sukumaran P. Sharma J. Singh B. B. Mishra B. B. (2014). Inhibition of store-operated calcium entry in microglia by helminth factors: implications for immune suppression in neurocysticercosis. J. Neuroinflammation11:210. 10.1186/s12974-014-0210-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 252

  Sun Y. Vashisht A. A. Tchieu J. Wohlschlegel J. A. Dreier L. (2012). Voltage-dependent anion channels (VDACs) recruit Parkin to defective mitochondria to promote mitochondrial autophagy. J. Biol. Chem.287, 40652–40660. 10.1074/jbc.M112.419721

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 253

  Supnet C. Noonan C. Richard K. Bradley J. Mayne M. (2010). Up-regulation of the type 3 ryanodine receptor is neuroprotective in the TgCRND8 mouse model of Alzheimer’s disease. J. Neurochem.112, 356–365. 10.1111/j.1471-4159.2009.06487.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 254

  Szalai G. Krishnamurthy R. Hajnóczky G. (1999). Apoptosis driven by IP(3)-linked mitochondrial calcium signals. EMBO J.18, 6349–6361. 10.1093/emboj/18.22.6349

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 255

  Takeo Y. Kurabayashi N. Nguyen M. D. Sanada K. (2016). The G protein-coupled receptor GPR157 regulates neuronal differentiation of radial glial progenitors through the Gq-IP3 pathway. Sci. Rep.6:25180. 10.1038/srep25180

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 256

  Temme S. J. Bell R. Z. Fisher G. L. Murphy G. G. (2016). Deletion of the mouse homolog of CACNA1C disrupts discrete forms of hippocampal-dependent memory and neurogenesis within the dentate gyrus. eNeuro3:ENEURO.0118-16.2016. 10.1523/ENEURO.0118-16.2016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 257

  Tharmalingam S. Wu C. Hampson D. R. (2016). The calcium-sensing receptor and integrins modulate cerebellar granule cell precursor differentiation and migration. Dev. Neurobiol.76, 375–389. 10.1002/dneu.22321

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 258

  Thinnes F. P. (2011). Apoptogenic interactions of plasmalemmal type-1 VDAC and Aβ peptides via GxxxG motifs induce Alzheimer’s disease - a basic model of apoptosis. Wien Med. Wochenschr.161, 274–276. 10.1007/s10354-011-0887-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 259

  Thomas M. P. Morrisett R. A. (2000). Dynamics of NMDAR-mediated neurotoxicity during chronic ethanol exposure and withdrawal. Neuropharmacology39, 218–226. 10.1016/s0028-3908(99)00107-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 260

  Tolar M. Keller J. N. Chan S. Mattson M. P. Marques M. A. Crutcher K. A. (1999). Truncated apolipoprotein E (ApoE) causes increased intracellular calcium and may mediate ApoE neurotoxicity. J. Neurosci.19, 7100–7110. 10.1523/JNEUROSCI.19-16-07100.1999

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 261

  Tong B. C. Wu A. J. Li M. Cheung K. H. (2018). Calcium signaling in Alzheimer’s disease and therapies. Biochim. Biophys. Acta Mol. Cell Res.1865, 1745–1760. 10.1016/j.bbamcr.2018.07.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 262

  Toth A. B. Shum A. K. Prakriya M. (2016). Regulation of neurogenesis by calcium signaling. Cell Calcium59, 124–134. 10.1016/j.ceca.2016.02.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 263

  Turovskaya M. V. Turovsky E. A. Zinchenko V. P. Levin S. G. Godukhin O. V. (2012). Interleukin-10 modulates [Ca2+]i response induced by repeated NMDA receptor activation with brief hypoxia through inhibition of InsP(3)-sensitive internal stores in hippocampal neurons. Neurosci. Lett.516, 151–155. 10.1016/j.neulet.2012.03.084

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 264

  Ueda K. Shinohara S. Yagami T. Asakura K. Kawasaki K. (1997). Amyloid beta protein potentiates Ca2+ influx through L-type voltage-sensitive Ca2+ channels: a possible involvement of free radicals. J. Neurochem.68, 265–271. 10.1046/j.1471-4159.1997.68010265.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 265

  Valladares D. Utreras-Mendoza Y. Campos C. Morales C. Diaz-Vegas A. Contreras-Ferrat A. et al . (2018). IP(3) receptor blockade restores autophagy and mitochondrial function in skeletal muscle fibers of dystrophic mice. Biochim. Biophys. Acta Mol. Basis. Dis.1864, 3685–3695. 10.1016/j.bbadis.2018.08.042

