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The neuronal Ca2+ signalling toolkit. Neuronal Ca2+ signals are shaped by the interaction between Ca2+ inflow from the outside and Ca2+ mobilization from the endoplasmic reticulum (ER), their most abundant endogenous Ca2+ pool. At excitatory synapses, the signaling cascade is initiated when glutamate is released into the synaptic cleft. Glutamate binds to receptor-operated channels, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs), and to metabotropic receptors, such as type 1 metabotropic glutamate receptors (mGluR1). AMPAR gates Na+ entry, thereby causing the excitatory postsynaptic potential (EPSP) that removes the Mg2+ block from NMDAR , enabling it to open in response to Glu and to mediate Ca2+ inflow. Moreover, the EPSP recruits an additional pathway for Ca2+ entry by activating voltage-operated Ca2+ channels (VOCCs). Outside the postsynaptic density is located mGluR1, that is coupled to PLCb by a trimeric Gq protein and, therefore, leads to inositol-1,4,5-trisphosphate (InsP3) synthesis. InsP3, in turn, induces Ca2+ release from ER by binding to and gating the so-called InsP3 receptors (InsP3Rs). ER-dependent Ca2+ discharge also involves ryanodine receptors (RyRs) which are activated by Ca2+ delivered either by adjoining InsP3Rs or by plasmalemmal VOCs or NMDARs according to the process of Ca2+-induced Ca2+ release (CICR). An additional route for Ca2+ influx is provided by store-operated Ca2+ entry, which is mediated by the interaction between the ER Ca2+-sensors, Stim1 and Stim2, and the Ca2+-permeable channels, Orai1 and Orai2. As more extensively illustrated in the text, depending on the species (rat, mouse, or human) and on the brain region (cortex, hippocampus, or cerebellum), Stim and Orai isoforms interact to mediate Ca2+ entry either in the presence or in the absence of synaptic activity to ensure adequate replenishment of ER Ca2+ loading and engage in Ca2+-sensitive decoders.
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Stim1 and Orai1 are ubiquitous proteins that have long been known to mediate Ca2+ release-activated Ca2+ (CRAC) current (ICRAC) and store-operated Ca2+ entry (SOCE) only in non-excitable cells. SOCE is activated following the depletion of the endogenous Ca2+ stores, which are mainly located within the endoplasmic reticulum (ER), to replete the intr...
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... One of these is its involvement in SOCE, which can activate transcription factors such as CREB, NFAT and NFκB and thus modulate gene expression 51 . Another is the maintenance of basal calcium levels in neurons, which is crucial for normal neuronal excitability 52,53 . Although there is currently no direct evidence linking STIM1/2 with glaucoma, TRPC1 and TRPC6 channels, which are known interacting partners of STIM isoforms, were upregulated in glaucomatous lamina cribrosa leading to NFAT4-mediated gene expression remodeling 54 . ...
Calcium is involved in vision processes in the retina and implicated in various pathologies, including glaucoma. Rod cells rely on store-operated calcium entry (SOCE) to safeguard against the prolonged lowering of intracellular calcium ion concentrations. Zebrafish that lacked the endoplasmic reticulum Ca²⁺ sensor Stim2 (stim2 knockout [KO]) exhibited impaired vision and lower light perception-related gene expression. We sought to understand mechanisms that are responsible for vision impairment in stim2 KO zebrafish. The single-cell RNA (scRNA) sequencing of neuronal cells from brains of 5 days postfertilization larvae distinguished 27 cell clusters, 10 of which exhibited distinct gene expression patterns, including amacrine and γ-aminobutyric acid (GABA)ergic retinal interneurons and GABAergic optic tectum cells. Five clusters exhibited significant changes in cell proportions between stim2 KO and controls, including GABAergic diencephalon and optic tectum cells. Transmission electron microscopy of stim2 KO zebrafish revealed decreases in width of the inner plexiform layer, ganglion cells, and their dendrites numbers (a hallmark of glaucoma). GABAergic neuron densities in the inner nuclear layer, including amacrine cells, as well as photoreceptors significantly decreased in stim2 KO zebrafish. Our study suggests a novel role for Stim2 in the regulation of neuronal insulin expression and GABAergic-dependent vision causing glaucoma-like retinal pathology.
... Many neurotransmitters and modulators transduce signal via G-protein-coupled, PLC-mediated store-operated Ca 2+ influx (Moccia et al, 2015). Key molecular components of this pathway include the IP 3 receptor, ER Ca 2+ sensor STIM, and the Ca influx channel ORAI; we found that the transcript levels of PLCb4, ITPR2, STIM1, and ORAI2 were all down-regulated in Li-treated neurons compared with controls ( Fig 6E). ...
