Neurons are highly specialised cells that need to relay information over long distances and integrate signals from thousands of synaptic inputs. The complexity of neuronal function is evident in the morphology of their plasma membrane (PM), by far the most intricate of all cell types. Yet, within the neuron lies an organelle whose architecture adds another level to this morphological sophistication — the endoplasmic reticulum (ER). Neuronal ER is abundant in the cell body and extends to distant axonal terminals and postsynaptic dendritic spines. It also adopts specialised structures like the spine apparatus in the postsynapse and the cisternal organelle in the axon initial segment. At membrane contact sites (MCSs) between the ER and the PM, the two membranes come in close proximity to create hubs of lipid exchange and Ca2+ signalling called ER-PM junctions. The development of electron and light microscopy techniques extended our knowledge on the physiological relevance of ER-PM MCSs. Equally important was the identification of ER and PM partners that interact in these junctions, most notably the STIM-ORAI and VAP-Kv2.1 pairs. The physiological functions of ER-PM junctions in neurons are being increasingly explored, but their molecular composition and the role in the dynamics of Ca2+ signalling are less clear. This review aims to outline the current state of research on the topic of neuronal ER-PM contacts. Specifically, we will summarise the involvement of different classes of Ca2+ channels in these junctions, discuss their role in neuronal development and neuropathology and propose directions for further research.

The endoplasmic reticulum (ER) is the biggest cellular organelle and plays critical functions such as protein and lipid synthesis. In neurons, the ER is present in the soma and extends to dendritic spines and axon terminals (Figure 1, [1]). Because of its intricate morphology and the crucial role as a Ca2+ store, it is capable of modulating neuronal function in all compartments. The ER can shape the Ca2+ homeostasis by generating Ca2+ signals via its own Ca2+ channels and pumps (inositol triphosphate receptors [IP3Rs], ryanodine receptors [RyRs], sarco-/ER Ca2+ ATPase [SERCA] and leak channels) or by modulating the function of plasma membrane (PM) Ca2+ channels. The latter is possible because of the presence of membrane contact sites (MCSs) between the ER and the PM, termed ER-PM junctions.

Overview of proteins that regulate Ca2+ signals in neuronal ER-PM junctions.

Figure 1.
Overview of proteins that regulate Ca2+ signals in neuronal ER-PM junctions.

The ER extends throughout the whole neuron, including the soma, dendrites and axons, and adopts specialised forms like the cisternal organelle and the spine apparatus. Notice that although ER-PM junctions are present in all neuronal compartments, the ER does not come in direct contact with the active zone (AZ) of neurotransmitter secretion or with the postsynaptic density (PSD) [1]. Letters denote the most important or newly identified ER-PM partners that are described in the main text. (A) Somatic plasma membrane Kv2.1 channels cluster with VAP proteins in the ER and recruit Cav1.2 and RyRs to ER-PM junctions to regulate excitation-transcription coupling [71,75,76]; (B and C) it has been suggested that VGCC-RyR and ORAI-IP3R pairs create two functionally independent ER Ca2+ pools [61]; (D) ORAI was implied to impact neuronal excitability [53–57]; (E) axonal ER in developing neurons was shown to adopt a ladder-like morphology, with STIM1 molecules colocalising with ORAI1 in structures termed ‘ER rungs’ [120]; (F) presynaptic STIMs were reported to play a role in neurotransmitter release via activation of ORAIs (by STIM2) [14] and by control of axonal ER Ca2+ stores (by STIM1) [15]; (G) VAP-Kv2.1 clusters are implicated in activity-dependent uptake of Ca2+ to axonal ER, loss of Kv2.1 impaired action-potential evoked Ca2+ influx into the presynapse and the release of neurotransmitter [16]; (H) STIM1 was shown to provide NMDAR-dependent feedback-inhibition of Cav1.2 channels to limit excessive Ca2+ influx during glutamatergic neurotransmission [44]; (I) neuronal insults impact the morphology of ER-PM junctions: treatment with high doses of extracellular NMDA, which mimics glutamate spillover, significantly decreased the extent of ER-PM junctions [83], while nerve injury increased it [165]; (J) there is evidence for a direct interaction of STIM proteins with NMDA and AMPA receptors, impacting their activity and trafficking [39–43]; (K) TRPCs are a diverse family of proteins that can act as store-operated channels [45,46]; (L) pannexin has recently been identified as another store-operated channel; its activation is coupled to NMDARs and controlled by STIM1 [89]. Red dots represent glutamate. Kv2.1, voltage-gated potassium channel 2.1; Cav1.2, 2.1, 2.2, voltage-gated Ca2+ channels 1.2, 2.1, 2.2; VAP, VAMP-associated protein; RyR, ryanodine receptor; JPH, junctophilin; SERCA, sarco-/endopolasmic reticulum Ca2+ ATPase; STIM, stromal interaction molecule; IP3R, inositol triphosphate receptor; NMDAR, NMDA receptor; AMPAR, AMPA receptor; TRPC, transient receptor potential channel; PANX, pannexin; AZ, active zone; PSD, postsynaptic density. Figure created with BioRender®.

Figure 1.
Overview of proteins that regulate Ca2+ signals in neuronal ER-PM junctions.

The ER extends throughout the whole neuron, including the soma, dendrites and axons, and adopts specialised forms like the cisternal organelle and the spine apparatus. Notice that although ER-PM junctions are present in all neuronal compartments, the ER does not come in direct contact with the active zone (AZ) of neurotransmitter secretion or with the postsynaptic density (PSD) [1]. Letters denote the most important or newly identified ER-PM partners that are described in the main text. (A) Somatic plasma membrane Kv2.1 channels cluster with VAP proteins in the ER and recruit Cav1.2 and RyRs to ER-PM junctions to regulate excitation-transcription coupling [71,75,76]; (B and C) it has been suggested that VGCC-RyR and ORAI-IP3R pairs create two functionally independent ER Ca2+ pools [61]; (D) ORAI was implied to impact neuronal excitability [53–57]; (E) axonal ER in developing neurons was shown to adopt a ladder-like morphology, with STIM1 molecules colocalising with ORAI1 in structures termed ‘ER rungs’ [120]; (F) presynaptic STIMs were reported to play a role in neurotransmitter release via activation of ORAIs (by STIM2) [14] and by control of axonal ER Ca2+ stores (by STIM1) [15]; (G) VAP-Kv2.1 clusters are implicated in activity-dependent uptake of Ca2+ to axonal ER, loss of Kv2.1 impaired action-potential evoked Ca2+ influx into the presynapse and the release of neurotransmitter [16]; (H) STIM1 was shown to provide NMDAR-dependent feedback-inhibition of Cav1.2 channels to limit excessive Ca2+ influx during glutamatergic neurotransmission [44]; (I) neuronal insults impact the morphology of ER-PM junctions: treatment with high doses of extracellular NMDA, which mimics glutamate spillover, significantly decreased the extent of ER-PM junctions [83], while nerve injury increased it [165]; (J) there is evidence for a direct interaction of STIM proteins with NMDA and AMPA receptors, impacting their activity and trafficking [39–43]; (K) TRPCs are a diverse family of proteins that can act as store-operated channels [45,46]; (L) pannexin has recently been identified as another store-operated channel; its activation is coupled to NMDARs and controlled by STIM1 [89]. Red dots represent glutamate. Kv2.1, voltage-gated potassium channel 2.1; Cav1.2, 2.1, 2.2, voltage-gated Ca2+ channels 1.2, 2.1, 2.2; VAP, VAMP-associated protein; RyR, ryanodine receptor; JPH, junctophilin; SERCA, sarco-/endopolasmic reticulum Ca2+ ATPase; STIM, stromal interaction molecule; IP3R, inositol triphosphate receptor; NMDAR, NMDA receptor; AMPAR, AMPA receptor; TRPC, transient receptor potential channel; PANX, pannexin; AZ, active zone; PSD, postsynaptic density. Figure created with BioRender®.

Close modal

ER-PM junctions are specialised contact sites that are defined as areas of close apposition of the two membranes (∼10 nm in neurons, but the distance can reach hundreds of nm in non-excitable cells [2]). They are highly abundant in neurons, covering ∼10% of the PM [3], compared with 1–2% in non-excitable cells [2,4,5]. Multiple ER and PM proteins have been shown to localise to neuronal ER-PM contacts, including junctophilins (JPHs), vesicle-associated membrane protein (VAMP)-associated proteins (VAPs) and stromal interaction molecules (STIMs) in the ER membrane and voltage-gated potassium channels 2.1 (Kv2.1) and ORAIs on the PM. The topic of MCSs has recently received considerable attention, in part due to advancements in methods that allow the examination of subcellular compartments at a nanometre scale [6–8]. These include cryo-electron tomography (cryo-ET), super-resolution light microscopy techniques, such as stimulated emission-depletion microscopy, structured-illumination microscopy, photoactivated localisation microscopy, total-internal reflection microscopy and others, and assays such as proximity ligation assay (PLA). These tools significantly expanded our understanding of neuronal ER-PM contacts. It is now well established that processes occurring in these junctions play critical roles in phenomena like neuronal excitability and plasticity (reviewed in [9]).

ER-PM junctions are most prominent on cell bodies, with fewer contacts present in dendritic and axonal branches [1]. Nonetheless, the ER has been shown to play direct roles in synaptic function. Already in the early 2000s, intracellular Ca2+ stores were reported to modulate neurotransmitter release [10–13]. These studies provided functional evidence for the role of ER in neurotransmission, but did not address the question whether ER impacts this process via direct contact sites with the PM. Because ER-PM junctions are excluded from active zones of transmitter secretion, it seems unlikely that these MCSs modulate neurotransmitter release by direct interaction with the vesicle fusion machinery (Figure 1, [1]). Nevertheless, research from the last decade has provided evidence for many presynaptic phenotypes for ER junctional proteins [14–16]. This progress in our understanding of ER actions in MCSs has been possible largely due to the discovery of molecular players responsible for store-operated calcium entry (SOCE) [17–22].

