Reduction of the Ca²⁺ permeability of ligand-gated ion channels as a strategy against excitotoxicity

Abstract

Excitotoxic damage is due to an excessive Ca²⁺ entry in cells following overactivation of Ca²⁺-permeable ion channels. In neurons, Ca²⁺-dependent excitotoxicity is linked to the prominent activation of N-Methyl-d-Aspartate receptors (NMDARs), exhibiting a high permeability to Ca²⁺. Different neurodegenerative diseases share glutamate-and NMDAR-dependent excitotoxicity as a pathogenic mechanism, but also different ligand-gated ion channels (LGICs) may be involved in excitotoxic-related pathologies, such as muscle nicotinic acetylcholine receptor in some forms of congenital myasthenic syndrome. We posit that excitotoxicity due to the overactivation of Ca²⁺-permeable LGICs may be counteracted by using molecules able to reduce selectively the Ca²⁺ entry, without blocking Na⁺ influx, thus reducing the adverse effects induced by channel blockers. In this review, we recapitulate: (i) the techniques used to quantify the Ca²⁺ permeability of LGICs, with a particular focus on the fractional Ca²⁺ current (P_f, i.e., the percentage of the total current carried by Ca²⁺); (ii) the known Pf values of the main LGICs; (iii) the modulation of the LGIC P_f values induced by drugs and measured to date. These data support the possibility of fighting excitotoxicity-related pathologies with a new therapeutic approach.

Introduction

Ca²⁺ is the most widespread and versatile intracellular second messenger, used by all cells as a signal to control their activities in response to extrinsic and intrinsic stimuli (Berridge et al., 2000; Bootman and Bultynck, 2020). In particular, the intracellular free Ca²⁺ concentration ([Ca²⁺]_i) is fundamental in several processes in neuronal physiology: it regulates the release of neurotransmitters from the presynaptic terminals, influencing long-term potentiation (LTP; Grover and Teyler, 1990) and long-term depression (Bolshakov and Siegelbaum, 1994) through N-Methyl-D-Aspartate receptor (NMDAR)-related influx. In neurons, Ca²⁺ regulates gene expression, membrane excitability, dendrite development, synaptogenesis, and many other processes contributing to the neuronal primary functions of information processing and memory storage (Kawamoto et al., 2012). Most of [Ca²⁺]_i changes result from influx into the cell regulated through the opening of voltage-dependent Ca²⁺ channels (VDCCs), NMDARs, or other types of ligand-gated ion channels (LGICs) located in the plasma membrane (Kawamoto et al., 2012). Additionally, [Ca²⁺]_i levels can be increased by Ca²⁺ release from ER intracellular Ca²⁺ stores via ryanodine receptors (RyRs) and inositol-1,4,5-triphosphate receptors (IP₃Rs), or by Na⁺-dependent Ca²⁺ efflux (Na⁺/Ca²⁺ exchanger) from mitochondria (Kawamoto et al., 2012). The return to basal [Ca²⁺]_i is achieved by Ca²⁺ extrusion or organelle uptake, which uses proteins like sarcoplasmic–endoplasmic reticulum Ca²⁺-ATPase and mitochondrial uniporter (Kawamoto et al., 2012). Moreover, given its importance and potential danger, a high variety of proteins and mechanisms are related to [Ca²⁺]_i sensing and buffering. In particular, neurons possess specialized homeostatic mechanisms to ensure a tight command of cytosolic Ca²⁺ levels (Arundine and Tymianski, 2003), such as specialized Ca²⁺-permeable ionic channels, Ca²⁺ pumps, intracellular and intracellular Ca²⁺ buffering systems (Tymianski and Tator, 1996). Any alteration in cellular Ca²⁺ signaling and/or Ca²⁺ homeostasis can lead to serious pathological outcomes and has been linked to the activation of death pathways, which in the Central Nervous System (CNS) cause neuropathologies and neurodegenerative diseases (Sun et al., 2024) sharing excitotoxicity as a fundamental cause, such as amyotrophic lateral sclerosis (ALS; Van Den Bosch et al., 2006), Alzheimer’s disease (AD; Hynd et al., 2004), Parkinson’s disease (PD; Beal, 1998), Huntington’s disease (HD; Sepers and Raymond, 2014), epilepsy (Meldrum, 1993) and schizophrenia (Plitman et al., 2014).