Lithium (Li) is widely used as a mood stabilizer to treat bipolar affective disorder. However, the molecular targets of Li that underpin its therapeutic effect remain unresolved. Inositol monophosphatase (IMPA1) is an enzyme involved in phosphatidylinositol 4,5-bisphosphate (PIP 2 ) resynthesis after PLC signaling. In vitro, Li inhibits IMPA1, but the relevance of this inhibition within neural cells remains unknown. Here, we report that treatment with therapeutic concentrations of Li reduces receptor-activated calcium release from intracellular stores and delays PIP 2 resynthesis. These effects of Li are abrogated in IMPA1 deleted cells. We also observed that in human forebrain cortical neurons, treatment with Li reduced neuronal excitability and calcium signals. After Li treatment of human cortical neurons, transcriptome analyses revealed down-regulation of signaling by glutamate, a key excitatory neurotransmitter in the human brain. Collectively, our findings suggest that inhibition of IMPA1 by Li reduces receptor-activated PLC signaling and neuronal excitability.
... The CRAC channel is a two component Ca 2+ entry mechanism comprised of the ER Ca 2+ sensors stromal interacting molecule 1 and 2 (STIM1 and STIM2), and the PM located and highly Ca 2+ -selective Orai channels, of which there are three isoforms, Orai1, Orai2, and Orai3 (15,[17][18][19][20][21][22][23][24]. When the ER stores are depleted, Ca 2+ is released from the low affinity Ca 2+ -binding EF-hand domain of STIM proteins, causing STIM activation, aggregation, and localization to the ER-PM junctions, where they physically trap and gate Orai channels (22,25,26). ...
... The CRAC channel is a two component Ca 2+ entry mechanism comprised of the ER Ca 2+ sensors stromal interacting molecule 1 and 2 (STIM1 and STIM2), and the PM located and highly Ca 2+ -selective Orai channels, of which there are three isoforms, Orai1, Orai2, and Orai3 (15,(17)(18)(19)(20)(21)(22)(23)(24). When the ER stores are depleted, Ca 2+ is released from the low affinity Ca 2+ -binding EF-hand domain of STIM proteins, causing STIM activation, aggregation, and localization to the ER-PM junctions, where they physically trap and gate Orai channels (22,25,26). ...
T-cell receptor stimulation triggers cytosolic Ca²⁺ signaling by inositol-1,4,5-trisphosphate (IP3)-mediated Ca²⁺ release from the endoplasmic reticulum (ER) and Ca²⁺ entry through Ca²⁺ release-activated Ca²⁺ (CRAC) channels gated by ER-located stromal-interacting molecules (STIM1/2). Physiologically, cytosolic Ca²⁺ signaling manifests as regenerative Ca²⁺ oscillations, which are critical for nuclear factor of activated T-cells-mediated transcription. In most cells, Ca²⁺ oscillations are thought to originate from IP3 receptor-mediated Ca²⁺ release, with CRAC channels indirectly sustaining them through ER refilling. Here, experimental and computational evidence support a multiple-oscillator mechanism in Jurkat T-cells whereby both IP3 receptor and CRAC channel activities oscillate and directly fuel antigen-evoked Ca²⁺ oscillations, with the CRAC channel being the major contributor. KO of either STIM1 or STIM2 significantly reduces CRAC channel activity. As such, STIM1 and STIM2 synergize for optimal Ca²⁺ oscillations and activation of nuclear factor of activated T-cells 1 and are essential for ER refilling. The loss of both STIM proteins abrogates CRAC channel activity, drastically reduces ER Ca²⁺ content, severely hampers cell proliferation and enhances cell death. These results clarify the mechanism and the contribution of STIM proteins to Ca²⁺ oscillations in T-cells.
... Nevertheless, STIM2 can sustain SOCE elicited by agonist-induced sub-threshold depletion of the ER Ca 2+ content [68,71] as well as support STIM1-dependent recruitment to the ER-plasma membrane during supra-threshold stimulation [68,72]. In addition, STIM1 can be activated even in the absence of an extracellular agonist when the resting [Ca 2+ ] ER is too low to prevent its constitutive activation [73][74][75]. Orai1 has long been regarded as the primary pore-forming subunit of CRAC channels [5,69]. However, recent evidence suggests that Orai2 and/or Orai3 can assemble into heteromultimeric channels with Orai1 and serve as negative modulators of the I CRAC in naïve cells [76][77][78]. ...
... Interestingly, the Mn 2+ quenching assay, which is widely employed to monitor basal Ca 2+ entry in non-excitable cells [70,75,101], revealed that SOCE was constitutively activated in C-hMSCs and was significantly enhanced in ACM C-hMSCs ( Figure 4C,D) [4]. Constitutive SOCE regulates resting [Ca 2+ ] i and maintains [Ca 2+ ] ER , thereby finely tuning the magnitude and duration of InsP 3 -induced ER Ca 2+ release [70,[73][74][75]101,102]. In accordance, basal [Ca 2+ ] i and InsP 3 -induced ER Ca 2+ release were both up-regulated in ACM C-hMSCs [4]. ...
Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder that may lead patients to sudden cell death through the occurrence of ventricular arrhythmias. ACM is characterised by the progressive substitution of cardiomyocytes with fibrofatty scar tissue that predisposes the heart to life-threatening arrhythmic events. Cardiac mesenchymal stromal cells (C-MSCs) contribute to the ACM by differentiating into fibroblasts and adipocytes, thereby supporting aberrant remodelling of the cardiac structure. Flecainide is an Ic antiarrhythmic drug that can be administered in combination with β-adrenergic blockers to treat ACM due to its ability to target both Nav1.5 and type 2 ryanodine receptors (RyR2). However, a recent study showed that flecainide may also prevent fibro-adipogenic differentiation by inhibiting store-operated Ca2+ entry (SOCE) and thereby suppressing spontaneous Ca2+ oscillations in C-MSCs isolated from human ACM patients (ACM C-hMSCs). Herein, we briefly survey ACM pathogenesis and therapies and then recapitulate the main molecular mechanisms targeted by flecainide to mitigate arrhythmic events, including Nav1.5 and RyR2. Subsequently, we describe the role of spontaneous Ca2+ oscillations in determining MSC fate. Next, we discuss recent work showing that spontaneous Ca2+ oscillations in ACM C-hMSCs are accelerated to stimulate their fibro-adipogenic differentiation. Finally, we describe the evidence that flecainide suppresses spontaneous Ca2+ oscillations and fibro-adipogenic differentiation in ACM C-hMSCs by inhibiting constitutive SOCE.
... This is a finding that may have relevant implications for the pathogenesis and progression of BD, especially with respect to STIM2. Specifically, of the two effectors, STIM2 is more widely expressed and is the most prominent effector of SOCE in the mouse hippocampus [61]. A key feature of STIM2 is its role in regulating basal Ca 2+ concentrations in the cytosol due to its higher dissociation constant (K D ) and sensitivity to smaller Ca 2+ fluctuations [41,[62][63][64]. ...
While most of the efforts to uncover mechanisms contributing to bipolar disorder (BD) focused on phenotypes at the mature neuron stage, little research has considered events that may occur during earlier timepoints of neurodevelopment. Further, although aberrant calcium (Ca²⁺) signaling has been implicated in the etiology of this condition, the possible contribution of store-operated Ca²⁺ entry (SOCE) is not well understood. Here, we report Ca²⁺ and developmental dysregulations related to SOCE in BD patient induced pluripotent stem cell (iPSC)-derived neural progenitor cells (BD-NPCs) and cortical-like glutamatergic neurons. First, using a Ca²⁺ re-addition assay we found that BD-NPCs and neurons had attenuated SOCE. Intrigued by this finding, we then performed RNA-sequencing and uncovered a unique transcriptome profile in BD-NPCs suggesting accelerated neurodifferentiation. Consistent with these results, we measured a slower rate of proliferation, increased neurite outgrowth, and decreased size in neurosphere formations with BD-NPCs. Also, we observed decreased subventricular areas in developing BD cerebral organoids. Finally, BD NPCs demonstrated high expression of the let-7 family while BD neurons had increased miR-34a, both being microRNAs previously implicated in neurodevelopmental deviations and BD etiology. In summary, we present evidence supporting an accelerated transition towards the neuronal stage in BD-NPCs that may be indicative of early pathophysiological features of the disorder.
... In the present study, we detected TRPC1, Orai1 and STIM1 expression in cells stained with the stem cell marker SOX2, both in area postrema neurosphere cultures and in vivo in brainstem sections, supporting that area postrema NSCs are endowed with proteins than can form SOCs and with their activator STIM1. In addition to STIM1, STIM2 is expressed in the brain, particularly in the hippocampus and cortex and may contribute to SOCE (Kraft, 2015;Moccia et al., 2015). However, STIM2 is mostly expressed in mature neurons while STIM1 predominates in immature cells (Kushnireva et al., 2020). ...