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 266

  Vander Heiden M. G. Li X. X. Gottleib E. Hill R. B. Thompson C. B. Colombini M. (2001). Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane. J. Biol. Chem.276, 19414–19419. 10.1074/jbc.M101590200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 267

  Veinbergs I. Everson A. Sagara Y. Masliah E. (2002). Neurotoxic effects of apolipoprotein E4 are mediated via dysregulation of calcium homeostasis. J. Neurosci. Res.67, 379–387. 10.1002/jnr.10138

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 268

  Vergarajauregui S. Connelly P. S. Daniels M. P. Puertollano R. (2008). Autophagic dysfunction in mucolipidosis type IV patients. Hum. Mol. Genet.17, 2723–2737. 10.1093/hmg/ddn174

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 269

  Vervliet T. Pintelon I. Welkenhuyzen K. Bootman M. D. Bannai H. Mikoshiba K. et al . (2017). Basal ryanodine receptor activity suppresses autophagic flux. Biochem. Pharmacol.132, 133–142. 10.1016/j.bcp.2017.03.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 270

  Vierling C. Baumgartner C. M. Bollerhey M. Erhardt W. D. Stampfl A. Vierling W. (2014). The vasodilating effect of a Hintonia latiflora extract with antidiabetic action. Phytomedicine21, 1582–1586. 10.1016/j.phymed.2014.07.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 271

  Villegas S. Villarreal F. J. Dillmann W. H. (2000). Leukemia inhibitory factor and Interleukin-6 downregulate sarcoplasmic reticulum Ca2+ ATPase (SERCA2) in cardiac myocytes. Basic Res. Cardiol.95, 47–54. 10.1007/s003950050007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 272

  Viviani B. Bartesaghi S. Gardoni F. Vezzani A. Behrens M. M. Bartfai T. et al . (2003). Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J. Neurosci.23, 8692–8700. 10.1523/JNEUROSCI.23-25-08692.2003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 273

  Viviani B. Gardoni F. Bartesaghi S. Corsini E. Facchi A. Galli C. L. et al . (2006). Interleukin-1 beta released by gp120 drives neural death through tyrosine phosphorylation and trafficking of NMDA receptors. J. Biol. Chem.281, 30212–30222. 10.1074/jbc.M602156200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 274

  Vogl C. Mochida S. Wolff C. Whalley B. J. Stephens G. J. (2012). The synaptic vesicle glycoprotein 2A ligand levetiracetam inhibits presynaptic Ca2+ channels through an intracellular pathway. Mol. Pharmacol.82, 199–208. 10.1124/mol.111.076687

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 275

  Wahlestedt C. Golanov E. Yamamoto S. Yee F. Ericson H. Yoo H. et al . (1993). Antisense oligodeoxynucleotides to NMDA-R1 receptor channel protect cortical neurons from excitotoxicity and reduce focal ischaemic infarctions. Nature363, 260–263. 10.1038/363260a0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 276

  Wallström E. Diener P. Ljungdahl A. Khademi M. Nilsson C. G. Olsson T. (1996). Memantine abrogates neurological deficits, but not CNS inflammation, in Lewis rat experimental autoimmune encephalomyelitis. J. Neurol. Sci.137, 89–96. 10.3390/ijms22105335

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 277

  Wang W. Gao Q. Yang M. Zhang X. Yu L. Lawas M. et al . (2015). Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation. Proc. Natl. Acad. Sci. U S A112, E1373–1381. 10.1073/pnas.1419669112

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 278

  Wang S. E. Ko S. Y. Kim Y. S. Jo S. Lee S. H. Jung S. J. et al . (2018). Capsaicin upregulates HDAC2 via TRPV1 and impairs neuronal maturation in mice. Exp. Mol. Med.50:e455. 10.1038/emm.2017.289

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 279

  Wang D. M. Li S. Q. Zhu X. Y. Wang Y. Wu W. L. Zhang X. J. (2013). Protective effects of hesperidin against amyloid-β (Aβ) induced neurotoxicity through the voltage dependent anion channel 1 (VDAC1)-mediated mitochondrial apoptotic pathway in PC12 cells. Neurochem. Res.38, 1034–1044. 10.1007/s11064-013-1013-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 280

  Wang Z. Liu S. Kakizaki M. Hirose Y. Ishikawa Y. Funato H. et al . (2014). Orexin/hypocretin activates mTOR complex 1 (mTORC1) via an Erk/Akt-independent and calcium-stimulated lysosome v-ATPase pathway. J. Biol. Chem.289, 31950–31959. 10.1074/jbc.M114.600015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 281