Excitotoxicity

Ca²⁺-related excitotoxicity is considered one of the key processes of neuropathologies and neurodegenerative diseases (Schlaepfer and Bunge, 1973). Several Ca²⁺-permeable LGICs are involved in excitotoxicity generation, in particular glutamate receptors (Lau and Tymianski, 2010) and ATP P2X receptors (Sáez-Orellana et al., 2016). On the other hand, several studies reported that the activation of neuronal nAChRs (nicotinic acetylcholine receptors) containing the α7 subunit promotes neuronal survival (Dajas-Bailador et al., 2000; Laudenbach et al., 2002). So, despite its fundamental role, an imbalance in glutamate homeostasis and the consequent overactivation of glutamate receptors can damage and kill neurons (Mattson, 2019). Neuronal excitotoxic damage is mostly due to a massive influx of Ca²⁺ through NMDAR (Choi et al., 1988) and VDCCs that cause reactive oxygen species (ROS) release and consequent mitochondrial dysfunction (Mattson, 2003, 2019). Another example of excitotoxic damage happens in the muscular endplate due to rare genetic disorders, such as congenital myasthenic syndromes (CMS; Grassi and Fucile, 2020), which involves mutations in the genes of proteins related to neuromuscular transmission, mostly (about 15%) AChE gene (Beeson et al., 2005; Engel, 2012). Endplate overstimulation causes excitotoxic endplate damage (endplate myopathy) due to the sustained Ca²⁺ influx through ε-nAChR-channels, and the Ca²⁺ overloading triggers degenerative events of the endplate structure (Grassi and Fucile, 2014).