Neural stem cells (NSCs) persist in specific brain germinative niches and sustain neurogenesis throughout life in adult mammals. In addition to the two major stem cell niches in the subventricular zone and the hippocampal dentate gyrus, the area postrema located in the brainstem has been identified as a neurogenic zone as well. NSCs are regulated by signals from the microenvironment that adjust stem cell response to the needs of the organism. Evidence accumulated over the past decade indicates that Ca2+ channels play pivotal functions in NSC maintenance. In this study, we explored in area postrema NSCs the presence and roles of a subset of Ca2+ channels, the store-operated Ca2+ channels (SOCs) that have the capacity to transduce extracellular signals into Ca2+ signals. Our data show that NSCs derived from the area postrema express TRPC1 and Orai1, known to form SOCs, as well as their activator STIM1. Ca2+ imaging indicated that NSCs exhibit store-operated Ca2+ entries (SOCEs). Pharmacological blockade of SOCEs with SKF-96365, YM-58483 (also known as BTP2) or GSK-7975A resulted in decreased NSC proliferation and self-renewal, indicating a major role for SOCs in maintaining NSC activity within the area postrema. Furthermore, our results show that leptin, an adipose tissue-derived hormone whose ability to control energy homeostasis is dependent on the area postrema, decreased SOCEs and reduced self-renewal of NSCs in the area postrema. As aberrant SOC function has been linked to an increasing number of diseases, including brain disorders, our study opens new perspectives for NSCs in brain pathophysiology.
... It was suggested that it plays an important function in the maintenance of dendritic spines and memory storage [275]. In addition, growing evidence suggests that ORAI1 and STIM2 may be implicated in the pathogenesis of neurodegeneration [276]. On the other hand, a recent study showed that the downregulation of ORAI2 increases SOCE activity and decreases Aβ 42 accumulation [277]. ...
Alzheimer’s disease (AD) is a chronic neurodegenerative disease and the most frequent cause of progressive dementia in senior adults. It is characterized by memory loss and cognitive impairment secondary to cholinergic dysfunction and N-methyl-D-aspartate (NMDA)-mediated neurotoxicity. Intracellular neurofibrillary tangles, extracellular plaques composed of amyloid-β (Aβ), and selective neurodegeneration are the anatomopathological hallmarks of this disease. The dysregulation of calcium may be present in all the stages of AD, and it is associated with other pathophysiological mechanisms, such as mitochondrial failure, oxidative stress, and chronic neuroinflammation. Although the cytosolic calcium alterations in AD are not completely elucidated, some calcium-permeable channels, transporters, pumps, and receptors have been shown to be involved at the neuronal and glial levels. In particular, the relationship between glutamatergic NMDA receptor (NMDAR) activity and amyloidosis has been widely documented. Other pathophysiological mechanisms involved in calcium dyshomeostasis include the activation of L-type voltage-dependent calcium channels, transient receptor potential channels, and ryanodine receptors, among many others. This review aims to update the calcium-dysregulation mechanisms in AD and discuss targets and molecules with therapeutic potential based on their modulation.
... been found in the brain of animal models like xenopus [127], zebrafish [128,129], and drosophila [130]. STIM expression has been thoroughly investigated in the central nervous system of rodents [131,132], notably in the cortex, hippocampus, and cerebellum [133][134][135][136]. Although STIM1-2 proteins are present in these three brain areas [122], STIM2 is considered as the major STIM member in the mouse hippocampus and cortex [117,121,134,135,137,138]. STIM1 is expressed throughout the rodent brain, notably in the cortex [139], predominating over STIM2 in the cerebellum [109,[133][134][135] and the hypothalamus [122]. ...
The endoplasmic reticulum (ER) is the major intracellular calcium (Ca²⁺) storage compartment in eukaryotic cells. In most instances, the mobilization of Ca²⁺ from this store is followed by a delayed and sustained uptake of Ca²⁺ through Ca²⁺-permeable channels of the cell surface named store-operated Ca²⁺ channels (SOCCs). This gives rise to a store-operated Ca²⁺ entry (SOCE) that has been thoroughly investigated in electrically non-excitable cells where it is the principal regulated Ca²⁺ entry pathway. The existence of this Ca²⁺ route in neurons has long been a matter of debate. However, a growing body of experimental evidence indicates that the recruitment of Ca²⁺ from neuronal ER Ca²⁺ stores generates a SOCE. The present review summarizes the main studies supporting the presence of a depletion-dependent Ca²⁺ entry in neurons. It also addresses the question of the molecular composition of neuronal SOCCs, their expression, pharmacological properties, as well as their physiological relevance.