  Wang P. Wang Z. Y. (2017). Metal ions influx is a double edged sword for the pathogenesis of Alzheimer’s disease. Ageing Res. Rev.35, 265–290. 10.1016/j.arr.2016.10.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 282

  Wang Q. Yang L. Wang Y. (2015). Enhanced differentiation of neural stem cells to neurons and promotion of neurite outgrowth by oxygen-glucose deprivation. Int. J. Dev. Neurosci.43, 50–57. 10.1016/j.ijdevneu.2015.04.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 283

  Wang G. Zhang J. Xu C. Han X. Gao Y. Chen H. (2016). Inhibition of SOCs attenuates acute lung injury induced by severe acute pancreatitis in rats and PMVECs injury induced by lipopolysaccharide. Inflammation39, 1049–1058. 10.1007/s10753-016-0335-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 284

  Wang Z. J. Zhao F. Wang C. F. Zhang X. M. Xiao Y. Zhou F. et al . (2019). Xestospongin C, a reversible IP3 receptor antagonist, alleviates the cognitive and pathological impairments in APP/PS1 mice of Alzheimer’s disease. J. Alzheimers Dis.72, 1217–1231. 10.3233/JAD-190796

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 285

  Wang X. Zheng W. (2019). Ca(2+) homeostasis dysregulation in Alzheimer’s disease: a focus on plasma membrane and cell organelles. FASEB J33, 6697–6712. 10.1096/fj.201801751R

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 286

  Wei H. Liang G. Yang H. Wang Q. Hawkins B. Madesh M. et al . (2008). The common inhalational anesthetic isoflurane induces apoptosis via activation of inositol 1,4,5-trisphosphate receptors. Anesthesiology108, 251–260. 10.1097/01.anes.0000299435.59242.0e

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 287

  Weissman T. A. Riquelme P. A. Ivic L. Flint A. C. Kriegstein A. R. (2004). Calcium waves propagate through radial glial cells and modulate proliferation in the developing neocortex. Neuron43, 647–661. 10.1016/j.neuron.2004.08.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 288

  Weisthal S. Keinan N. Ben-Hail D. Arif T. Shoshan-Barmatz V. (2014). Ca(2+)-mediated regulation of VDAC1 expression levels is associated with cell death induction. Biochim. Biophys. Acta1843, 2270–2281. 10.1016/j.bbamcr.2014.03.021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 289

  Whitney N. P. Peng H. Erdmann N. B. Tian C. Monaghan D. T. Zheng J. C. (2008). Calcium-permeable AMPA receptors containing Q/R-unedited GluR2 direct human neural progenitor cell differentiation to neurons. FASEB J.22, 2888–2900. 10.1096/fj.07-104661

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 290

  Wigerblad G. Huie J. R. Yin H. Z. Leinders M. Pritchard R. A. Koehrn F. J. et al . (2017). Inflammation-induced GluA1 trafficking and membrane insertion of Ca(2+) permeable AMPA receptors in dorsal horn neurons is dependent on spinal tumor necrosis factor, PI3 kinase and protein kinase A. Exp. Neurol.293, 144–158. 10.1016/j.expneurol.2017.04.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 291

  Williams A. Sarkar S. Cuddon P. Ttofi E. K. Saiki S. Siddiqi F. H. et al . (2008). Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway. Nat. Chem. Biol.4, 295–305. 10.1038/nchembio.79

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 292

  Wong A. Grubb D. R. Cooley N. Luo J. Woodcock E. A. (2013). Regulation of autophagy in cardiomyocytes by Ins(1,4,5)P(3) and IP(3)-receptors. J. Mol. Cell Cardiol.54, 19–24. 10.1016/j.yjmcc.2012.10.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 293

  Wu H. Y. Huang C. H. Lin Y. H. Wang C. C. Jan T. R. (2018). Cannabidiol induced apoptosis in human monocytes through mitochondrial permeability transition pore-mediated ROS production. Free Radic. Biol. Med.124, 311–318. 10.1016/j.freeradbiomed.2018.06.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 294

  Xia Y. Ragan R. E. Seah E. E. Michaelis M. L. Michaelis E. K. (1995). Developmental expression of N-methyl-D-aspartate (NMDA)-induced neurotoxicity, NMDA receptor function and the NMDAR1 and glutamate-binding protein subunits in cerebellar granule cells in primary cultures. Neurochem. Res.20, 617–629. 10.1007/BF01694545