Based on the pathogenic concept of overactivation of the excitatory pathways, NMDA receptors have been a longstanding therapeutic target for designing drugs that could be used against these otherwise heterogeneous and complex pathologies (Villmann and Becker, 2007). NMDAR-mediated excitotoxicity seems to start from a signaling mechanism regulated by extrasynaptic NMDARs (Sattler et al., 1999a,b). Conditions that specifically attenuated synaptic NMDAR function did not affect the toxicity caused by exogenous NMDA or glutamate, meaning that extrasynaptic NMDARs must be linked to a molecular pathway triggering neuronal damage (Sattler et al., 1999a,b). Extrasynaptic NMDARs are enriched with the subunit GluN2B, forming GluN2B-containing heterodimers, supporting the hypothesis that extrasynaptic NMDARs constitute a distinct population, serving a specific function; moreover, GluN2B-containing NMDARs have a higher affinity for glutamate, whose concentration is lower in the extrasynaptic space (Papouin and Oliet, 2014). The prevailing theory suggests that synaptic and extrasynaptic NMDAR activation have opposing effects on cell fate: the activity of synaptic NMDARs is thought to favor neuronal survival, via the phosphorylation of intracellular factors such as CREB or Erk1/2; in contrast, cell death is mainly mediated by the activation of extrasynaptic NMDARs, which inhibits the above pathways and promotes the expression of caspase-3, a pro-apoptotic signal (Hardingham et al., 2002; Papouin and Oliet, 2014). To date, the intense research into the mechanisms of excitotoxicity has not enlightened the key intracellular steps responsible for neuronal death in glutamate-dependent excitotoxic processes, mostly because of the heterogeneity of the neurodegeneration that follows glutamate application (Lau and Tymianski, 2010). First, neuronal death in cellular cultures can happen through both apoptosis and necrosis, depending on the severity of NMDA insult: necrotic-like damage predominates in response to acute, relatively intense excitotoxicity (2 mM NMDA), while apoptotic-like neuronal death may develop over many hours after less severe insults, using 300 μM NMDA (Bonfoco et al., 1995). The first to recognize the central role of [Ca²⁺]_i in glutamate excitotoxicity-mediated neuronal damage and death was Choi in 1985, demonstrating that excitotoxicity in neuronal cultures was potentiated in a Ca²⁺-rich extracellular solution, while neurodegeneration was markedly reduced in a Ca²⁺-free extracellular solution (Choi, 1985). Furthermore, intracellular Ca²⁺ chelation by cell-permeant molecules such as BAPTA-AM and EGTA-AM protects neurons against excitotoxic injury both in vitro and in vivo (Tymianski et al., 1994a, 1994b). However, it seems that neuronal mortality is not directly connected to [Ca²⁺]_i: higher lethality is associated with lower Ca²⁺ influxes via NMDARs compared to higher Ca²⁺ influxes via other Ca²⁺-permeant channels, probably due to the spatial link NMDARs share with neuronal nitric oxide synthase (nNOS), which can produce toxic levels of nitric oxide (NO), through postsynaptic density protein of 95 kDa, the PSD-95 (Chariton and Hafner, 1998; Sattler et al., 1999a,b). Some evidence also supports the idea of free radical generation in mitochondria after the Ca²⁺ influx via NMDARs; radicals, especially superoxide, can interact with other radicals, such as nitric oxide, to form powerful oxidants (Lau and Tymianski, 2010). In fact, the increasing [Ca²⁺]_i accompanying NMDAR activation is partially buffered by the intracellular mitochondria, but this Ca²⁺ accumulation causes several dysfunctions, with resultant effects on mitochondrial membrane potential, ATP synthesis and glycolysis (key processes in a cell that consumes a lot of energy, like a neuron), reactive oxygen species generation (ROS) and ultimately failure of cytoplasmic Ca²⁺ homeostasis (Nicholls and Budd, 1998). Moreover, this mitochondrial impairment leads to the release (from the mitochondrial membrane) of Cytochrome C, which causes not only a defect in mitochondrial electron transport (Luetjens et al., 2000) but also caspase-9-dependent caspase-3 activation, which is an “executioner” caspase that leads to neuronal death through the activation of the apoptotic signaling (Seo et al., 2009). More recently, a physical interaction between NMDAR and TRPM4 (a Ca²⁺-impermeant Ca²⁺-activated cationic channel; Rajamanickam et al., 2025) has been shown to be required to observe glutamate-induced excitotoxicity (Yan et al., 2020), introducing a new chapter in the large field of excitotoxicity. All these excitotoxic mechanisms are linked to Ca²⁺ overload, suggesting that avoiding an excessive Ca²⁺ influx could exert neuroprotection.