SOCE, earlier termed capacitative-calcium entry, is a ubiquitous mechanism that is of crucial importance in non-excitable cells, where it serves as the main pathway for Ca2+ influx from the extracellular space [23]. Because neurons are equipped with a variety of Ca2+ permeable channels, most notably N-methyl-d-aspartic acid receptors (NMDARs) and voltage-gated Ca2+ channels (VGCCs), there has been controversy regarding the physiological relevance of neuronal SOCE [24] and it is still unclear to which cellular processes it contributes to. Is it important for synaptic plasticity, homeostatic plasticity or excitability? In general, accumulating evidence suggests the role of SOCE and the proteins involved in this mechanism in neuronal function (see [25–31] for reviews). The molecules responsible for SOCE include STIMs, the Ca2+ sensors within the ER, and Ca2+ channels on the PM, most notably ORAI proteins. The STIM-ORAI system is a prime example of ER-PM signalling. Upon a drop in ER Ca2+ concentration, STIM proteins oligomerise and accumulate in ER-PM junctions, where they activate ORAI channels [32]. The resulting Ca2+ influx serves to replenish the ER stores and triggers intracellular signalling pathways. Both mammalian STIM isoforms, STIM1 and STIM2, have been suggested to affect neurotransmitter release, either by directly impacting presynaptic cytoplasmic [Ca2+] [14] or via control of axonal ER [Ca2+] [15]. The function of the presynapse was also shown to depend on a different ER-PM protein pair, namely clusters of PM voltage-gated potassium channels (Kv2.1) and ER-resident VAMP-associated proteins (VAPs) [16,33,34]. Clusters of Kv2.1 were shown to be indispensable for activity-dependent refilling of presynaptic ER Ca2+, with direct implications on vesicle fusion [16]. Despite these findings, our understanding of presynaptic ER actions is far from complete.

The ER also extends to postsynaptic sites, where it is estimated to be present in ∼40% of dendritic spines [35]. Here, the ER adopts a specialised form called the spine apparatus, which is suggested to play a role in synaptic plasticity [36]. Similarly as for the presynaptic side, ER-PM contacts are not expected to impact neurotransmission by direct interaction with the postsynaptic density (PSD), because they are localised away from the PSD (Figure 1, [1]). Nevertheless, different research groups reported a variety of ER-PM related postsynaptic effects, mainly involving the ER-resident STIM proteins. STIM1 and STIM2 have been suggested to differentially regulate dendritic Ca2+ signals [37], while lack of STIM2 prevented the maturation of mushroom spines [38]. STIM proteins have also been shown to impact the activity and trafficking of ionotropic glutamate receptors [39–43] and inhibit dendritic voltage-gated Cav1.2 channels [44].

This review aims to summarise the most recent advancements in our understanding of neuronal ER-PM junctions with the focus on Ca2+ channels, particularly store-operated channels (SOCs), and their role in neuronal physiology, development and neurodegeneration.

To date, two families of proteins have been established to function as SOCs: ORAI proteins and transient-receptor potential channels (TRPCs). Because the characterisation of neuronal TRPCs is beyond the scope of this review, the Reader is referred to other works on this topic [45,46], while this review will focus on the role of neuronal ORAIs. ORAI proteins (ORAI1, 2 and 3 isoforms in mammals) form hexameric Ca2+-release activated channels, whose hallmarks are a high selectivity to Ca2+ ions and small conductance [47]. To the best of our knowledge, there have been no reports of ORAI activation independent of ER-resident STIM proteins in neurons (although in non-excitable cells, ORAI1 and ORAI3 build store-independent arachidonate-regulated Ca2+ channels [ARC channels] that are activated by PM-resident STIM1 [48,49]). Therefore, it is valid to assume that the only sites of neuronal ORAI-mediated Ca2+ entry are ER-PM junctions. Complexes of endogenous neuronal STIM1 and STIM2 with ORAI1 were first shown by the Kuźnicki group by PLA [50]. Here, positive PLA signals were found mostly on cell bodies and only occasionally in neuronal processes. In later studies, ORAI was reported to be present in dendritic spines of cultured rat hippocampal neurons, where its role in long-term potentiation (LTP) and spine formation was proposed [51,52]. The same group reported that Ca2+ influx via ORAI1 underlies the impact of ER Ca2+ stores on neuronal excitability [53]. Evidence for the role of ORAI in excitability also comes from studies on animal models: rodents, in the context of epilepsy and nociception [54–56], and the fruit fly, where Ca2+ influx through ORAIs impacted the expression of excitability-related genes [57].

Recently, a link between ORAI and NMDAR was identified: knockout of ORAI1 significantly diminished NMDAR-dependent postsynaptic Ca2+ signals, impacting LTP of hippocampal CA1 neurons [58]. Whether NMDARs themselves are present in ORAI-containing ER-PM junctions was not investigated in this study. The aforementioned work sparked an intriguing controversy, whereby an independent research group highlighted the importance of ORAI2, but not ORAI1, in shaping Ca2+ signals in CA1 hippocampal neurons [59,60]. Of note, the latter group suggested the existence of two functionally distinct ER Ca2+ pools in these cells, one dependent on the ORAI2-IP3R pair and the other on the VGCC-RyR dyad [61,62]. This concept supports the idea that neurons possess different classes of ER-PM junctions that independently control distinct ER Ca2+ pools.

The coupling between the IP3R and SOCE was first established by the use of HEK cells as a model [63]. Here, it was shown that activation of IP3Rs via IP3 leads to depletion of ER Ca2+ and induction of a store-operated current via TRP channels. More recently, an intricate relationship between IP3Rs and all five STIM and ORAI isoforms was described, with implications on spontaneous cytosolic Ca2+ oscillations in HEK cells [64]. Evidence for the role of neuronal IP3Rs in ER-PM junctions comes from the Hasan laboratory, who showed that in Drosophila neurons, migration of IP3Rs to ER-PM contact sites promotes STIM-ORAI coupling and consequently SOCE [65]. Interestingly, recent data from this group suggest that IP3Rs impact SOCE independently of their canonical function as Ca2+ channels [66].

The studies mentioned so far used the classical Ca2+ — addback protocol or induction of synaptic activity to study the role of ORAIs in neurons. Of note, the presence of store-operated Ca2+ signals was also reported in dendritic spines in the absence of synaptic activity, suggesting that ORAI channels are stochastically active in the postsynapse [67]. Interestingly, ORAI-dependent ER store replenishment was shown to occur more prominently in the spine head, while RyR-dependent Ca2+-induced Ca2+ release (CICR) in the spine base. The authors propose an elegant mechanism, whereby spatial isolation of ORAI-SERCA pair and RyR clusters conveys a functional separation of the two ER-dependent Ca2+ signalling modes: Ca2+ replenishment (ER as a Ca2+ sink, ORAI-SERCA) and Ca2+ release (ER as a Ca2+ source, RyR). Future studies are expected to shed more light on the involvement of ORAI in synaptic function in both the pre- and the postsynapse.

Voltage-gated Ca2+ channels

VGCCs play a pivotal role in neuronal signalling and their function is critically determined by subcellular localisation. For instance, clustering of VGCCs in the presynaptic active zone is essential for their well-studied role in neurotransmitter release [68,69]. The localisation of VGCCs in relation to the ER had been an unexplored field until recently, when membrane proteins Kv2.1 and JPHs were shown to facilitate VGCC clustering at ER-PM junctions (reviewed in [70]). In hippocampal neurons, Kv2.1 promotes the clustering of somatic Cav1.2, altering their kinetics and enhancing their activity [71]. Several studies have shown a connection between VGCC, Ca2+ sensitive potassium channels and RyRs [72,73]. Sahu et al. identified a complex of RyRs, Cav1 and KCa3.1, tethered by ER-resident JPHs, which controlled excitability of hippocampal neurons. This work was expanded by studies of Perni and Beam, who used a heterologous expression system to show that JPHs promote RyR localisation in ER-PM contacts in an isoform-specific manner, and that they modulate the function of VGCCs [74]. Functionally, RyRs that are present in ER-PM junctions organised by the Kv2.1 — VAP pair were shown to control excitation-transcription coupling in rat hippocampal neurons [71,75,76]. For a thorough description of the role of RyR and VGCC coupling in ER-PM junctions, the Reader is referred to a recent excellent review [70].

In contrast with the stimulatory effect of Kv2.1 on intracellular Ca2+ signals, STIM proteins were shown to act as inhibitors of Cav1.2 [77,78]. In [44], the researchers proposed an elegant mechanism by which glutamatergic transmission depolarised the postsynaptic membrane, triggering the opening of Cav1.2 and leading to CICR, subsequently causing activation of STIM1 molecules that feedback-inhibited Cav1.2 channels. While STIMs, JPHs and Kv2.1 have all been shown to impact the distribution and activity of VGCCs, it is unlikely that they populate the same ER-PM junctions at a given time point. VAP, the ER partner of Kv2.1, localises specifically to Kv2.1 junctions, but not to those mediated by JPHs [34]. Moreover, glutamate has been shown to dissolve clusters of Kv2.1 [79], but induction of CICR causes clustering of STIM molecules [44].

Recently, compartmentalisation of ER voltage signals has been reported [80]. With the use of a novel genetically-coded fluorescent voltage indicator targeted to the ER, ASAP3ER, the authors demonstrated that stimulation of both RyR and IP3R results in a voltage change across the ER in the range of tens of millivolts. Importantly, these signals were spatially restricted by the activity of PM BK channels. This adds another factor to the complexity of ER-PM communication and opens the possibility that ER voltage signals directly impact the function of VGCCs that are localised to ER-PM junctions, e.g. to modulate neuronal excitability.

Ligand gated Ca2+ channels

Research from the last two decades provided evidence that the two most widely studied ionotropic glutamate receptors, NMDARs and AMPARs, participate in signalling in ER-PM junctions. Glutamate stimulation was shown to dissolve VAP- and Kv2.1-dependent ER-PM junctions via Ca2+ — dependent dephosphorylation [79,81,82]. A decrease in the extent of ER-PM contacts upon NMDAR stimulation was later confirmed with electron-microscopy studies [83]. Similarly to Kv2.1 channels, pro-neuregulin-2 (ProNRG2), an epidermal-growth factor-like ligand of ErbB3/4 receptor tyrosine kinases, also acts as an activity-dependent organiser of ER-PM junctions, by binding to VAPs on the ER membrane [84,85]. Here, the authors showed that NMDARs activation led to dephosphorylation of ProNRG2, disrupting its interaction with VAPs and causing dissociation from ER-PM junctions. Additionally, NMDAR-induced Ca2+ influx alters the lipid composition of ER-PM junctions by facilitating the recruitment of the lipid transporter TMEM24 to these contacts [86]. Whereas the aforementioned publications highlight the impact of NMDAR activity on the integrity and composition of the ER-PM contacts, it is important to acknowledge the reciprocal effect on NMDARs. While the recruitment and removal of NMDARs from the PM depend on Ca2+ flux and their phosphorylation status, the lipid composition of ER-PM junctions also influences their retention [87,88]. Weesner et al. [87] proposed that GM1-ganglioside promotes the retention of active, phosphorylated NMDARs in ER-PM junctions, which in turn activate Ca2+-mediated ERK signalling and facilitate dendritic spine formation.