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 295

  Xu H. X. Cui S. M. Zhang Y. M. Ren J. (2020). Mitochondrial Ca(2+) regulation in the etiology of heart failure: physiological and pathophysiological implications. Acta Pharmacol. Sin.41, 1301–1309. 10.1038/s41401-020-0476-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 296

  Xu D. Peng Y. (2017). Apolipoprotein E 4 triggers multiple pathway-mediated Ca2+ overload, causes CaMK II phosphorylation abnormity and aggravates oxidative stress caused cerebral cortical neuron damage. Eur. Rev. Med. Pharmacol. Sci.21, 5717–5728. 10.26355/eurrev_201712_14018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 297

  Xu Y. Y. Wan W. P. Zhao S. Ma Z. G. (2020). L-type calcium channels are involved in iron-induced neurotoxicity in primary cultured ventral mesencephalon neurons of rats. Neurosci. Bull.36, 165–173. 10.1007/s12264-019-00424-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 298

  Xue Z. Guo Y. Fang Y. (2016). Moderate activation of autophagy regulates the intracellular calcium ion concentration and mitochondrial membrane potential in beta-amyloid-treated PC12 cells. Neurosci. Lett.618, 50–57. 10.1016/j.neulet.2016.02.044

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 299

  Yagami T. Ueda K. Asakura K. Kuroda T. Hata S. Sakaeda T. et al . (2002). Effects of endothelin B receptor agonists on amyloid beta protein (25–35)-induced neuronal cell death. Brain Res.948, 72–81. 10.1016/s0006-8993(02)02951-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 300

  Yang C. W. Borowitz J. L. Gunasekar P. G. Isom G. E. (1996). Cyanide-stimulated inositol 1,4,5-trisphosphate formation: an intracellular neurotoxic signaling cascade. J. Biochem. Toxicol.11, 251–256. 10.1002/(SICI)1522-7146(1996)11:5<251::AID-JBT6>3.0.CO;2-J

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 301

  Yang B. Li J. J. Cao J. J. Yang C. B. Liu J. Ji Q. M. et al . (2013). Polydatin attenuated food allergy via store-operated calcium channels in mast cell. World J. Gastroenterol.19, 3980–3989. 10.3748/wjg.v19.i25.3980

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 302

  Yang Z. Y. Liu J. Chu H. C. (2020). Effect of NMDAR-NMNAT1/2 pathway on neuronal cell damage and cognitive impairment of sevoflurane-induced aged rats. Neurol. Res.42, 108–117. 10.1080/01616412.2019.1710393

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 303

  Yang N. N. Shi H. Yu G. Wang C. M. Zhu C. Yang Y. et al . (2016). Osthole inhibits histamine-dependent itch via modulating TRPV1 activity. Sci. Rep.6:25657. 10.1038/srep25657

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 304

  Yang J. Wang R. Cheng X. Qu H. Qi J. Li D. et al . (2020). The vascular dilatation induced by Hydroxysafflor yellow A (HSYA) on rat mesenteric artery through TRPV4-dependent calcium influx in endothelial cells. J. Ethnopharmacol.256:112790. 10.1016/j.jep.2020.112790

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 305

  Yang M. Wang Y. Liang G. Xu Z. Chu C. T. Wei H. (2019). Alzheimer’s disease presenilin-1 mutation sensitizes neurons to impaired autophagy flux and propofol neurotoxicity: role of calcium dysregulation. J. Alzheimers Dis.67, 137–147. 10.3233/JAD-180858

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 306

  Ye F. Li X. Li F. Li J. Chang W. Yuan J. et al . (2016). Cyclosporin s protects against Lead neurotoxicity through inhibiting mitochondrial permeability transition pore opening in nerve cells. Neurotoxicology57, 203–213. 10.1016/j.neuro.2016.10.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 307

  Yeh K. C. Hung C. F. Lin Y. F. Chang C. Pai M. S. Wang S. J. (2020). Neferine, a bisbenzylisoquinoline alkaloid of nelumbo nucifera, inhibits glutamate release in rat cerebrocortical nerve terminals through 5-HT(1A) receptors. Eur. J. Pharmacol.889:173589. 10.1016/j.ejphar.2020.173589

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 308

  Yoon H. Kim D. S. Lee G. H. Kim K. W. Kim H. R. Chae H. J. (2011). Apoptosis induced by manganese on neuronal SK-N-MC cell line: endoplasmic reticulum (ER) stress and mitochondria dysfunction. Environ. Health Toxicol.26:e2011017. 10.5620/eht.2011.26.e2011017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 309