Techniques for the quantitative measure of the Ca²⁺ permeability of ion channels

The high relevance of Ca²⁺ influx in physiological processes and its key role in the onset of several neuropathologies and neurodegenerative diseases makes it crucial to understand how to measure and modulate Ca²⁺ entry. The Ca²⁺ permeability of ion channels has been calculated for decades by measuring the channel reversal potential alterations induced by different [Ca²⁺]_o (Lewis, 1979), but estimating the Ca²⁺ entry at non-zero electrochemical driving forces, functionally more important, rested on the assumption that there is no interaction among ions passing through the channel (Zhou and Neher, 1993). Then, a new method to quantify the Ca²⁺ flowing through a cationic ion channel was introduced in 1992, involving the simultaneous use of both electrophysiological and Ca²⁺ imaging techniques (Augustine and Neher, 1992): a Ca²⁺ indicator (e.g., Fura-2) is loaded into the cells using a patch micropipette (Zhou and Neher, 1993), and the cell response to an agonist is measured both as a current and a fluorescence emission variation. This mixed approach has been used in the late 90s to measure the P_f (the fractional Ca²⁺ current, which represents the percentage of the total current carried by Ca²⁺ ions, at a given membrane potential) of several Ca²⁺ permeable cationic channels: nAChRs (2.5–11.4%, based on species and subunits composition; Zhou and Neher, 1993; Fucile et al., 2003; Fucile, 2004), human AMPAR (from 0.5 to 3.9%, based on subunits composition; (Burnashev et al., 1995) and human NMDAR (from 8.2 to 11%, based on subunits composition). The NMDARs P_f is the highest among all the glutamate-gated ion channels currently known (Burnashev et al., 1995). More recently, our group introduced a new way to evaluate the ion influxes through the human NMDARs (and other Ca²⁺-permeable cationic channel) and demonstrate the possibility of modulating the ion selectivity of these receptors, pharmacologically reducing their fractional Ca²⁺ current, causing the consequent reduction of NMDA-mediated Ca²⁺ entry in human neurons (D’Andrea et al., 2024). This approach allows us to record simultaneously the intracellular free Ca²⁺ and Na⁺ concentrations ([Ca²⁺]_i and [Na⁺]_i, respectively D’Andrea et al., 2024). Our innovative approach is no longer centered on directly measuring ionic fluxes, but on the influx-related changes of [Ca²⁺]_i and [Na⁺]_i, measured simultaneously by fluoresce microscopy. This technique, already described in different contexts (Miyazaki et al., 2019), was used by us for the first time to evaluate the LGICs Ca²⁺ permeability.

Ca²⁺-permeable LGICs and related pathologies

Ca²⁺ ions enter the cells, following their strong concentration gradient, through many kinds of ion channels, exhibiting a large spectrum of functional properties, such as open kinetics, conductance, and ionic selectivity. This wide range of differently regulated pathways, together with the possibility to mobilize Ca²⁺ from intracellular stores, allow cells to strictly regulate the intracellular free Ca²⁺ concentration ([Ca²⁺]_i), which in turn drives the function of Ca²⁺-dependent proteins and related mechanisms (Berridge et al., 2000). Many Ca²⁺ permeable channels are driven by changes in membrane potential, transducing electrical signals in cellular responses (Zamponi et al., 2015). These VDCCs are highly selective for Ca²⁺ (Tsien et al., 1987), and their activation and inactivation kinetics are crucial to allow Ca²⁺ entry avoiding excitotoxic damage (Christel and Lee, 2012). By contrast, cationic LGICs exhibit a much lower Ca²⁺ selectivity, with Na⁺ being the ion conducting most of the inward current (Burnashev, 1998; Pankratov and Lalo, 2014). Nevertheless, Ca²⁺ flowing through LGICs has a paramount physiological function, in processes such as synaptogenesis (Pagano et al., 2021), synaptic plasticity (Gnegy, 2000), and neuromodulation (Kunz et al., 2013), while excessive activation of these channels has been causally related to relevant pathologies (Sattler and Tymianski, 2001; Spalloni et al., 2013; Guo and Ma, 2021). Obviously, the higher the Ca²⁺ permeability of a channel, the bigger the risk that channel overactivation may lead to excitotoxicity. For these reasons in the last decades many different cationic LGICs have been characterized in terms of their fractional Ca²⁺ current, which is the percentage of the total current carried by Ca²⁺ at a certain membrane potential (Zhou and Neher, 1993; Neher, 1995). These experiments explained how different subunits determine the Ca²⁺ permeability of channels of the same subfamily (Fucile, 2004), and the crucial role of the number and position of electrically charged aminoacidic residues in building the Ca²⁺ selectivity filter (Watanabe et al., 2002; Fucile, 2017). In Table 1 we summarize the known fractional Ca²⁺ currents of different kinds of LGICs, as well as the same parameter measured in mutated channels, some of them resulting in Ca²⁺-related channelopathies. We included in Table 1 only mutated channels with known P_f values, but other mutated LGICs with increased Ca²⁺ permeability have been described in pathologies (Lemke et al., 2014; Amin et al., 2018).

Physiological modulation of the Ca²⁺ permeability of LGICs

The Ca²⁺ permeability of NMDARs can be modulated by physiological processes. Subunits composition of the NMDAR greatly alters several physical and pharmacological properties of the channel: the expression and insertion of the GluN3B subunit, which can co-assemble with endogenous GluN1 and GluN2A and play an important role in modulating synaptic plasticity and neuronal death, reduces the Ca²⁺ permeability of the NMDAR (Matsuda et al., 2003). PKA signaling cascade controls NMDAR Ca²⁺ permeability and NMDAR-mediated [Ca²⁺]_i rise in dendritic spines, and in this way PKA directly modulates the induction of NMDAR-dependent LTP at hippocampal Schaffer collateral-CA1 synapses (Skeberdis et al., 2006). NMDAR-mediated Ca²⁺ influx can also be greatly potentiated by the EphB receptor, a member of the Ephrin receptors family, a large family of receptor tyrosine kinases (Takasu et al., 2002).

Recently, GluA2-containing AMPARs, the most abundant in the central nervous system, have been shown to possess a spectrum of different Ca²⁺ permeabilities depending on the subunit composition of AMPAR tetramers, as well as the spatial orientation of transmembrane AMPAR and regulatory proteins and cornichon auxiliary subunits (Miguez-Cabello et al., 2025). The extreme complexity in the physiological Ca²⁺ permeability modulation of Ca²⁺ permeable LGICs demonstrates the importance of those processes and the possibility to alter and modulate the influx of Ca²⁺ through ion channels.

Pharmacological modulation of the Ca²⁺-permeability of LGICs

Given the high number of Ca²⁺ permeable LGICs, and their causative role in Ca²⁺-related pathologies (calciumopathies; Stutzmann, 2007), we posit the possibility to reduce the noxious impact of their activation by the selective reduction of their Ca²⁺ permeation. We started to investigate this strategy more than a decade ago, analyzing the effect on the P_f of the human muscle nicotinic acetylcholine receptor (nAChR) exerted by molecules shown to beneficially act in patients with the slow channel myasthenic syndrome (SCMS; Sadeh et al., 2011). SCMS is a genetic muscle pathology due to mutations of the endplate nAChR dramatically increasing the channel open time and causing a Ca²⁺-dependent degeneration of the endplate (Engel et al., 1982; Sine et al., 1995; Zhu et al., 2015). The same mutations cause a more severe phenotype in human than in rodent animal models, due to the higher Ca²⁺ permeability of the human adult nAChR subtype (containing the e subunit; Gomez et al., 2002; Fucile et al., 2006a). Our data explained why nifedipine, salbutamol and verapamil were able to reduce SCMS symptoms in patients, highlighting their capacity to reduce the fractional Ca²⁺ current through human muscle nAChRs (Piccari et al., 2011). This approach has a crucial aspect: the reduction of Ca²⁺ entry without blocking the channel. This point is extremely relevant, in particular for pathologies due to channel overactivation, in which it is not possible to completely eliminate channel openings. This is true for the endplate, whose proper function requires nAChR opening with precise kinetics: even fast channel mutations produce myasthenia, although without endplate degeneration (Engel et al., 1993). Similar consideration may be done for excessive activation of synaptic and extrasynaptic glutamate-gated ion channels, functionally linked to Ca²⁺-related excitotoxicity and to several forms of neurodegeneration: overactivation is harmful, but block is not possible, leading to severe adverse effects (Hargreaves et al., 1994; Parsons et al., 1999). For this reason, a partial block of NMDAR is one of the few therapeutic options for Alzheimer’s disease, in particular using memantine (partial open channel blocker; Kornhuber et al., 1994; Rammes et al., 2008; Karimi Tari et al., 2024). Despite its neuroprotective potential, memantine is not sufficient to significantly ameliorate AD course (Matsunaga et al., 2015), and other therapeutic approaches must be found. In the last few years, we have focused our attention on the possibility to reduce the P_f value of the human NMDAR (Plutino et al., 2019; D’Andrea et al., 2024). We have shown that mild acidosis (pH 6.8–6.5) is not only able to reduce the open probability of NMDARs (as already known; Traynelis and Cull-Candy, 1990), but also to decrease significantly their Ca²⁺ permeability, with a one-third reduction of the P_f value (Plutino et al., 2019), further explain the known neuroprotective role of mild acidosis (Tombaugh and Sapolsky, 1990). More recently, we have quantified in terms of P_f the observations of Stephen Traynelis group, which investigated the effects of newly developed negative allosteric modulators (NAMs) of NMDARs (Katzman et al., 2015; Hansen et al., 2018). Some of these NAMs were found to reduce the Ca²⁺ permeability of the human NMDAR, measured by the shift of the reversal potential and calculated in terms of PCa/PNa (Perszyk et al., 2021). We measured the P_f value of human GluN1/GluN2A NMDARs in the presence of one of these compounds, EU1794-4, showing a significant 40% reduction (D’Andrea et al., 2024). We included in Table 2 all the P_f values measured to date, to our knowledge, in the presence of modulators able to reduce the Ca²⁺ permeability of LGICs. This list is rather short.

Discussion

Different therapeutic strategies have been investigated to fight neurodegeneration (see Table 3 for references), but with little impact on clinical applications.

Our data demonstrate that the selective reduction of Ca²⁺ entry through LGICs is possible, in principle. Reducing Ca²⁺ influx could also lead to adverse effects. Reduced NMDAR-mediated Ca²⁺ signaling can alter physiological Ca²⁺-dependent mechanisms, potentially leading to impaired learning and memory. While excessive NMDAR-mediated Ca²⁺ influx can trigger pathways leading to neuronal death, insufficient Ca²⁺ signaling due to reduced NMDAR activity can also be detrimental: this reduction may contribute to the pathophysiology of neurological diseases, as it can hinder the normal signaling required for neuronal health and function (Painuli et al., 2023). Understanding the processes of NMDAR-mediated Ca²⁺ signaling and its implications for neuronal health will help the design of new drugs, and to maintain a good intracellular Ca²⁺ homeostasis. In this context, different Ca²⁺-targeting approaches may be possible. A chelation-based therapy against stroke, head trauma and neurological damage has been proposed, by using DP-b99, a Ca²⁺/Zn²⁺ chelator derived from BAPTA (Yeung, 2004). Despite a good tolerability in healthy young and elderly volunteers within the dose range evaluated (Rosenberg et al., 2005), DP-b99 showed no evidence of efficacy in treating human ischemic stroke (Lees et al., 2013). In our opinion, a neuroprotective strategy aiming to reduce Ca²⁺ entry through LGIC is worth of experimental attention, being in principle applicable to a wide range of Ca²⁺-related pathologies, especially to the diseases caused by excessive Ca²⁺ entry through LGICs. Many molecules with described neuroprotective effects may indeed be tried for their ability to selectively reduce Ca²⁺ entry, with a particular focus on positively charged compounds already known to reduce the channel (sub)conductance levels. For instance, EU1794-4 reduced the single-channel conductance of NMDAR (Perszyk et al., 2021). With this hypothesis in mind, we measured the P_f value of human NMDAR in the presence of memantine, spermine (an intracellular polyamine known to block cation fluxes through LGICs; Tombaugh and Sapolsky, 1990), IEM 1754 and IEM 1460 (open channel blockers; Antonov and Johnson, 1996). None of these molecules was able to reduce the P_f of GluN1/GluN2A NMDAR (Plutino et al., 2019), and to date, besides protons, to our knowledge only NAMs developed by the Traynelis groups exhibit this property.

The search for new molecules able to reduce the P_f of excitotoxicity-related Ca²⁺-permeable LGICs may produce highly relevant results to improve our pharmacological tools for neuroprotection.

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