The putative localisation of NMDARs at ER-PM junctions positions them strategically for potential interaction with STIM proteins. Using immunoprecipitation, Gruszczynska-Biegała et al. [40] demonstrated that STIM1 and STIM2 interacted with the NMDAR subunits GluN2A/B in rat cortical neurons. Activated STIMs were proposed to negatively regulate the Ca2+ influx via NMDARs. The same group demonstrated that STIM2 promoted internalisation GluN2A/B subunits after their overactivation [41]. A recent study provided evidence that pannexins, proteins that build nonselective PM channels, could be activated in an NMDAR- and STIM1-dependent manner [89]. This work identified pannexins as another SOC, with potential implications for the role of ER-PM junctions in coordinating neuronal communication between chemical and electrical synapse [90,91].

Although NMDARs and VGCCs are regarded as the main contributors to neuronal Ca2+ signals, a subset of AMPA receptors, particularly GluA2 lacking AMPARs, are permeable to Ca2+. Accumulating data suggest vital roles for Ca2+-permeable AMPARs in physiology and disease [92–94]. Importantly, AMPARs were shown to colocalise with STIM proteins and to directly contribute to Ca2+ influx via SOCE [39]. The notion that AMPARs shape Ca2+ signals in ER-PM junctions is strengthened by a recent finding that extended synaptotagmins (E-Syts), a family of ER junctional proteins, play a role in LTP-induced increase in surface expression of AMPARs [95]. In earlier work [42], STIM2 was shown to promote phosphorylation of GluA1 subunits, likely in extra-synaptic ER-PM junctions. Knockout of STIM2 resulted in impaired LTP and dendritic spine morphology, highlighting the importance of ER-PM Ca2+ signalling in synaptic plasticity [43].

ER-PM calcium signalling in neuronal development

One of the main challenges that neurons face during development is providing the substrates for the rapidly growing axon [96]. The ER, with its capacity of lipid synthesis and transport, provides a platform to supply the PM with lipids during growth [97]. Indeed, many lipid transfer proteins bind to VAPs, ER-PM membrane tethers that are crucial for neuronal physiology [98,99]. A recent study identified the presence of VAP oligomers in neurites of young (7 DIV), but not in more mature (14 DIV) dendrites of mouse hippocampal neurons [100]. Interestingly, the abundance of Kv2.1 clusters, which colocalise with VAPs in neuronal ER-PM junctions [33,34], increases with in vitro ageing [101]. Kv2.1 and VAPs were recently shown to colocalise with a lipid transporter TMEM24/C2CD2L, which is also found in neuronal ER-PM junctions and whose expression increases with age [86]. Both Kv2.1 and TMEM24 clusters depend on Ca2+, in that the influx of Ca2+ via NMDARs alters the phosphorylation state of the two proteins, leading to dissolution of Kv2.1 and TMEM24 clusters [79,86]. These studies suggest that ER-PM MCS are remodelled during neuronal development in Ca2+ — dependent processes.

A recent work demonstrated that STIM1 is enriched in the spine apparatus [102], an ER structure that is predominantly found in mature spines [103]. Interestingly, lack of STIM2, but not STIM1, was reported to impair the formation of mushroom spines in mouse hippocampal neuronal culture, with implications in the pathology of Alzheimer's disease (AD) [38,104]. Kushnireva et al. [37] suggested that STIM1 and STIM2 play differential roles in mouse hippocampal dendritic spines, with STIM1 being expressed most prominently in developing spines, while STIM2 localising mostly to mature ones. In this study, it was also observed that STIM puncta were mobile along the dendrite and their movement correlated with Ca2+ sparks, suggesting occasional visits of STIM molecules to ER-PM junctions populated by SOCs. The notion that Ca2+ influx through SOCs can play a role in neuronal development is strengthened by an earlier work, where the authors reported a higher amplitude of SOCE in 4–8 DIV neurons, compared with 15 DIV [105]. In the same study, older neurons were shown to have a higher concentration of ER Ca2+.

Age-related changes in ER Ca2+ have been demonstrated by multiple research groups and support the so-called Ca2+-hypothesis of ageing [106–109], but the potential impact of ER stores on neuronal development is less well characterised. ER Ca2+ has been shown to contribute to dendritic NMDA-dependent Ca2+ signals in young neurons [110], but this effect appeared to be less prominent, or even negligible, in mature cells [111–114]. More recently, CICR that occurred exclusively in developing dendritic spines was shown to prolong NMDAR-dependent dendritic Ca2+ signals and drive local cooperative plasticity along the dendrites of mouse CA1 pyramidal neurons [115]. The potential contribution of ORAI channels was not discussed in this work. Notably, studies from a different research group suggest that deletion of ORAI1 significantly affects LTP, but has no impact on spine density in mouse CA1 pyramidal neurons [58]. Further investigations are needed to clarify what is the role of ORAI in synaptic development and homeostasis.

Recent data has provided evidence that cross-talk between ER-resident proteins and microtubules is crucial for the establishment of neuronal polarity [116]. In rat DRG neurons, STIM1 and ORAI1 were shown to preferentially localise towards neuronal growth cone and knockdown of STIM1 interfered with growth cone turning in response to physiological cues [117]. STIM1 knockdown also abolished brain-derived neurotrophic factor — induced SOCE in growth cones, suggesting that STIM-ORAI signalling is important for axonal development. The role of SOCE in neurite outgrowth was also confirmed in Xenopus spinal cord neuron growth cones [118] and in differentiated rat PC-12 cells [119]. Whether ER-PM MCSs undergo dynamic changes during development of axonal ER remains an outstanding question. Yet, recent data provide evidence that the morphology of mature axonal ER significantly differs from that of a developing neuron [120]. In 3–7 DIV, but not 18–21 DIV mouse hippocampal neurons, the ER adopted a characteristic form that the authors termed the ‘ER ladder’, with ER ‘rails’ running along microtubule bundles, and ER ‘rungs’ arranged perpendicularly. Of note, depletion of ER Ca2+ caused STIM1 to accumulate in ER ‘rungs’, in puncta that were co-localised with ORAI1. This highlights the notion that Ca2+ channel signalling in neuronal ER-PM MCSs plays a role in the maturation of axonal ER. What exactly is the function of ORAI-dependent Ca2+ signals in this context remains to be discovered.

ER-PM calcium signalling in neurodegeneration

A number of studies have linked neurodegenerative processes with the altered functions of the ER. These include disturbances in the activity of ER Ca2+ channels [106,121–125] and changes in the structure of the ER (reviewed in [126]). Despite the high abundance of ER-PM contacts in neurons, surprisingly little is known about the involvement of these MCSs in neurodegenerative processes. Indirect evidence comes from the links between mutations in genes coding junctional proteins and neurological disorders. A repeat expansion in JPH3 is implicated in Huntington's disease (HD)-like 2 [127], while nucleotide variants of JPH1 were linked to a Charcot–Marie–Tooth disease [128,129]. Loss-of-function mutations in VAP-B cause a rare form of amyotrophic lateral sclerosis, ALS8 [130,131]. VAP-A and its interaction with Kv2.1 have been implicated in the pathology of ischaemic injury [132], whereas VAP-B is involved in the pathology of Parkinson's disease and multiple system atrophy [133–135]. Because both VAPs and JPHs have been shown to cluster in the proximity of ER and PM Ca2+ channels, it is plausible to assume that altered Ca2+ homeostasis in ER-PM junctions plays a role in these neurodegenerative phenotypes.

In spite of the paucity of studies that directly address the subject of ER-PM contact sites in the context of neuropathology, there is now ample evidence for the involvement of SOCE signalling in neurodegenerative diseases (reviewed in [28,126]). Alterations in expression of STIM2 were reported in lymphocytes from familial AD (fAD) patients [136] and later confirmed in presenilin-knock-in hippocampal neurons, a model of fAD [38]. Moreover, a down-regulation of STIM2 expression was found in lysates of cortical samples from sporadic AD patients, and the level of STIM2 positively correlated with the patients' score in mini-mental status test [38]. Moreover, a complex of ORAI2, TRPC6 and STIM2 was identified as a potential target to combat AD-related memory loss [137,138]. Later studies suggested that also STIM1 plays a role in the disturbed neuronal SOCE in a model of fAD [139]. A link between SOCE and fAD has recently been confirmed in a study which showed that signalling via SOCs and mGluRs contributes to the dysregulation of Ca2+ homeostasis seen in mouse fAD models [140]. Moreover, multiple disturbances in the function of ER Ca2+ release channels, IP3Rs and RyRs, have been linked to AD (reviewed in [141–144]).

Alterations in ER-PM signalling have also been reported to underlie the pathology of (HD, reviewed in [145]). In early 2000s, mutated huntingin (mHTT) and huntingtin-associated protein 1 were shown to sensitise IP3R to activation by IP3 [122,123]. Subsequently, increased Ca2+ influx via SOCE was reported in medium spiny neurons isolated from YAC128 mice, a model of HD [146–148], as well as in patient-derived induced pluripotent stem cells [149,150]. Excessive SOCE caused synaptic loss characteristic of HD [151] and could be prevented by knockdown of ORAI1/2 and TRPC1/6 [152]. These works provided first indirect evidence for the involvement of mHTT in ER-PM Ca2+ signalling. Notably, recent data obtained from skeletal muscle suggest that mHTT may directly act at ER-PM junctions via an interaction with JPH1 [153]. Whether such mechanism takes place also in neurons remains an open question.

The activity of SOCs has also been implicated in the pathology of epilepsy. Increased levels of STIM1 and STIM2 were found in hippocampi of temporal lobe epilepsy patients and inhibition of SOCE normalised the activity of chronically epileptic hippocampal slices [154]. Hippocampal preparations isolated from mice with neuronal overexpression of ORAI1 showed changes in electrical activity upon stimulation with pro-epileptic drugs [54]. Interestingly, aged female mice used in this study developed spontaneous seizures, suggesting sex-specific differences in SOCE signalling. Subsequent RNAseq analysis of hippocampi isolated from these mice showed changes in the expression of genes that are implicated in rare epilepsy-associated disorders [155]. Soon thereafter, ORAI1 was shown to control the excitability of mouse hippocampal GABAergic neurons, whereby loss of ORAI1 sensitised the animals to chemiconvulsant-induced epileptic seizures [56]. Altogether, these studies provide solid evidence for the role of ORAI1-mediated ER-PM signalling in neuronal excitability in the context of epilepsy.

ER-PM signalling is implicated not only in chronic, but also in acute neuropathology. Berna-Erro et al. established STIM2 as a basal regulator of neuronal Ca2+ level and suggested the role of STIM2 in neuronal death during focal-cerebral ischaemia [156]. A later work from this group identified ORAI2 as the STIM2-activated channel that provided excessive Ca2+ in ischaemic conditions [157]. Interestingly, two other research groups proposed that it is the STIM1-ORAI1 mediated SOCE that contributes to ischaemia-related neuronal loss [158,159]. This discrepancy in STIM-ORAI isoforms could lie in the different experimental models used by the researchers (mouse in the former, and rat in the two latter groups).

Interestingly, blockade of SOCE prevented autophagic processes triggered by ischaemia-modelling treatments [160]. Autophagy of the ER, termed ER-phagy, is an exciting chapter in the field of neurodegeneration [161]. Of note, loss of autophagy related 5 protein (ATG5) was shown to trigger accumulation of tubular ER in the axon, resulting in higher density of RyRs and consequently facilitation of neurotransmission [162]. Autophagic processes are suggested to play a role in neuronal injury, although their exact contribution to trauma-related pathophysiology of the neuron is poorly understood [163,164]. Notably, the extent of ER-PM contacts was reported to significantly increase following injury [165], and there is substantial evidence suggesting the involvement of ER-PM communication in the formation of autophagosome [9,166]. The yet undiscovered link between autophagic processes and Ca2+ signalling at ER-PM junctions is an intriguing avenue of future studies.

Perspectives
  • ER-PM communication is increasingly recognised as an important factor that shapes neuronal physiology. Recent advancements in super-resolution microscopy and cryo-ET allowed us to broaden our understanding how Ca2+ signals generated at ER-PM junctions impact neuronal function.

  • Some of the outstanding questions include: are there different classes of ER-PM junctions that are regulated by spatially and functionally separated ER Ca2+ pools? Will the family of SOC channels expand beyond ORAI and TRPC proteins and include e.g. pannexins? What is the role of ER-PM junctions in ER-phagy? How stable are these junctions? What is the turnover of their molecular composition?

  • Recent studies suggest that dynamic changes in ER-PM junctions occur during development and neurodegenerative processes. Deciphering their nature is expected to translate into clinically relevant therapeutic approaches.

The authors declare that there are no competing interests associated with the manuscript.

This work has been funded by DFG grant, project FOR 2419 (P4), to M.H., and Leibniz project SynERCa to M.H.

F.M. and M.H. conceptualised the work. F.M. and A.C. wrote the paper. F.M. prepared the figure. M.H. acquired funding. All authors have read and approved on the final version of the paper.

AD

Alzheimer's disease

CICR

Ca2+-induced Ca2+ release

cryo-ET

cryo-electron tomography

ER

endoplasmic reticulum

fAD

familial AD

HD

Huntington's disease

JPH

junctophilin

LTP

long-term potentiation

MCS

membrane contact site

mHTT

mutated huntingin

NMDAR

N-methyl-d-aspartic acid receptor

PLA

proximity ligation assay

PM

plasma membrane

PSD

postsynaptic density

SOCE

store-operated calcium entry

SOC

store-operated channel

STIM

stromal interaction molecule

TRPC

transient-receptor potential channel

VAMP

vesicle-associated membrane protein

VGCC

voltage-gated Ca2+ channel

1
Wu
,
Y.
,
Whiteus
,
W.
,
Shan Xu
,
C.
,
Hayworth
,
K.J.
,
Weinberg
,
R.J.
,
Hess
,
H.F.
et al (
2017
)
Contacts between the endoplasmic reticulum and other membranes in neurons
.
Proc. Natl Acad. Sci. U.S.A.
114
,
E4859
E4867
2
Orci
,
L.
,
Ravazolla
,
M.
,
Le Coadic
,
M.
,
Shen
,
W.W.
,
Demaurex
,
N.
and
Cosson
,
P.
(
2009
)
From the cover: STIM1-induced precortical and cortical subdomains of the endoplasmic reticulum
.
Proc. Natl Acad. Sci. U.S.A.
106
,
19358
19362
3
Chen
,
Y.
,
Quintanilla
,
C.G.
and
Liou
,
J.
(
2019
)
Recent insights into mammalian ER-PM junctions
.
Curr. Opin. Cell Biol.
57
,
99
105
4
Giordano
,
F.
,
Saheki
,
Y.
,
Idevall-Hagren
,
O.
,
Colombo
,
S.F.
,
Pirruccello
,
M.
,
Milosevic
,
I.
et al (
2013
)
PI(4,5)P(2)-dependent and Ca2+-regulated ER-PM interactions mediated by the extended synaptotagmins
.
Cell
153
,
1494
1509
5
Perni
,
S.
,
Dynes
,
J.L.
,
Yeromin
,
A.V.
,
Cahalan
,
M.D.
and
Franzini-Armstrong
,
A.
(
2015
)
Nanoscale patterning of STIM1 and Orai1 during store-operated Ca2+ entry
.
Proc. Natl Acad. Sci. U.S.A.
112
,
E5533
E5542
6
Chang
,
C.
,
Chen
,
Y.
and
Liou
,
J.
(
2017
)
ER-plasma membrane junctions: why and how do we study them?
Biochim. Biophys. Acta Mol. Cell Res.
1864
,
1494
1506
7
Collado
,
J.
and
Fernández-Busnadieg
,
R.
(
2017
)
Deciphering the molecular architecture of membrane contact sites by cryo-electron tomography
.
Biochim. Biophys. Acta Mol. Cell Res.
1864
,
1507
1512
8
Nieto-Garai
,
J.A.
,
Olazar-Intxausti
,
J.
,
Anso
,
I.
,
Lorizate
,
M.
,
Terrones
,
O.
and
Contreras
,
F.X.
(
2022
)
Super-resolution microscopy to study interorganelle contact sites
.
Int. J. Mol. Sci.
23
,
15354
9
Hewlett
,
B.
,
Singh
,
N.P.
,
Vannier
,
C.
and
Galli
,
T.
(
2021
)
ER-PM contact sites - SNARING actors in emerging functions
.
Front. Cell Dev. Biol.
9
,
635518
10
Emptage
,
N.J.
,
Reid
,
C.A.
and
Fine
,
A.
(
2001
)
Calcium stores in hippocampal synaptic boutons mediate short-term plasticity, store-operated Ca2+ entry, and spontaneous transmitter release
.
Neuron
29
,
197
208
11
Savić
,
N.
and
Sciancalepore
,
M.
(
1998
)
Intracellular calcium stores modulate miniature GABA-mediated synaptic currents in neonatal rat hippocampal neurons
.
Eur. J. Neurosci.
10
,
3379
3386
12
Bardo
,
S.
,
Robertson
,
B.
and
Stephens
,
G.J.
(
2002
)
Presynaptic internal Ca2+ stores contribute to inhibitory neurotransmitter release onto mouse cerebellar Purkinje cells
.
Br. J. Pharmacol.
137
,
529
537
13
Galante
,
M.
and
Marty
,
A.
(
2003
)
Presynaptic ryanodine-sensitive calcium stores contribute to evoked neurotransmitter release at the basket cell–Purkinje cell synapse
.
J. Neurosci.
23
,
11229
11234
14
Chanaday
,
N.L.
,
Nosyreva
,
E.
,
Shin
,
O.
,
Zhang
,
H.
,
Aklan
,
I.
,
Atasoy
,
D.
et al (
2021
)
Presynaptic store-operated Ca2+ entry drives excitatory spontaneous neurotransmission and augments endoplasmic reticulum stress
.
Neuron
109
,
1314
1332
15
de Juan-Sanz
,
J.
,
Holt
,
G.
,
Schreiter
,
E.
,
de Juan
,
F.
,
Kim
,
D.S.
and
Ryan
,
T.A.
(
2017
)
Axonal endoplasmic reticulum Ca2+ content controls release probability in CNS nerve terminals
.
Neuron
93
,
867
881
16
Panzera
,
L.C.
,
Johnson
,
B.
,
Quinn
,
J.A.
,
Cho
,
I.H.
,
Tamkun
,
M.M.
and
Hoppa
,
M.B.
(
2022
)
Activity-dependent endoplasmic reticulum Ca2+ uptake depends on Kv2.1-mediated endoplasmic reticulum/plasma membrane junctions to promote synaptic transmission
.
Proc. Natl Acad. Sci. U.S.A.
119
,
e2117135119
17
Roos
,
J.
,
DiGregorio
,
P.J.
,
Yeromin
,
A.V.
,
Ohlsen
,
K.
,
Lioudyno
,
M.
,
Zhang
,
S.
et al (
2005
)
STIM1, an essential and conserved component of store-operated Ca2+ channel function
.
J. Cell Biol.
169
,
435
445
18
Zhang
,
S.L.
,
Yu
,
Y.
,
Roos
,
J.
,
Kozak
,
A.
,
Deerinck
,
T.J.
,
Ellisman
,
M.H.
et al (
2005
)
STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane
.
Nature
437
,
902
905
19
Liou
,
J.
,
Kim
,
M.L.
,
Heo
,
W.D.
,
Jones
,
J.T.
,
Myers
,
J.W.
,
Ferell
,
J.E.
et al (
2005
)
STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx
.
Curr. Biol.
15
,
1235
1241
20
Feske
,
S.
,
Gwack
,
Y.
,
Prakriya
,
M.
,
Srikanth
,
S.
,
Puppel
,
S.-H.
,
Tanasa
,
B.
et al (
2006
)
A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function
.
Nature
441
,
179
185
21
Zhang
,
S.L.
,
Yeromin
,
A.V.
,
Zhang
,
X.
,
Yu
,
H.-F.
,
Safrina
,
Y.
,
Penna
,
O.
(
2006
)
Genome-wide RNAi screen of Ca(2+) influx identifies genes that regulate Ca2+ release-activated Ca2+ channel activity
.
Proc. Natl Acad. Sci. U.S.A.
103
,
9357
9362
22
Vig
,
M.
,
Peinelt
,
C.
,
Beck
,
A.
,
Koomoa
,
D.L.
,
Rabah
,
D.
,
Koblan-Huberson
,
M.
et al (
2006
)
CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry
.
Science
312
,
1220
1223
23
Rosado
,
J.A.
(
2016
)
Calcium entry pathways in non-excitable cells. Preface
.
Adv. Exp. Med. Biol.
898
,
vii
viii
ISBN-10: 3319269720; ISBN-13: 978-3319269726
24
Lu
,
B.
and
Fivaz
,
M.
(
2016
)
Neuronal SOCE: myth or reality?
Trends Cell Biol.
26
,
890
893
25
Bouron
,
A.
(
2023
)
Neuronal store-operated calcium channels
.
Mol. Neurobiol.
60
,
4517
4546
26
Courjaret
,
R.
,
Prakriya
,
M.
and
Machaca
,
K.
(
2023
)
SOCE as a regulator of neuronal activity
.
J. Physiol.
602
,
1449
1462
27
Zhang
,
I.
and
Hu
,
H.
(
2020
)
Store-operated calcium channels in physiological and pathological states of the nervous system
.
Front. Cell. Neurosci.
14
,
600758
28
Wegierski
,
T.
and
Kuznicki
,
J.
(
2018
)
Neuronal calcium signaling via store-operated channels in health and disease
.
Cell Calcium
74
,
102
111
29
Majewski
,
L.
and
Kuznicki
,
J.
(
2015
)
SOCE in neurons: signaling or just refilling?
Biochim. Biophys. Acta
1853
,
1940
1952
30
Moccia
,
F.
,
Zuccolo
,
E.
,
Soda
,
T.
,
Tanzi
,
F.
,
Guerra
,
G.
,
Mapelli
,
L.
et al (
2015
)
Stim and Orai proteins in neuronal Ca2+ signaling and excitability
.
Front. Cell. Neurosci.
9
,
153
31
Kraft
,
R.
(
2015
)
STIM and ORAI proteins in the nervous system
.
Channels (Austin)
9
,
245
252
32
Lopez
,
J.J.
,
Jardin
,
I.
,
Albarrán
,
L.
,
Sanchez-Collado
,
J.
,
Cantonero
,
C.
,
Salido
,
G.M.
et al (
2020
)
Molecular basis and regulation of store-operated calcium entry
.
Adv. Exp. Med. Biol.
1131
,
445
469
33
Kirmiz
,
M.
,
Vierra
,
N.C.
,
Palacio
,
S.
and
Trimmer
,
J.S.
(
2018
)
Identification of VAPA and VAPB as Kv2 channel-interacting proteins defining endoplasmic reticulum-plasma membrane junctions in mammalian brain neurons
.
J. Neurosci.
38
,
7562
7584
34
Johnson
,
B.
,
Leek
,
A.N.
,
Solé
,
L.
,
Maverick
,
E.E.
,
Levine
,
T.P. and
Tamkun
,
M.M.
(
2018
)
Kv2 potassium channels form endoplasmic reticulum/plasma membrane junctions via interaction with VAPA and VAPB
.
Proc. Natl Acad. Sci. U.S.A.
115
,
7562
7584
35
Perez-Alvarez
,
A.
,
Yin
,
S.
,
Schulze
,
C.
,
Hammer
,
J.A.
,
Wagner
,
W.
and
Oertner
,
T.G.
(
2020
)
Endoplasmic reticulum visits highly active spines and prevents runaway potentiation of synapses
.
Nat. Commun.
11
,
5083
36
Konietzny
,
A.
,
Wegmann
,
S.
and
Mikhaylova
,
M.
(
2023
)
The endoplasmic reticulum puts a new spin on synaptic tagging
.
Trends Neurosci.
46
,
32
44
37
Kushnireva
,
L.
,
Korkotian
,
E.
and
Segal
,
M.
(
2021
)
Calcium sensors STIM1 and STIM2 regulate different calcium functions in cultured hippocampal neurons
.
Front. Synaptic Neurosci.
12
,
573714
38
Sun
,
S.
,
Zhang
,
H.
,
Popugayeva
,
E.
,
Xu
,
N.-J.
,
Feske
,
S.
,
White
,
C.L.
et al (
2014
)
Reduced synaptic STIM2 expression and impaired store-operated calcium entry cause destabilization of mature spines in mutant presenilin mice
.
Neuron
82
,
79
93
39
Gruszczynska-Biegala
,
J.
,
Sladowska
,
M.
and
Kuznicki
,
J.
(
2016
)
AMPA receptors are involved in store-operated calcium entry and interact with STIM proteins in rat primary cortical neurons
.
Front. Cell. Neurosci.
10
,
251
40
Gruszczynska-Biegala
,
J.
,
Strucinska
,
K.
,
Maciag
,
F.
,
Majewski
,
L.
,
Sladowska
,
M.
and
Kuznicki
,
J.
(
2020
)
STIM protein-NMDA2 receptor interaction decreases NMDA-dependent calcium levels in cortical neurons
.
Cells
9
,
160
41
Serwach
,
K.
,
Nurowska
,
E.
,
Klukowska
,
M.
,
Zablocka
,
B.
and
Gruszczynska-Biegala
,
J.
(
2023
)
STIM2 regulates NMDA receptor endocytosis that is induced by short-term NMDA receptor overactivation in cortical neurons
.
Cell. Mol. Life Sci.
80
,
368
42
Garcia-Alvarez
,
G.
,
Lu
,
B.
,
Yap
,
K.A.F.
,
Wong
,
L.C.
,
Thevathasan
,
J.V.
,
Lim
,
L.
et al (
2015
)
STIM2 regulates PKA-dependent phosphorylation and trafficking of AMPARs
.
Mol. Biol. Cell
26
,
1141
1159
43
Yap
,
K.A.F.
,
Shetty
,
M.S.
,
Garcia-Alvarez
,
G.
,
Lu
,
B.
,
Alagappan
,
D.
,
Oh-Hora
,
M.
et al (
2017
)
STIM2 regulates AMPA receptor trafficking and plasticity at hippocampal synapses
.
Neurobiol. Learn. Mem.
138
,
54
61
44
Dittmer
,
P.J.
,
Wild
,
A.R.
,
Dell'Acqua
,
M.L.
and
Sather
,
W.A.
(
2017
)
STIM1 Ca2+ sensor control of L-type Ca2+-channel-dependent dendritic spine structural plasticity and nuclear signaling
.
Cell Rep.
19
,
321
334
45
Lee
,
K.
,
Jo
,
Y.Y.
,
Chung
,
G.
,
Jung
,
J.H.
,
Kim
,
Y.H.
and
Park
,
C.-K.
(
2021
)
Functional importance of transient receptor potential (TRP) channels in neurological disorders
.
Front. Cell Dev. Biol.
9
,
611773
46
Held
,
K.
and
Tóth
,
B.I.
(
2021
)
TRPM3 in brain (patho)physiology
.
Front. Cell Dev. Biol.
9
,
635659
47
Krizova
,
A.
,
Maltan
,
L.
and
Derler
,
I.
(
2019
)
Critical parameters maintaining authentic CRAC channel hallmarks
.
Eur. Biophys. J.
48
,
425
445
48
Mingen
,
O.
,
Thompson
,
J.L.
and
Shuttleworth
,
T.J.
(
2007
)
STIM1 regulates Ca2+ entry via arachidonate-regulated Ca2+-selective (ARC) channels without store depletion or translocation to the plasma membrane
.
J. Physiol.
579
,
703
715
49
Mingen
,
O.
,
Thompson
,
J.L.
and
Shuttleworth
,
T.J.
(
2008
)
Both Orai1 and Orai3 are essential components of the arachidonate-regulated Ca2+-selective (ARC) channels
.
J. Physiol.
586
,
185
195
50
Gruszczynska-Biegala
,
J.
and
Kuznicki
,
J.
(
2013
)
Native STIM2 and ORAI1 proteins form a calcium-sensitive and thapsigargin-insensitive complex in cortical neurons
.
J. Neurochem.
126
,
727
738
51
Korkotian
,
E.
,
Oni-Biton
,
E.
and
Segal
,
M.
(
2017
)
The role of the store-operated calcium entry channel Orai1 in cultured rat hippocampal synapse formation and plasticity
.
J. Physiol.
595
,
125
140
52
Tshuva
,
R.Y.
,
Korkotian
,
E.
and
Segal
,
M.
(
2017
)
ORAI1-dependent synaptic plasticity in rat hippocampal neurons
.
Neurobiol. Learn. Mem.
140
,
1
10
53
Segal
,
M.
(
2018
)
Calcium stores regulate excitability in cultured rat hippocampal neurons
.
J. Neurophysiol.
120
,
2694
2705
54
Maciag
,
F.
,
Majewski
,
Ł.
,
Boguszewski
,
P.M.
,
Gupta
,
R.K.
,
Wasilewska
,
I.
,
Wojtaś
,
B.
et al (
2019
)
Behavioral and electrophysiological changes in female mice overexpressing ORAI1 in neurons
.
Biochim. Biophys. Acta Mol. Cell Res.
1866
,
1137
1150
55
Dou
,
Y.
,
Xia
,
J.
,
Gao
,
R.
,
Gao
,
X.
,
Munoz
,
F.M.
,
Wei
,
D.
et al (
2018
)
Orai1 plays a crucial role in central sensitization by modulating neuronal excitability
.
J. Neurosci.
38
,
887
900
56
Hori
,
K.
,
Tsujikawa
,
S.
,
Novakovic
,
M.M.
,
Yamashita
,
M.
and
Prakriya
,
M.
(
2020
)
Regulation of chemoconvulsant-induced seizures by store-operated Orai1 channels
.
J. Physiol.
598
,
5391
5409
57
Mitra
,
R.
,
Richhariya
,
S.
and
Hasan
,
G.
(
2024
)
Orai-mediated calcium entry determines activity of central dopaminergic neurons by regulation of gene expression
.
eLife
12
,
RP88808
58
Maneshi
,
M.M.
,
Toth
,
A.B.
,
Ishii
,
T.
,
Hori
,
K.
,
Tsujikawa
,
S.
,
Shum
,
A.K.
et al (
2020
)
Orai1 channels are essential for amplification of glutamate-evoked Ca2+ signals in dendritic spines to regulate working and associative memory
.
Cell Rep.
33
,
108464
59
Hartmann
,
J.
,
Chen-Engerer
,
H.-J.
and
Konnerth
,
A.
(
2021
)
Where have all the Orais gone? Commentary on “Orai1 channels are essential for amplification of glutamate-evoked Ca2+ signals in dendritic spines to regulate working and associative memory”
.
Cell Calcium
96
,
102372
60
Prakriya
,
M.
(
2021
)
Orai1 is in neurons: reply to “where have all the Orais gone?”
.
Cell Calcium
96
,
102389
61
Chen-Engerer
,
H.J.
,
Hartmann
,
J.
,
Karl
,
R.M.
,
Yang
,
J.
,
Feske
,
S.
and
Konnerth
,
A.
(
2019
)
Two types of functionally distinct Ca2+ stores in hippocampal neurons
.
Nat. Commun.
10
,
3223
62
Peng
,
S.
and
Petersen
,
O.
(
2019
)
One or two Ca2+ stores in the neuronal endoplasmic reticulum?
Trends Neurosci.
42
,
755
757
63
Boulay
,
G.
,
Brown
,
D.M.
,
Qin
,
N.
,
Jiang
,
M.
,
Dietrich
,
A.
,
Zhu
,
M.X.
et al (
1999
)
Modulation of Ca2+ entry by polypeptides of the inositol 1,4,5-trisphosphate receptor (IP3R) that bind transient receptor potential (TRP): evidence for roles of TRP and IP3R in store depletion-activated Ca2+ entry
.
Proc. Natl Acad. Sci. U.S.A.
96
,
14955
14960
64
Emrich
,
S.M.
,
Yoast
,
R.E.
,
Xin
,
P.
,
Arige
,
V.
,
Wagner
,
L.E.
,
Hempel
,
N.
et al. (
2021
)
Omnitemporal choreographies of all five STIM/Orai and IP3Rs underlie the complexity of mammalian Ca2+ signaling
Cell Rep.
34
,
108760
65
Chakraborty
,
S.
,
Deb
,
B.K.
,
Chorna
,
T.
,
Konieczny
,
V.
,
Taylor
,
C.W.
and
Hasan
,
G.
(
2016
)
Mutant IP3 receptors attenuate store-operated Ca2+ entry by destabilizing STIM-Orai interactions in Drosophila neurons
.
J. Cell Sci.
129
,
3903
3910
66
Chakraborty
,
S.
,
Deb
,
B.K.
,
Arige
,
V.
,
Musthafa
,
T.
,
Malik
,
S.
,
Yule
,
D.I.
et al
Regulation of store-operated Ca2+ entry by IP3 receptors independent of their ability to release Ca2
.
eLife
12
,
e80447
67
Basnayake
,
K.
,
Mazaud
,
D.
,
Kushnireva
,
L.
,
Bemelmans
,
A.
,
Rouach
,
N.
,
Korkotian
,
E.
et al (
2021
)
Nanoscale molecular architecture controls calcium diffusion and ER replenishment in dendritic spines
.
Sci. Adv.
7
,
eabh1376
68
Heine
,
M.
,
Heck
,
J.
,
Ciuraszkiewicz
,
A.
and
Bikbaev
,
A.
(
2020
)
Dynamic compartmentalization of calcium channel signalling in neurons
.
Neuropharmacology
169
,
107556
69
Heck
,
J.
,
Parutto
,
P.
,
Ciuraszkiewicz
,
A.
,
Bikbaev
,
A.
,
Freund
,
R.
,
Mitlöhner
,
J.
et al (
2019
)
Transient confinement of CaV2.1 Ca2+-channel splice variants shapes synaptic short-term plasticity
.
Neuron
103
,
66
79.e12
70
Dixon
,
R.E.
and
Trimmer
,
J.S.
(
2023
)
Endoplasmic reticulum-plasma membrane junctions as sites of depolarization-induced Ca2+ signaling in excitable cells
.
Annu. Rev. Physiol.
85
,
217
243
71
Vierra
,
N.C.
,
O'Dwyer
,
S.C.
,
Matsumoto
,
C.
,
Santana
,
L.F.
and
Trimmer
,
J.S.
(
2021
)
Regulation of neuronal excitation-transcription coupling by Kv2.1-induced clustering of somatic L-type Ca2+ channels at ER-PM junctions
.
Proc. Natl Acad. Sci. U.S.A.
118
,
e2110094118
72
Sahu
,
G.
,
Wazen
,
R.-M.
,
Colaruso
,
P.
,
Chen
,
S.R.W.
,
Zamponi
,
G.W.
and
Turner
,
R.W.
(
2019
)
Junctophilin proteins tether a Cav1-RyR2-KCa3.1 tripartite complex to regulate neuronal excitability
.
Cell Rep.
28
,
2427
2442
73
Itie
,
T.
and
Trussell
,
L.O.
(
2017
)
Double-nanodomain coupling of calcium channels, ryanodine receptors, and BK channels controls the generation of burst firing
.
Neuron
96
,
856
870.e4
74
Perni
,
S.
and
Beam
,
K.
(
2021
)
Neuronal junctophilins recruit specific CaV and RyR isoforms to ER-PM junctions and functionally alter CaV2.1 and CaV2.2
.
eLife
10
,
e64249
75
Vierra
,
N.C.
,
Kirmiz
,
M.
,
van der List
,
D.
,
Santana
,
F.L.
and
Trimmer
,
J.S.
(
2019
)
Kv2.1 mediates spatial and functional coupling of L-type calcium channels and ryanodine receptors in mammalian neurons
.
Elife
8
,
e49953
76
Vierra
,
N.C.
,
Riberio-Silva
,
L.
,
Kirmiz
,
M.
,
van der List
,
D.
,
Bhandari
,
P.
,
Mack
,
O.A.
et al (
2023
)
Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling
.
Nat. Commun.
14
,
5231
77
Park
,
C.Y.
,
Shcheglovitov
,
A.
and
Dolmetsch
,
R.
(
2010
)
The CRAC channel activator STIM1 binds and inhibits L-type voltage-gated calcium channels
.
Science
330
,
101
105
78
Wang
,
Y.
,
Deng
,
X.
,
Mancarella
,
S.
,
Hendron
,
E.
,
Eguchi
,
S.
,
Soboloff
,
J.
et al (
2010
)
The calcium store sensor, STIM1, reciprocally controls Orai and CaV1.2 channels
.
Science
330
,
105
109
79
Misonou
,
H.
,
Mohapatra
,
D.P.
,
Park
,
E.W.
,
Leung
,
V.
,
Zhen
,
D.
,
Misonou
,
K.
et al (
2004
)
Regulation of ion channel localization and phosphorylation by neuronal activity
.
Nat. Neurosci.
7
,
711
718
80
Campbell
,
E.P.
,
Abushawish
,
A.A.
,
Valdez
,
L.A.
,
Bell
,
M.K.
,
Haryono
,
M.
,
Rangamani
,
P.
et al (
2023
)
Electrical signals in the ER are cell type and stimulus specific with extreme spatial compartmentalization in neurons
.
Cell Rep.
42
,
111943
81
Mulholland
,
P.J.
,
Carpenter-Hyland
,
E.P.
,
Hearing
,
M.C.
,
Becker
,
H.C.
,
Woodward
,
J.J.
and
Chandler
,
J.
(
2008
)
Glutamate transporters regulate extrasynaptic NMDA receptor modulation of Kv2.1 potassium channels
.
J. Neurosci.
28
,
8801
8809
82
Fox
,
P.D.
,
Haberkorn
,
C.H.J.
,
Akin
,
E.J.
,
Seel
,
P.J.
,
Krapf
,
D.
and
Tamkun
,
M.M.
(
2015
)
Induction of stable ER-plasma-membrane junctions by Kv2.1 potassium channels
.
J. Cell Sci.
128
,
2096
2105
83
Tao-Cheng
,
J.-H.
(
2018
)
Activity-dependent decrease in contact areas between subsurface cisterns and plasma membrane of hippocampal neurons
.
Mol. Brain
11
,
23
84
Vullhorst
,
D.
,
Mitchell
,
R.M.
,
Keating
,
C.
,
Roychowdhury
,
S.
,
Karavanova
,
I.
,
Tao-Cheng
,
J.-H.
et al (
2015
)
A negative feedback loop controls NMDA receptor function in cortical interneurons via neuregulin 2/ErbB4 signalling
.
Nat. Commun.
6
,
7222
85
Vullhorst
,
D.
,
Bloom
,
M.S.
,
Akella
,
N.
and
Buonanno
,
A.
(
2023
)
ER-PM junctions on GABAergic interneurons are organized by neuregulin 2/VAP interactions and regulated by NMDA receptors
.
Int. J. Mol. Sci.
24
,
2908
86
Sun
,
E.W.
,
Guillén-Samander
,
A.
,
Bian
,
X.
,
Wu
,
Y.
,
Cai
,
Y.
,
Messa
,
M.
et al (
2019
)
Lipid transporter TMEM24/C2CD2L is a Ca2+-regulated component of ER-plasma membrane contacts in mammalian neurons
.
Proc. Natl Acad. Sci. U.S.A.
116
,
5775
5784
87
Weesner
,
J.A.
,
Annunziata
,
I.
,
van de Vlekkert
,
D.
,
Robinson
,
C.G.
,
Cmapos
,
Y.
,
Mishra
,
A.
et al (
2023
)
Altered GM1 catabolism affects NMDAR-mediated Ca2+ signaling at ER-PM junctions and increases synaptic spine formation. bioRxiv
88
Chen
,
B.-S.
and
Roche
,
K.W.
(
2007
)
Regulation of NMDA receptors by phosphorylation
.
Neuropharmacology
53
,
362
368
89
Patil
,
C.S.
,
Li
,
H.
,
Lavine
,
N.E.
,
Shi
,
R.
,
Bodalia
,
A.
,
Siddiqui
,
T.J.
et al (
2022
)
ER-resident STIM1/2 couples Ca2+ entry by NMDA receptors to pannexin-1 activation
.
Proc. Natl Acad. Sci. U.S.A.
119
,
e2112870119
90
Bruzzone
,
R.
,
Hormuzdi
,
A.H.
,
Barbe
,
M.T.
,
Herb
,
A.
and
Monyer
,
H.
(
2003
)
Pannexins, a family of gap junction proteins expressed in brain
.
Proc. Natl Acad. Sci. U.S.A.
100
,
13644
13649
91
Abudra
,
V.
,
Retamal
,
M.A.
,
Del Rio
,
R.
and
Orellana
,
J.A.
(
2018
)
Synaptic functions of hemichannels and pannexons: a double-edged sword
.
Front. Mol. Neurosci.
11
,
435
92
Lalanne
,
T.
,
Oyer
,
J.
,
Farrant
,
M.
and
Sjöstrom
,
P.J.
(
2018
)
Synapse type-dependent expression of calcium-permeable AMPA receptors
.
Front. Synaptic Neurosci.
10
,
34
93
Park
,
P.
,
Kang
,
H.
,
Sanderson
,
T.M.
,
Bortolotto
,
Z.A.
,
Georgiou
,
J.
,
Zhuo
,
M.
et al (
2018
)
The role of calcium-permeable AMPARs in long-term potentiation at principal neurons in the rodent hippocampus
.
Front. Synaptic Neurosci.
10
,
42
94
Cull-Candy
,
S.G.
and
Farrant
,
M.
(
2021
)
Ca2+-permeable AMPA receptors and their auxiliary subunits in synaptic plasticity and disease
.
J. Physiol.
599
,
2655
2671
95
Mao
,
R.
,
Tong
,
C.
and
Liu
,
J.-J.
(
2023
)
E-Syt1 regulates neuronal activity-dependent endoplasmic reticulum-plasma membrane junctions and surface expression of AMPA receptors
.
Contact (Thousand Oaks)
6
,
25152564231185011
96
Muzio
,
M.R.
and
Cascella
,
M
. (
2022
) Histology, axon. In
StatPearls
.
StatPearls Publishing,
Treasure Island, FL
97
Kuijpers
,
M.
,
Nguyen
,
P.T.
and
Haucke
,
V.
(
2023
)
The endoplasmic reticulum and its contacts: emerging roles in axon development, neurotransmission, and degeneration
.
Neuroscientist
24
,
10738584231162810
98
Lev
,
S.
,
Halevy
,
D.B.
,
Peretti
,
D.
and
Dahan
,
N.
(
2008
)
The VAP protein family: from cellular functions to motor neuron disease
.
Trends Cell Biol.
18
,
282
290
99
Kors
,
S.
,
Costello
,
J.L.
and
Schrader
,
M.
(
2022
)
VAP proteins - from organelle tethers to pathogenic host interactors and their role in neuronal disease
.
Front. Cell Dev. Biol.
10
,
895856
100
Weber-Boyvat
,
M.
,
Trimbuch
,
T.
,
Shah
,
S.
,
Jäntti
,
J.
,
Olkkonen
,
V.
and
Rosenmund
,
C.
(
2021
)
ORP/osh mediate cross-talk between ER-plasma membrane contact site components and plasma membrane SNAREs
.
Cell. Mol. Life Sci.
78
,
1689
1708
101
Antonucci
,
D.E.
,
Lim
,
S.T.
and
Trimmer
,
J.S.
(
2001
)
Dynamic localization and clustering of dendritic Kv2.1 voltage-dependent potassium channels in developing hippocampal neurons
.
Neuroscience
108
,
69
81
102
Falahati
,
H.
,
Wu
,
Y.
,
Feuerer
,
V.
,
Simon
,
H.-G.
and
De Camilli
,
P.
(
2022
)
Proximity proteomics of synaptopodin provides insight into the molecular composition of the spine apparatus of dendritic spines
.
Proc. Natl Acad. Sci. U.S.A.
119
,
e2203750119
103
Spacek
,
J.
and
Harris
,
K.H.
(
1997
)
Three-dimensional organization of smooth endoplasmic reticulum in hippocampal CA1 dendrites and dendritic spines of the immature and mature rat
.
J. Neurosci.
17
,
190
203
104
Popugayeva
,
E.
,
Pchitskaya
,
E.
,
Speshilova
,
A.
,
Alexandrov
,
S.
,
Zhang
,
H.
,
Vlasova
,
O.
et al (
2015
)
STIM2 protects hippocampal mushroom spines from amyloid synaptotoxicity
.
Mol. Neurodegener.
10
,
37
105
Calvo-Rodríguez
,
M.
,
García-Durillo
,
M.
,
Villalobos
,
C.
and
Núñez
,
L.
(
2016
)
In vitro aging promotes endoplasmic reticulum (ER)-mitochondria Ca2+ cross talk and loss of store-operated Ca2+ entry (SOCE) in rat hippocampal neurons
.
Biochim. Biophys. Acta
1863
,
2637
2649
106
Thibault
,
O.
,
Gant
,
J.C.
and
Landfield
,
P.W.
(
2007
)
Expansion of the calcium hypothesis of brain aging and Alzheimer's disease: minding the store
.
Aging Cell
6
,
307
317
107
Gibson
,
G.E.
and
Peterson
,
C.
(
1987
)
Calcium and the aging nervous system
.
Neurobiol. Aging
8
,
329
343
108
Disterhoft
,
J.F.
,
Moyer
, Jr,
J.R.,
and
Thompson
,
L.T.
(
1994
)
The calcium rationale in aging and Alzheimer's disease. Evidence from an animal model of normal aging
.
Ann. N. Y. Acad. Sci.
747
,
382
406
109
Khachaturian
,
Z.S.
(
1994
)
Calcium hypothesis of Alzheimer's disease and brain aging
.
Ann. N. Y. Acad. Sci.
747
,
1
11
110
Emptage
,
N.
,
Bliss
,
T.V.
and
Fine
,
A.
(
1999
)
Single synaptic events evoke NMDA receptor-mediated release of calcium from internal stores in hippocampal dendritic spines
.
Neuron
22
,
115
124
111
Kovalchuk
,
Y.
,
Eilers
,
J.
and
Konnerth
,
A.
(
2000
)
NMDA receptor-mediated subthreshold Ca2+ signals in spines of hippocampal neurons
.
J. Neurosci.
20
,
1791
1799
112
Garaschuk
,
O.
,
Schneggenburger
,
R.
,
Schirra
,
C.
,
Tempia
,
T.
and
Konnerth
,
A.
(
1996
)
Fractional Ca2+ currents through somatic and dendritic glutamate receptor channels of rat hippocampal CA1 pyramidal neurones
.
J. Physiol.
491
,
757
772
113
Oertner
,
T.G.
,
Sabatini
,
B.L.
,
Nimchinsky
,
E.A.
and
Svoboda
,
K.
(
2002
)
Facilitation at single synapses probed with optical quantal analysis
.
Nat. Neurosci.
5
,
657
664
114
Sabatini
,
B.L.
,
Oertner
,
T.G.
and
Svoboda
,
K.
(
2002
)
The life cycle of Ca2+ ions in dendritic spines
.
Neuron
33
,
439
452
115
Lee
,
K.F.H.
,
Soares
,
C.
,
Thivierge
,
J.-P.
and
Béïque
,
J.-C.
(
2016
)
Correlated synaptic inputs drive dendritic calcium amplification and cooperative plasticity during clustered synapse development
.
Neuron
89
,
784
799
116
Farías
,
G.G.
,
Fréal
,
A.
,
Tortosa
,
E.
,
Stucchi
,
R.
,
Pan
,
X.
,
Portegies
,
S.
et al (
2019
)
Feedback-driven mechanisms between microtubules and the endoplasmic reticulum instruct neuronal polarity
.
Neuron
102
,
184
201.e8
117
Pavez
,
M.
,
Thompson
,
A.C.
,
Arnott
,
H.J.
,
Mitchell
,
C.B.
,
D'Atri
,
I.
,
Don
,
E.K.
et al (
2019
)
STIM1 is required for remodeling of the endoplasmic reticulum and microtubule cytoskeleton in steering growth cones
.
J. Neurosci.
39
,
5095
5114
118
Shim
,
S.
,
Zheng
,
J.Q.
and
Ming
,
G.-L.
(
2013
)
A critical role for STIM1 in filopodial calcium entry and axon guidance
.
Mol. Brain
6
,
51
119
Li
,
J.
,
Yan
,
B.
,
Si
,
H.
,
Peng
,
X.
,
Zhang
,
S.L.
and
Hu
,
J.
(
2017
)
Atlastin regulates store-operated calcium entry for nerve growth factor-induced neurite outgrowth
.
Sci. Rep.
7
,
43490
120
Zamponi
,
E.
,
Meehl
,
J.B.
and
Voeltz
,
G.K.
(
2022
)
The ER ladder is a unique morphological feature of developing mammalian axons
.
Dev. Cell
57
,
1369
1382.e6
121
Adeoye
,
T.
,
Shah
,
S.I.
,
Demuro
,
A.
,
Rabson
,
D.A.
and
Ullah
,
G.
(
2022
)
Upregulated Ca2+ release from the endoplasmic reticulum leads to impaired presynaptic function in familial Alzheimer's disease
.
Cells
11
,
2167
122
Tang
,
T.-S.
,
Tu
,
H.
,
Orban
,
P.C.
,
Chan
,
E.Y.W.
,
Hayden
,
M.R.
and
Bezprozvanny
,
I.
(
2004
)
HAP1 facilitates effects of mutant huntingtin on inositol 1,4,5-trisphosphate-induced Ca release in primary culture of striatal medium spiny neurons
.
Eur. J. Neurosci.
20
,
1779
1787
123
Tang
,
T.-S.
,
Tu
,
H.
,
Chan
,
E.Y.W.
,
Maximov
,
A.
,
Wang
,
Z.
,
Wellington
,
C.L.
et al (
2003
)
Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1
.
Neuron
39
,
227
239
124
Zatti
,
G.
,
Burgo
,
A.
,
Giacomello
,
M.
,
Barbiero
,
L.
,
Ghidoni
,
R.
,
Sinigaglia
,
G.
et al (
2006
)
Presenilin mutations linked to familial Alzheimer's disease reduce endoplasmic reticulum and Golgi apparatus calcium levels
.
Cell Calcium
39
,
539
550
125
Lacampagne
,
A.
,
Liu
,
X.
,
Reiken
,
S.
,
Bussiere
,
R.
,
Meli
,
A.C.
,
Lauritzen
,
I.
et al (
2017
)
Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer's disease-like pathologies and cognitive deficits
.
Acta Neuropathol.
134
,
749
767
126
Özturk
,
Z.
,
O'Kane
,
C.J.
and
Pérez-Moreno
,
J.J.
(
2020
)
Axonal endoplasmic reticulum dynamics and Its roles in neurodegeneration
.
Front. Neurosci.
14
,
48
127
Holmes
,
S.E.
,
O'Hearn
,
E.O.
,
Rosenblatt
,
A.
,
Callahan
,
C.
,
Hwang
,
H.S.
,
Ingersoll-Ashworth
,
R.G.
et al (
2001
)
A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2
.
Nat. Genet.
29
,
377
378
128
Pla-Martín
,
D.
,
Calpena
,
E.
,
Lupo
,
V.
,
Márquez
,
C.
,
Rivaz
,
E.
,
Sivera
,
R.
et al (
2015
)
Junctophilin-1 is a modifier gene of GDAP1-related Charcot-Marie-Tooth disease
.
Hum. Mol. Genet.
24
,
213
229
129
Kanwal
,
S.
and
Perveen
,
S.
(
2019
)
Association of SNP in JPH1 gene with severity of disease in Charcot Marie Tooth 2 K patients
.
J. Pak. Med. Assoc.
69
,
241
243
30804591
130
Nishimura
,
A.L.
,
Mitne-Neto
,
M.
,
Silva
,
H.C.A.
,
Richeri-Costa
,
A.
,
Middleton
,
S.
,
Cascio
,
D.
et al (
2004
)
A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis
.
Am. J. Hum. Genet.
75
,
822
831
131
Borgese
,
N.
,
Iacominp
,
N.
,
Colombo
,
S.F.
and
Navone
,
F.
(
2021
)
The link between VAPB loss of function and amyotrophic lateral sclerosis
.
Cells
10
,
1865
132
Schulien
,
A.J.
,
Yeh
,
C.-Y.
,
Orange
,
B.N.
,
Pav
,
O.J.
,
Hopkins
,
M.P.
,
Moutal
,
A.
et al (
2020
)
Targeted disruption of Kv2.1-VAPA association provides neuroprotection against ischemic stroke in mice by declustering Kv2.1 channels
.
Sci. Adv.
6
,
eaaz8110
133
Paillusson
,
S.
,
Gomey-Suaga
,
P.
,
Stoica
,
R.
,
Little
,
D.
,
Gissen
,
P.
,
Devine
,
M.J.
et al (
2017
)
α-Synuclein binds to the ER-mitochondria tethering protein VAPB to disrupt Ca2+ homeostasis and mitochondrial ATP production
.
Acta Neuropathol.
134
,
129
149
134
Gómez-Suaga
,
P.
,
Pérez-Nievas
,
B.G.
,
Glennon
,
E.B.
,
Lau
,
D.H.W.
,
Paillusson
,
S.
,
Mórotz
,
G.M.
et al (
2019
)
The VAPB-PTPIP51 endoplasmic reticulum-mitochondria tethering proteins are present in neuronal synapses and regulate synaptic activity
.
Acta Neuropathol. Commun.
7
,
35
135
Mori
,
F.
,
Miki
,
Y.
,
Tanji
,
K.
,
Kon
,
T.
,
Tomiyama
,
M.
,
Kakita
,
A.
et al (
2021
)
Role of VAPB and vesicular profiles in α-synuclein aggregates in multiple system atrophy
.
Brain Pathol.
31
,
e13001
136
Bojarski
,
L.
,
Pomorski
,
P.
,
Szybinska
,
A.
,
Drab
,
M.
,
Skibinska-Kijek
,
A.
,
Gruszczynska-Biegala
,
J.
et al (
2009
)
Presenilin-dependent expression of STIM proteins and dysregulation of capacitative Ca2+ entry in familial Alzheimer's disease
.
Biochim. Biophys. Acta
1793
,
1050
1057
137
Zhang
,
H.
,
Sun
,
S.
,
Wu
,
L.
,
Pchitskaya
,
E.
,
Zakharova
,
O.
,
Tacer
,
K.F.
et al (
2016
)
Store-operated calcium channel complex in postsynaptic spines: a new therapeutic target for Alzheimer's disease treatment
.
J. Neurosci.
36
,
11837
11850
138
Huang
,
A.S.
,
Tong
,
B.C.K.
,
Wu
,
A.J.
,
Chen
,
X.
,
Sreenivasmurthy
,
S.G.
,
Zhu
,
Z.
et al (
2020
)
Rectifying attenuated store-operated calcium entry as a therapeutic approach for Alzheimer's disease
.
Curr. Alzheimer Res.
17
,
1072
1087
139
Skobeleva
,
K.
,
Shalygin
,
A.
,
Mikhaylova
,
E.
,
Guzhova
,
I.
,
Ryzantseva
,
M.
and
Kaznacheyeva
,
E.
(
2022
)
The STIM1/2-regulated calcium homeostasis is impaired in hippocampal neurons of the 5xFAD mouse model of Alzheimer's disease
.
Int. J. Mol. Sci.
23
,
14810
140
Kaar
,
A.
,
Weir
,
M.P.
and
Rae
,
M.G.
(
2024
)
Altered neuronal group 1 metabotropic glutamate receptor- and endoplasmic reticulum-mediated Ca2+ signaling in two rodent models of Alzheimer's disease
.
Neurosci. Lett.
823
,
137664
141
Hidalgo
,
C.
and
Paula/Lima
,
A.
(
2024
)
RyR-mediated calcium release in hippocampal health and disease
.
Trends Mol. Med.
30
,
25
36
142
Marks
,
A.R.
(
2023
)
Targeting ryanodine receptors to treat human diseases
.
J. Clin. Invest.
133
,
e162891
143
McDaid
,
J.
,
Mustaly-Kalimi
,
S.
and
Stutzmann
,
G.E.
(
2020
)
Ca2+ dyshomeostasis disrupts neuronal and synaptic function in Alzheimer's disease
.
Cells
9
,
2655
144
Chiami
,
M.
and
Checler
,
F.
(
2020
)
Alterations of the endoplasmic reticulum (ER) calcium signaling molecular components in Alzheimer's disease
.
Cells
9
,
2577
145
Czeredys
,
M.
(
2020
)
Dysregulation of neuronal calcium signaling via store-operated channels in Huntington's disease
.
Front. Cell Dev. Biol.
8
,
611735
 
146
Wu
,
J.
,
Shih
,
H.-P.
,
Vigont
,
V.
,
Hrdlicka
,
L.
,
Diggins
,
L.
,
Singh
,
C.
et al (
2011
)
Neuronal store-operated calcium entry pathway as a novel therapeutic target for Huntington's disease treatment
.
Chem. Biol.
18
,
777
793
147
Czeredys
,
M.
,
Maciag
,
F.
,
Methner
,
A.
and
Kuznicki
,
J.
(
2017
)
Tetrahydrocarbazoles decrease elevated SOCE in medium spiny neurons from transgenic YAC128 mice, a model of Huntington's disease
.
Biochem. Biophys. Res. Commun.
483
,
1194
1205
148
Czeredys
,
M.
,
Vigont
,
V.A.
,
Boeva
,
V.A.
,
Mikoshiba
,
K.
and
Kaznacheyeva
,
E.V.
(
2018
)
Huntingtin-associated protein 1A regulates store-operated calcium entry in medium spiny neurons from transgenic YAC128 mice, a model of Huntington's disease
.
Front. Cell. Neurosci.
12
,
381
149
Vigont
,
V.
,
Nekrasov
,
E.
,
Shalygin
,
A.
,
Gusev
,
K.
,
Klushnikov
,
S.
and
Illaroshkin
,
S.
(
2018
)
Patient-specific iPSC-based models of Huntington's disease as a tool to study store-operated calcium entry drug targeting
.
Front. Pharmacol.
9
,
696
150
Vigont
,
V.A.
,
Grekhnev
,
D.A.
,
Lebedeva
,
O.S.
,
Gusev
,
K.O.
,
Volovikov
,
E.A.
,
Skopin
,
A.Y.
et al (
2021
)
STIM2 mediates excessive store-operated calcium entry in patient-specific iPSC-derived neurons modeling a juvenile form of Huntington's disease
.
Front. Cell Dev. Biol.
9
,
625231
151
Wu
,
J.
,
Ryskamp
,
D.A.
,
Liang
,
X.
,
Egorova
,
P.
,
Zakharova
,
O.
,
Hung
,
G.
et al (
2016
)
Enhanced store-operated calcium entry leads to striatal synaptic loss in a Huntington's disease mouse model
.
J. Neurosci.
36
,
125
141
152
Wu
,
J.
,
Ryskamp
,
D.
,
Birnbaumer
,
L.
and
Bezprozvanny
,
I.
(
2018
)
Inhibition of TRPC1-dependent store-operated calcium entry improves synaptic stability and motor performance in a mouse model of Huntington's disease
.
J. Huntingtons Dis.
7
,
35
50
153
Chivet
,
M.
,
McCluskey
,
M.
,
Nicot
,
A.S.
,
Brocard
,
J.
,
Beaufils
,
M.
,
Giovannini
,
D.
et al (
2023
)
Huntingtin regulates calcium fluxes in skeletal muscle
.
J. Gen. Physiol.
155
,
e202213103
154
Steinbeck
,
J.A.
,
Hende
,
N.
,
Opatz
,
J.
,
Gruszczynska-Biegala
,
J.
,
Schneider
,
L.
,
Thiess
,
S.
et al (
2011
)
Store-operated calcium entry modulates neuronal network activity in a model of chronic epilepsy
.
Exp. Neurol.
232
,
185
194
155
Majewski
,
L.
,
Wojtas
,
B.
,
Maciąg
,
F.
and
Kuznicki
,
J.
(
2019
)
Changes in calcium homeostasis and gene expression implicated in epilepsy in hippocampi of mice overexpressing ORAI1
.
Int. J. Mol. Sci.
20
,
5539
156
Berna-Erro
,
A.
,
Braun
,
A.
,
Kraft
,
R.
,
Kleinschnitz
,
C.
,
Schuhmann
,
M.K.
,
Stegner
,
D.
et al (
2009
)
STIM2 regulates capacitive Ca2+ entry in neurons and plays a key role in hypoxic neuronal cell death
.
Sci. Signal.
2
,
ra67
157
Stegner
,
D.
,
Hofmann
,
S.
,
Schuhmann
,
M.K.
,
Kraft
,
P.
,
Herrmann
,
A.M.
,
Popp
,
S.
et al (
2019
)
Loss of Orai2-mediated capacitative Ca2+ entry is neuroprotective in acute ischemic stroke
.
Stroke
50
,
3238
3245
158
Secondo
,
A.
,
Petrozziello
,
T.
,
Tedeschi
,
V.
,
Boscia
,
F.
,
Vinciguerra
,
A.
,
Ciccone
,
R.
et al (
2019
)
ORAI1/STIM1 interaction intervenes in stroke and in neuroprotection induced by ischemic preconditioning through store-operated calcium entry
.
Stroke
50
,
1240
1249
159
Zhang
,
M.
,
Song
,
J.-S.
,
Wu
,
Y.
,
Zhao
,
Y.-L.
,
Pang
,
H.-G.
,
Fu
,
Z.-F.
et al (
2014
)
Suppression of STIM1 in the early stage after global ischemia attenuates the injury of delayed neuronal death by inhibiting store-operated calcium entry-induced apoptosis in rats
.
Neuroreport
25
,
507
513
160
Zhang
,
H.
,
Xie
,
W.
,
Feng
,
Y.
,
Wei
,
J.
,
Yang
,
C.
and
Luo
,
P.
(
2023
)
Stromal interaction molecule 1-mediated store-operated calcium entry promotes autophagy through AKT/mammalian target of rapamycin pathway in hippocampal neurons after ischemic stroke
.
Neuroscience
514
,
67
78
161
Hill
,
M.A.
,
Sykes
,
A.M.
and
Mellick
,
G.D.
(
2023
)
ER-phagy in neurodegeneration
.
J. Neurosci. Res.
101
,
1611
1623
162
Kuijpers
,
M.
,
Kochlamazashvili
,
G.
,
Stumpf
,
A.
,
Puchkov
,
D.
,
Swaminathan
,
A.
,
Lucht
,
M.T.
et al (
2021
)
Neuronal autophagy regulates presynaptic neurotransmission by controlling the axonal endoplasmic reticulum
.
Neuron
109
,
299
313
163
Galluzzi
,
L.
,
Bravo-San Pedro
,
J.M.
,
Blomgren
,
K.
and
Kroemer
,
G.
(
2016
)
Autophagy in acute brain injury
.
Nat. Rev. Neurosci.
17
,
467
484
164
Wu
,
J.
and
Lipinski
,
M.M.
(
2019
)
Autophagy in neurotrauma: good, bad, or dysregulated
.
Cells
8
,
693
165
Elgendy
,
M.
,
Tamada
,
H.
,
Taira
,
T.
,
Iiio
,
Y.
,
Kawamura
,
A.
,
Kunogi
,
A.
et al (
2024
)
Dynamic changes in endoplasmic reticulum morphology and its contact with the plasma membrane in motor neurons in response to nerve injury
.
Cell Tissue Res.
396
,
71
84
166
Nascimbeni
,
A.C.
,
Giordano
,
F.
,
Dupont
,
N.
,
Grasso
,
D.
,
Vaccaro
,
M.I.
,
Codogno
,
P.
et al (
2017
)
ER-plasma membrane contact sites contribute to autophagosome biogenesis by regulation of local PI3P synthesis
.
EMBO J.
36
,
2018
2033
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).