  Yoon W. S. Yeom M. Y. Kang E. S. Chung Y. A. Chung D. S. Jeun S. S. (2017). Memantine induces NMDAR1-mediated autophagic cell death in malignant glioma cells. J. Korean Neurosurg. Soc.60, 130–137. 10.3340/jkns.2016.0101.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 310

  Yu H. M. Wen J. Wang R. Shen W. H. Duan S. Yang H. T. (2008). Critical role of type 2 ryanodine receptor in mediating activity-dependent neurogenesis from embryonic stem cells. Cell Calcium43, 417–431. 10.1016/j.ceca.2007.07.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 311

  Yu J. Zhu C. Yin J. Yu D. Wan F. Tang X. et al . (2020). Tetrandrine suppresses transient receptor potential cation channel protein 6 overexpression- induced podocyte damage via blockage of RhoA/ROCK1 signaling. Drug. Des. Devel. Ther.14, 361–370. 10.2147/DDDT.S234262

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 312

  Yue C. Soboloff J. Gamero A. M. (2012). Control of type I interferon-induced cell death by Orai1-mediated calcium entry in T cells. J. Biol. Chem.287, 3207–3216. 10.1074/jbc.M111.269068

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 313

  Yun W. J. Zhang X. Y. Liu T. T. Liang J. H. Sun C. P. Yan J. K. et al . (2020). The inhibition effect of uncarialin A on voltage-dependent L-type calcium channel subunit alpha-1C: inhibition potential and molecular stimulation. Int. J. Biol. Macromol.159, 1022–1030. 10.1016/j.ijbiomac.2020.05.100

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 314

  Yuqi L. Lei G. Yang L. Zongbin L. Hua X. Lin W. et al . (2009). Voltage-dependent anion channel (VDAC) is involved in apoptosis of cell lines carrying the mitochondrial DNA mutation. BMC Med. Genet.10:114. 10.1186/1471-2350-10-114

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 315

  Zempel H. Thies E. Mandelkow E. Mandelkow E. M. (2010). Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous tau into dendrites, tau phosphorylation and destruction of microtubules and spines. J. Neurosci.30, 11938–11950. 10.1523/JNEUROSCI.2357-10.2010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 316

  Zhang E. Liao P. (2015). Brain transient receptor potential channels and stroke. J. Neurosci. Res.93, 1165–1183. 10.1002/jnr.23529

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 317

  Zhang X. Yu L. Xu H. (2016). Lysosome calcium in ROS regulation of autophagy. Autophagy12, 1954–1955. 10.1080/15548627.2016.1212787

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 318

  Zhao P. Leonoudakis D. Abood M. E. Beattie E. C. (2010). Cannabinoid receptor activation reduces TNFalpha-induced surface localization of AMPAR-type glutamate receptors and excitotoxicity. Neuropharmacology58, 551–558. 10.1016/j.neuropharm.2009.07.035

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 319

  Zhou C. (2010). [Inhibition effect of IL-1beta on calcium channels currents in cultured cortical neurons of rat]. Dongwuxue Yanjiu31, 89–93. 10.3724/sp.j.1141.2010.01089

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 320

  Zhou C. Tai C. Ye H. H. Ren X. Chen J. G. Wang S. Q. et al . (2006). Interleukin-1beta downregulates the L-type Ca2+ channel activity by depressing the expression of channel protein in cortical neurons. J. Cell Physiol.206, 799–806. 10.1002/jcp.20518

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 321

  Zhou G. H. Zhang F. Wang X. N. Kwon O. J. Kang D. G. Lee H. S. et al . (2014). Emodin accentuates atrial natriuretic peptide secretion in cardiac atria. Eur. J. Pharmacol.735, 44–51. 10.1016/j.ejphar.2014.04.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 322

  Zhu Y. G. Chen X. C. Chen Z. Z. Zeng Y. Q. Shi G. B. Su Y. H. et al . (2004). Curcumin protects mitochondria from oxidative damage and attenuates apoptosis in cortical neurons. Acta Pharmacol. Sin.25, 1606–1612.

  • Pubmed Abstract
  • Google Scholar

• 323

  Zhu Z. D. Yu T. Liu H. J. Jin J. He J. (2018). SOCE induced calcium overload regulates autophagy in acute pancreatitis via calcineurin activation. Cell Death Dis.9:50. 10.1038/s41419-017-0073-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar