MINI REVIEW article

Front. Cell. Neurosci., 30 July 2021
Sec. Non-Neuronal Cells
https://doi.org/10.3389/fncel.2021.695817

Astrocytic IP3Rs: Beyond IP3R2

  • 1University of Bordeaux, INSERM, Neurocentre Magendie, U1215, Bordeaux, France
  • 2University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, Bordeaux, France
  • 3ShanghaiTech University, Shanghai, China
  • 4Faculty of Science, Toho University, Funabashi, Japan
  • 5RIKEN CLST, Kobe, Japan

Astrocytes are sensitive to ongoing neuronal/network activities and, accordingly, regulate neuronal functions (synaptic transmission, synaptic plasticity, behavior, etc.) by the context-dependent release of several gliotransmitters (e.g., glutamate, glycine, D-serine, ATP). To sense diverse input, astrocytes express a plethora of G-protein coupled receptors, which couple, via Gi/o and Gq, to the intracellular Ca2+ release channel IP3-receptor (IP3R). Indeed, manipulating astrocytic IP3R-Ca2+ signaling is highly consequential at the network and behavioral level: Depleting IP3R subtype 2 (IP3R2) results in reduced GPCR-Ca2+ signaling and impaired synaptic plasticity; enhancing IP3R-Ca2+ signaling affects cognitive functions such as learning and memory, sleep, and mood. However, as a result of discrepancies in the literature, the role of GPCR-IP3R-Ca2+ signaling, especially under physiological conditions, remains inconclusive. One primary reason for this could be that IP3R2 has been used to represent all astrocytic IP3Rs, including IP3R1 and IP3R3. Indeed, IP3R1 and IP3R3 are unique Ca2+ channels in their own right; they have unique biophysical properties, often display distinct distribution, and are differentially regulated. As a result, they mediate different physiological roles to IP3R2. Thus, these additional channels promise to enrich the diversity of spatiotemporal Ca2+ dynamics and provide unique opportunities for integrating neuronal input and modulating astrocyte–neuron communication. The current review weighs evidence supporting the existence of multiple astrocytic-IP3R isoforms, summarizes distinct sub-type specific properties that shape spatiotemporal Ca2+ dynamics. We also discuss existing experimental tools and future refinements to better recapitulate the endogenous activities of each IP3R isoform.

Introduction

Over the last three decades, Ca2+ imaging has revealed new roles for astrocytes. Indeed, astrocytic Ca2+ signaling was shown to regulate synaptic transmission, synaptic plasticity, and to influence behavior (Araque et al., 2014; Park and Lee, 2020). Inositol 1,4,5-trisphosphate receptors (IP3Rs) mediated Ca2+ signaling (IP3R-Ca2+) is regarded a primary generator of astrocytic Ca2+ signaling. Upon activation of Gq-GPCRs, the main input pathway of astrocytes, phospholipase C breaks down PIP2 into DAG and IP3, activating IP3R predominantly located on the membrane of endoplasmic reticulum (ER) resulting in Ca2+ release (Bootman et al., 2001). This IP3R-mediated Ca2+ signaling is considered to trigger the activity-dependent and selective release of chemical transmitters (gliotransmitters) such as glutamate, D-serine, and ATP, which have distinct influences over neuronal activity. Initially, IP3R subtype 2 (IP3R2) was the only recognized Ca2+ channel in astrocytes; However, advanced Ca2+ imaging techniques have since identified novel Ca2+ sources, including mitochondria (Agarwal et al., 2017), transient receptor potential ankyrin 1 (Shigetomi et al., 2012, 2013b), L-type voltage gated Ca2+ channels (Letellier et al., 2016), sodium/calcium exchanger (Kirischuk et al., 1997; Boddum et al., 2016; Rose et al., 2020), and transient receptor potential canonical (Shiratori-Hayashi et al., 2020) amongst others, thereby expanding the known Ca2+ signaling toolkit of astrocytes. Doubtlessly additional Ca2+ channels and sources will emerge in the future.

While the field’s focus has moved on from understanding IP3Rs to identifying new Ca2+ sources, understanding IP3R signaling in astrocytes remains highly relevant. Indeed, IP3Rs are the primary target for manipulating astrocytic activity, and such manipulations have proven to be very consequential in many studies. Since most of these manipulations indiscriminately influence all IP3R subtypes, this could reflect the key role played by IP3R subtypes other than IP3R2, namely IP3R1 and IP3R3, which were mostly overlooked. In this review, we summarize the evidence for different subtypes of IP3R and discuss how we can better study the role of IP3R-Ca2+ signaling in astrocytes which is one of the core issues in understanding astrocyte physiology.

Evidence for Three Subtypes

The Dogma: IP3R2 the Sole Functional Astrocytic IP3R

There are three mammalian IP3R subtypes, i.e., IP3R1 (Furuichi et al., 1989; Mignery et al., 1989; Yamada et al., 1994), IP3R2 (Mignery et al., 1990; Südhof et al., 1991; Yamamoto-Hino et al., 1994; Iwai et al., 2005), and IP3R3 (Blondel et al., 1993; Yamamoto-Hino et al., 1994; Iwai et al., 2005). Among them, IP3R2 has widely been accepted as the only functional IP3R subtype present in astrocytes, and consequently, the IP3R2KO model mouse has been at the center of numerous important studies (Agulhon et al., 2010; Takata et al., 2011; Chen et al., 2012; Navarrete et al., 2012, 2019; Cao et al., 2013; Perez-Alvarez et al., 2014; Petravicz et al., 2014; Gómez-Gonzalo et al., 2015, 2017; Mariotti et al., 2016; Monai et al., 2016; Perea et al., 2016; Martin-Fernandez et al., 2017; Tanaka et al., 2017). Although an important model in the astrocyte field, the belief that knocking out IP3R type-2 abolishes IP3 induced Ca2+ release (IICR) entirely appears to need remedying. This section considers the historical data from which the dogmatic view of astrocytic-IP3R2 has flowed and reviews the evidence for other IP3R subtypes.

Astrocyte Proteome

Several studies explored IP3Rs using immunohistochemistry which provided a consensus over the expression of IP3R2 in hippocampal/cortical astrocytes and Bergmann glia (Sharp et al., 1999; Holtzclaw et al., 2002; Hertle and Yeckel, 2007; Takata et al., 2011; Chen et al., 2012). While there are some conflicting reports over the immunoreactivity of IP3R3 in astrocytes and Bergmann glia (Sugiyama et al., 1994; Yamamoto-Hino et al., 1995; Hamada et al., 1999; Sharp et al., 1999; Holtzclaw et al., 2002), IP3R1 immunoreactivity was not initially observed in glia (Nakanishi et al., 1991; Dent et al., 1996; Hamada et al., 1999; Sharp et al., 1999; Holtzclaw et al., 2002; Hertle and Yeckel, 2007). These findings supported the view that IP3R2 is the predominant astrocytic IP3R. However, these results may also reflect limitations of the available IP3R antibodies or the difficulty of accurately assigning proteins located within ultrathin astrocyte processes, which are below the resolution limit of conventional microscopy (Panatier et al., 2014; Arizono et al., 2020) and buried amongst neuronal dendrites.

IP3R1 immunoreactivity was recently detected in spinal dorsal horn astrocytes (Shiratori-Hayashi et al., 2020) and, albeit with low stringency, in isolated astrocytes from adult mice (Chai et al., 2017). Using a state of the art TurboID construct to biotinylate proteins in the immediate proximity of tripartite synapses, Takano et al. (2020) report enrichment of IP3R1 protein in the peri-synaptic astrocytic compartment (Takano et al., 2020). This finding, however, should be interpreted with some caution as identified proteins were assigned to astrocytes based on published mRNA datasets (Zhang et al., 2014, 2016). Nevertheless, IP3R1 protein enrichment in fine astrocytic processes is consistent with Ca2+ imaging studies (Sherwood et al., 2017) and could account for the poor detection in various assays which favor detection in large subcellular compartments, i.e., major processes and soma of astrocytes. Notably, IP3R2, which is reported to be in the soma and main branches (Chen et al., 2012), was not enriched in peri-synaptic astrocytic compartments (Takano et al., 2020), likely reflecting the different subcellular distribution of IP3R1 and IP3R2 (Figure 1A and Table 1).

FIGURE 1
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Figure 1. Proposed distribution and Ca2+ profiles of IP3R1 and IP3R2 in astrocytes. (A) While IP3R2 is distributed in the soma and major branches (Takata et al., 2011; Chen et al., 2012; Petravicz et al., 2014), IP3R1 may be enriched in the peri-synaptic processes (Sherwood et al., 2017; Takano et al., 2020), for instance in the nodes which were recently shown to host 2-APB-sensitive local Ca2+ signals at the tripartite synapse (Arizono et al., 2020). (B) IP3R2 generates global Ca2+ waves and oscillations in both astrocytes (Srinivasan et al., 2015; Sherwood et al., 2017) and model cells (Miyakawa, 1999). IP3R1 mediated Ca2+ dynamics in astrocytes have not been observed directly, but may resemble IP3R1-dependent monophasic Ca2+ transients observed in model cells (Miyakawa, 1999) and dendritic spines of pyramidal neurons (Holbro et al., 2009).

TABLE 1
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Table 1. Dissecting IP3R subtypes.

Astrocyte Transcriptome

IP3R1, IP3R2, and IP3R3 are encoded by the respective genes ITPR1, ITPR2, and ITPR3. Notably, mRNA for all three genes have been detected in astrocytes isolated from young and aged mouse brain (Cahoy et al., 2008; Zhang et al., 2014; Chai et al., 2017; Clarke et al., 2018) as well as humans (Zhang et al., 2016). Furthermore, ITPR1 and ITPR2 are actively translated in astrocytes of adult mice (Srinivasan et al., 2016; Chai et al., 2017; Clarke et al., 2018; Yu et al., 2018) indicating that their proteins are produced in astrocytes. In astrocytes the isoform transcript abundance is generally ITPR2 > ITPR1 >>> ITPR3 (ITPR3 mRNA is present in very small amounts and may be negligible). However, these transcripts are developmentally and differentially regulated across brain regions and in some instances ITPR1 mRNA appears to be more abundant than ITPR2 mRNA (Yu et al., 2018; Table 1).

Ca2+ Imaging

Over the last decade, studies show that deletion of IP3R2 does not abolish Ca2+ signaling in astrocytes. It is now generally agreed that bulk/somatic cytosolic Ca2+ responses are hard to detect in IP3R2KO astrocytes (Petravicz et al., 2008, 2014; Agulhon et al., 2010, 2013; Takata et al., 2011, 2013; Nizar et al., 2013). However, with a detailed examination, rich Ca2+ activity can be observed within fine astrocyte processes (Di Castro et al., 2011; Haustein et al., 2014; Kanemaru et al., 2014; Srinivasan et al., 2015; Rungta et al., 2016; Agarwal et al., 2017; Sherwood et al., 2017). Non-IP3R2 Ca2+ activity has largely been interpreted as evidence for non-IP3R Ca2+ stores, nevertheless, these activities could equally arise from IP3R1 and or IP3R3 (Tamamushi et al., 2012; Sherwood et al., 2017). Indeed, Ca2+ release from the ER was recently reported for IP3R2KO astrocytes (Okubo et al., 2019). In Bergmann glia, while IP3R2 was shown to be a dominant subtype, IP3R1 and IP3R3 were also shown to contribute to rapid Ca2+ events in the processes (Tamamushi et al., 2012). Similarly, using IP3R2KO and IP3R2/3 double KO mice, we found that IP3R2 is involved in global Ca2+ release, whereas local Ca2+ signals involve IP3R1 and IP3R3 (Figure 1B) (Sherwood et al., 2017) in hippocampal astrocytes. Knock-down of IP3R1 in dorsal spinal cord astrocytes of IP3R2KO mice also unmasked IP3R1 mediated Ca2+ signals (Shiratori-Hayashi et al., 2020). Furthermore, the selective activation of Gq-GPCR/IP3R/Ca2+ signaling in astrocytes, using DREADDs (designer receptor exclusively activated by designer drug, see section “Activation of IP3 Induced Ca2+ Release in Astrocytes”), triggered Ca2+ events in the astrocytic processes of IP3R2KO mice (Wang et al., 2021) indicating the presence of IP3R1/3.

2-APB was introduced as an antagonist of IP3Rs (Maruyama et al., 1997) and has been widely used to investigate the contribution of IP3Rs to cellular Ca2+ signaling. 2-APB appears to preferentially block IP3R1 and IP3R3, whereas cells predominantly expressing IP3R2 seem largely insensitive (Kukkonen et al., 2001; Bootman et al., 2002; Saleem et al., 2014). Thus, the fact that 2-APB reduces astrocyte Ca2+ amplitude and responsiveness in diverse brain regions (Sul et al., 2004; Young et al., 2010; Tamura et al., 2014; Tang et al., 2015; Arizono et al., 2020) and spinal dorsal horn (Shiratori-Hayashi et al., 2020) may support the presence of functional IP3R1 and IP3R3 in astrocytes. The functional role of non-IP3R2 in astrocytic Ca2+ signaling remains to be determined, it is possible that some membrane receptors are functionally coupled solely to IP3R1 or IP3R3 and generate local Ca2+ events, which may or may not be involved in triggering IP3R2 dependent Ca2+ waves (Petravicz et al., 2008). Alternatively, it is possible that IP3Rs exist as heterotetramers (Wojcikiewicz and He, 1995; Nucifora et al., 1996).

Phenotypic Comparison

Comparison of WT and total IP3R2KO mice has revealed some important physiological roles of IP3R2 signaling in astrocytes, i.e., motor learning (Padmashri et al., 2015) modulating depressive-like behaviors (Cao et al., 2013) but this remains controversial (Petravicz et al., 2014). The possible roles of astrocytic IP3R1 and IP3R3 may be gleaned by comparing WT and IP3R2KOs with manipulations that impair all IP3R subtypes. For example, while IP3R2KO has no impact on sleep (Cao et al., 2013) overexpressing a transgene for the IP3 hydrolyzing enzyme, IP3-5-phosphatase, in astrocytes, suppresses Ca2+ release from all IP3R subtypes and disrupts sleep (Foley et al., 2017). Similarly, although IP3R2KO had no impact on hippocampal LTP (Agulhon et al., 2010), we showed that loading a single astrocyte with the membrane-impermeable pan-IP3R antagonist, heparin, blocks long-term synaptic potentiation (Sherwood et al., 2017). These studies, taken together, indicate that non-IP3R2 IP3Rs regulate sleep and hippocampal LTP.

Summary

The expression of multiple IP3R subtypes in astrocytes has a wide-reaching implication in the field. Studies using IP3R2KO as a model for blocked IICR would need to be re-assessed to include the possibility of IICR mediated by IP3R1 and IP3R3.

Prospectus/Advantage of Multiple Ip3R Isoforms

Different Properties of IP3R Subtypes

The three IP3R subtypes share only 65–85% homology accounting for many of the subtype-specific properties leading to particular spatiotemporal features of Ca2+ responses. Although high homology is observed in regions critical for forming the IP3−gated Ca2+ channel, each subtype has a different IP3 affinity; IP3R2 > IP3R1 > IP3R3 (Zhang et al., 2011). High IP3 affinity of IP3R2 has been associated with slower kinetics and more prolonged duration of IP3R2-mediated Ca2+ microdomains, or Ca2+ puffs (Mataragka and Taylor, 2018).

Importantly, IP3R channel activity is not only regulated by IP3 but also by Ca2+ (Finch et al., 1991). The synergy between IP3 and Ca2+ creates repetitive IP3R activation and inhibition, resulting in Ca2+ oscillations. Such oscillations are crucial to protect cells from extended Ca2+ elevation that can often be toxic to the cell (Berridge et al., 2000). The oscillatory pattern is considered necessary for many cellular processes, such as fertilization (Miyazaki et al., 1992). IP3R2 mediates long-lasting, regular Ca2+ oscillations, whereas IP3R1 or IP3R3 tend to exhibit mono-phasic transients or very rapidly dampened Ca2+ oscillations (Miyakawa, 1999).

The difference in IP3R subtype properties is further characterized by various binding partners, including kinase and phosphatases, which can further fine-tune Ca2+ profiles. Interestingly, while there are many interacting partners common to all three IP3R subtypes, the nature of their regulation can be subtype-specific. For instance, protein kinase C, depending on the IP3R subtype, can either be stimulatory or inhibitory; this difference likely reflects isoform-specific phosphorylation sites. Further detailed biochemical study (Hamada et al., 2017) is required to investigate how various IP3R binding molecules specifically regulate each IP3R isoform (Hamada and Mikoshiba, 2020).

Different Distribution and Role of IP3R Subtypes Within Various Tissues

One important feature that defines the subtype-specific role of IP3Rs in vivo is the tissue distribution patterns. While IP3R1 is mostly expressed in the central nervous system, IP3R2 and IP3R3 are broadly expressed in various organs such as the heart, pancreas, liver, and salivary glands (Hisatsune and Mikoshiba, 2017). This distribution pattern is tightly linked to the physiological role of IP3R subtypes. Reflecting its rich expression in Purkinje cells, mice lacking IP3R1 exhibit severe cerebellar ataxia, a seizure−like posture, impaired cerebellar LTD. (Inoue et al., 1998), and die within 3–4 weeks of birth (Matsumoto et al., 1996). The dysregulation of IP3R1 is linked with other brain disorders such as Huntington’s disease and Alzheimer’s disease (Hisatsune and Mikoshiba, 2017). IP3R2 is associated with sweating (Klar et al., 2014), bone formation (Kuroda et al., 2008), and heart hypertrophy (Nakayama et al., 2010; Drawnel et al., 2012; Vervloessem et al., 2015). IP3R3 plays a role in taste sensing (Hisatsune et al., 2007) and hair cycle (Sato-Miyaoka et al., 2012). IP3R2 and IP3R3 together are associated with the heart’s development (Uchida et al., 2010, 2016) and secretion of saliva and tears (Futatsugi, 2005; Inaba et al., 2014).

Different Distribution and Role of IP3R Subtypes Within a Cell

Some cells express multiple IP3R subtypes, enabling each subtype to uniquely contribute to Ca2+ profiles and cellular functions. For instance, in HeLa cells, knock-down of IP3R1 terminates Ca2+ oscillations, whereas knock-down of IP3R3 results in more robust and long-lasting Ca2+ oscillations (Hattori et al., 2004). The specific contribution of IP3R subtypes can also depend on their distinct subcellular distribution, as seen in pancreatic acinar cells (Lur et al., 2011), COS cells (Pantazaka and Taylor, 2011), and DT40 cells (Bartok et al., 2019). In Bergmann glia, knocking out IP3R2 resulted in decreased agonist-induced Ca2+ release while knocking out IP3R1 and IP3R3 resulted in delaying the peak of agonist-induced Ca2+ release specifically in astrocytic processes (Tamamushi et al., 2012), suggesting their subtype-specific distribution. It is likely that astrocytes, which express multiple IP3R subtypes, also take advantage of subtype-specific distribution.

In astrocytes, IP3Rs are predominantly located on thapsigargin sensitive ER Ca2+ store. The ER in astrocytes may be found throughout the cell in the soma, major processes (Okubo et al., 2019, 2020), and peri-synaptic astrocytic processes (Bergersen et al., 2012), in close association with adhesion junctions (puncta adherentia) between dendritic spines and astrocytic processes (Spacek and Harris, 1998). Although recent studies indicate that ER and other membrane-bound organelles are absent from peri-synaptic processes (Patrushev et al., 2013) this likely reflects their sensitivity to chemical fixation (Korogod et al., 2015). The ER store in astrocytes is heterogeneous and organized into sub-compartments that can release Ca2+ independently (Golovina and Blaustein, 1997, 2000). It would be fascinating to see if IP3R subtypes are located to specific functional domains, e.g., signaling domains of membrane receptors, ER-mitochondria contacts (Bartok et al., 2019), and ER-plasma membrane junctions (Thillaiappan et al., 2017). In addition to the ER, astrocytic IP3Rs can also be found on other Ca2+ stores, with unique properties, i.e., the large dense-core vesicles (Hur et al., 2010), which may be comparable to the thapsigargin insensitive, Bafilomycin A1 sensitive, acidic Ca2+ stores previously described in secretory cells (Gerasimenko et al., 1996, 2009, 2011; Hur et al., 2010). Notably, compared to the ER, acidic Ca2+ stores can exhibit enhanced sensitivity to IP3 (Yoo, 2010). Other potential IP3-sensitive Ca2+ stores include the nuclear envelope (Gerasimenko et al., 1995; Petersen et al., 1998), nucleoplasm (Echevarría et al., 2003), Golgi (Pinton et al., 1998), and plasma membrane (Dellis et al., 2006).

Summary

While IP3R subtypes are regulated by IP3 and Ca2+ and have many common interacting partners, they differ in how they are affected by these regulators. Such differences enrich the diversity of spatio-temporal Ca2+ profiles created by IP3Rs. The IP3R subtype expression pattern, in vivo, is tissue specific and their subcellular localization is highly variable and dependent on cell types, and this carries important functional implications. Together with recent reports showing the distinct role of IP3R1 and IP3R3 in Bergmann glia and astrocytes, these facts support the view that IP3R isoforms 1 and 3 are unique Ca2+ channels that need to be addressed independently of IP3R2.

Tools to Dissect the Role of Ip3R Isoforms

Experimental and Analytical Tools

To understand the role of the various Ca2+ signals in astrocyte physiology, it will be necessary to make quantitative measurements (Neher, 2008). Progress in this direction has been frustrated by the unique astrocyte morphology and difficulties in interpreting recorded Ca2+-dependent fluorescent signals (Rusakov, 2015). To accurately capture Ca2+ dynamics in sub-cellular compartments, there is a need to adopt imaging techniques with improved resolution and to develop tools for efficient analysis in three-dimensional (Bindocci et al., 2017; Romanos et al., 2019). Because of our poor understanding of functional compartments, analysis of astrocytic Ca2+ dynamics has been moving toward state-of-the-art event-based analysis (Romanos et al., 2019; Wang et al., 2019; Bjørnstad et al., 2021), nevertheless ROI (region-of-interest) based analysis, informed by cellular anatomy (functional compartments) and molecular architecture, has been critical for understanding neuron physiology (e.g., spines and boutons). To this end, the identification of morphologically distinct subcellular compartments are promising targets for classical ROI based analysis, i.e., “glial microdomains” on Bergmann glial processes (Grosche et al., 1999) and “astrocytic compartments” on major branches (Panatier et al., 2011), both revealed using confocal microscopy, and astrocytic nodes and shafts within the spongiform structure visualized using live STED microscopy (Arizono et al., 2020). The ultimate goal of extracting quantitative Ca2+ dynamics from fluorescent data is non-trivial but achievable using realistic biophysical cell models (Rusakov, 2015; Denizot et al., 2019), a task simplified by the recent development of the open-source flexible model builder ASTRO (Savtchenko et al., 2018). For an accurate understanding of Ca2+ dynamics, it will be necessary to constrain models further using empirically determined details, e.g., receptor kinetics, expression patterns, endogenous Ca2+ buffering, etc.

Pharmacological Tools

It is difficult to disentangle the physiological roles of IP3R subtypes in cells that typically express complex mixtures of homo- and hetero-tetrameric IP3Rs. There are no ligands that usefully distinguish among IP3R subtypes (Saleem et al., 2013a,b) and nor are there effective antagonists that lack serious side effects (Michelangeli et al., 1995). Of the available antagonists, heparin is currently the most useful. Heparin is a membrane impermeant pan-IP3R inhibitor that may be selectively loaded into astrocytes using a whole-cell patch-pipette (Sherwood et al., 2017). Recent developments report small impermeant competitive antagonists of IP3R1, which, compared to heparin, are likely to have fewer off-targets (Konieczny et al., 2016). Well-characterized function-blocking monoclonal antibodies are powerful tools to specifically inhibit IP3R subtypes (Miyazaki et al., 1992; Inoue et al., 1998; Nishiyama et al., 2000; Gerasimenko et al., 2009). This technology has not yet been applied to astrocytes.

Genetic Tools

Inhibition of IP3 Induced Ca2+ Release

IP3R2KO and conditional-KO (cKO) mice (Petravicz et al., 2014; Padmashri et al., 2015; Wang et al., 2021) are widely used, however, as highlighted above, deletion of IP3R2 does not abolish IICR. IICR can be suppressed, irrespective of the underlying receptor, using an IP3-sponge to buffer IP3 (Xie et al., 2010; Tanaka et al., 2013), or an IP3-5′-phospatase transgene to enhance IP3 metabolism (Kanemaru et al., 2007; Foley et al., 2017). To study the physiological role of IP3R subtypes it is necessary to develop inducible cKO for IP3R1 (Sugawara et al., 2013) and IP3R3. Specific knock-down of IP3R subtypes can also be achieved using viruses to introduce short hairpin RNA into astrocytes (Shiratori-Hayashi et al., 2020).

Activation of IP3 Induced Ca2+ Release in Astrocytes

Pharmacogenetics

DREADDs (designer receptor exclusively activated by designer drug) enable the selective activation of GPCR-IP3R-Ca2+ signaling in astrocytes. The most used DREADDs are the excitatory Gq or inhibitory Gi-coupled receptors, hM3Dq and hM4Di, respectively (derived from human M3/M4 muscarinic receptor). Both receptors are activated by a pharmacologically inert but bioavailable ligand clozapine-N-oxide (CNO) while being non-responsive to endogenous GPCR ligands (Agulhon et al., 2013). hM3Dq has been used to demonstrate an astrocytic role in behaviors such as food intake (Yang et al., 2015), fear response (Martin-Fernandez et al., 2017), and memory recall (Adamsky et al., 2018). While the DREADDs enables selective activation of astrocytes, they have two major drawbacks: Firstly, the exogenous receptors have not been targeted to specific signaling domains and are likely to be spatially uncoupled from signaling nanodomains critical to IP3R physiology (Bootman et al., 2001); Secondly, because of the sustained (hour-long) activation by exogenous ligands (Iwai et al., 2021), temporal features of astrocyte signaling are lost. While perhaps mimicking global Ca2+ surges, the available DREADDs are unlikely to recapitulate many of the local Ca2+ transients typically observed within fine astrocytic processes (Shigetomi et al., 2013a; Arizono et al., 2020).

Optogenetics

To achieve temporal control, an optogenetic approach has been developed for the reliable stimulation of endogenous GPCR-IP3R-Ca2+ signaling cascade using light. Light activation has been achieved by introducing to astrocytes either a mammalian light-sensitive Gq/Gi/o-protein-coupled photopigment, Melanopsin (Panda, 2005; Bailes and Lucas, 2013; Mederos et al., 2019), or light-activated chimeric GPCRs, termed OptoXRs. OptoXRs are generated by replacing the intracellular loops of a light-sensitive GPCR, e.g., rhodopsin, with those of a donor GPCR, e.g., Gq-coupled human adrenergic receptor α1a (Airan et al., 2009; Figueiredo et al., 2014; Tang et al., 2014; Adamsky et al., 2018; Iwai et al., 2021).

Summary – Future Developments

While having great potential for controlling astrocytic activation, a central question is to what extent do the chimeras mimic the signaling of wild-type receptors. GPCRs can have multiple signaling axis, e.g., multiple G-protein axes, β-arrestins, wnt-frizzled, or the hedgehog-smoothened axes (Bailes and Lucas, 2013; Tichy et al., 2019), and the signaling axes bias is often not characterized but can have profound side effects on physiology (Agulhon et al., 2013; Tichy et al., 2019). Indeed, the functional outcome of activating Gq in astrocytes using different exogenous receptor (i.e., hM3Dq and MrgA1) is not reproducible (Agulhon et al., 2010; Adamsky et al., 2018). While multiple signaling axis could confuse the role of IICR, they may be required to obtain an optimal IP3R response (Konieczny et al., 2017). Another primary concern is that DREADDs and optoXRs likely activate IP3Rs from cellular compartments distinct from those of the endogenous receptors, limiting their ability to recreate physiologically relevant Ca2+ profiles. To address this, next-generation activation tools are being engineered to mimic the subcellular distribution of endogenous receptors (Oh et al., 2010; Masseck et al., 2014; Spoida et al., 2014; Tichy et al., 2019).

In the last decade, substantial progress has been made revealing diverse spatio-temporal Ca2+ signaling in astrocytes. Understanding the subtleties of these signals will require detailed knowledge of the astrocytic Ca2+ signaling toolbox along with the generation and characterization of more sophisticated tools to control and accurately recapitulate the physiologically relevant Ca2+ signals.

Author Contributions

MS and MA performed the literature survey, wrote the manuscript, and prepared the figures and tables. MS, MA, AP, KM, and SHRO reviewed, finalized, and approved the final version.

Funding

This review was funded by the CNRS, INSERM, LabEx BRAIN, and the Agence Nationale de la Recherche, grant numbers ANR-17-CE16-0002 to SHRO, and ANR-16-CE16-0001-0 to AP. MS was supported by a Takeda Science Foundation fellowship (Japan), and MA was supported by postdoctoral fellowships from RIKEN and JSPS (Japan). KM was supported by Scientific Research S (25221002) of JSPS and ICORP; ICORP-SORST of Japan Science and Technology Agency.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

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Keywords: astrocyte, inositol triphosphate (IP3) receptor, IP3R subtypes, calcium, GPCR, tripartite synapse, gliotransmission

Citation: Sherwood MW, Arizono M, Panatier A, Mikoshiba K and Oliet SHR (2021) Astrocytic IP3Rs: Beyond IP3R2. Front. Cell. Neurosci. 15:695817. doi: 10.3389/fncel.2021.695817

Received: 15 April 2021; Accepted: 30 June 2021;
Published: 30 July 2021.

Edited by:

Yu-Wei Wu, Academia Sinica, Taiwan

Reviewed by:

Dmitri A. Rusakov, University College London, United Kingdom
Vladimir Grubišiæ, Michigan State University, United States

Copyright © 2021 Sherwood, Arizono, Panatier, Mikoshiba and Oliet. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Mark W. Sherwood, MWSherwood@protonmail.com; Misa Arizono, arizono0202@gmail.com

These authors have contributed equally to this work and share first authorship

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