... Although the role of SOCE in the brain cells is only beginning to be elucidated, its link to AD pathogenesis has been already suggested (Briggs et al., 2017;Kraft, 2015;Moccia et al., 2015;Pchitskaya et al., 2018;Secondo et al., 2018;Wegierski and Kuznicki, 2018). A mutationspecific and cell type-specific reduction of SOCE in AD was postulated (McLarnon, 2020;Wu, 2020). ...
Protein misfolding is prominent in early cellular pathology of Alzheimer's disease (AD), implicating pathophysiological significance of endoplasmic reticulum stress/unfolded protein response (ER stress/UPR) and highlighting it as a target for drug development. Experimental data from animal AD models and observations on human specimens are, however, inconsistent. ER stress and associated UPR are readily observed in in vitro AD cellular models and in some AD model animals. In the human brain, components and markers of ER stress as well as UPR transducers are observed at Braak stages III-VI associated with severe neuropathology and neuronal death. The picture, however, is further complicated by the brain region- and cell type-specificity of the AD-related pathology. Terms 'disturbed' or 'non-canonical' ER stress/UPR were used to describe the discrepancies between experimental data and the classic ER stress/UPR cascade. Here we discuss possible 'disturbing' or 'interfering' factors which may modify ER stress/UPR in the early AD pathogenesis. We focus on the dysregulation of the ER Ca2+ homeostasis, store-operated Ca2+ entry, and the interaction between the ER and mitochondria. We suggest that a detailed study of the CNS cell type-specific alterations of Ca2+ homeostasis in early AD may deepen our understanding of AD-related dysproteostasis.
... The mechanisms whereby a reduction in [Ca 2+ ]ER leads to SOCE activation in endothelial cells [28,30], as well as in both non-excitable [52] and excitable cells [74], have been object of intense scrutiny over the years. A groundbreaking discovery was published in 2005, when Roos et al. demonstrated that stromal interaction molecule 1 (STIM1) was crucial to elicit SOCE [75]. ...
... The mechanistic coupling between ER Ca 2+ release and I CRAC /SOCE activation is strengthened by the tonic inhibition of InsP 3 Rs by inactivated STIM proteins [96]. Subsequent evidence confirmed that STIM1 and Orai1 support SOCE in virtually all cell types [52,74,94,95]. Orai1 presents a shorter splicing variant, known as Orai1β, which lacks 64 a.a. in the NH 2 -terminal tail but is still activated by ER Ca 2+ depletion and can therefore mediate the I CRAC [97]. ...
... The pharmacological blockade of Orai1 inhibited NO release induced in human cerebrovascular endothelial cells by multiple neurotransmitters, such as glutamate [165,166], GABA [167,168], and acetylcholine [62], and neuromodulators, including histamine [169] and arachidonic acid [170]. Interestingly, Orai2 is the only isoform expressed in mouse cerebrovascular endothelial cells [21], which is consistent with the crucial role played by Orai2 in neuronal SOCE in mice [74]. The pharmacological inhibition of Orai2 also attenuated endothelium-derived NO production at the mouse neurovascular unit [21,171]. ...
Store-operated Ca²⁺ entry (SOCE) is activated in response to the inositol-1,4,5-trisphosphate (InsP3)-dependent depletion of the endoplasmic reticulum (ER) Ca²⁺ store and represents a ubiquitous mode of Ca²⁺ influx. In vascular endothelial cells, SOCE regulates a plethora of functions that maintain cardiovascular homeostasis, such as angiogenesis, vascular tone, vascular permeability, platelet aggregation, and monocyte adhesion. The molecular mechanisms responsible for SOCE activation in vascular endothelial cells have engendered a long-lasting controversy. Traditionally, it has been assumed that the endothelial SOCE is mediated by two distinct ion channel signalplexes, i.e., STIM1/Orai1 and STIM1/Transient Receptor Potential Canonical 1(TRPC1)/TRPC4. However, recent evidence has shown that Orai1 can assemble with TRPC1 and TRPC4 to form a non-selective cation channel with intermediate electrophysiological features. Herein, we aim at bringing order to the distinct mechanisms that mediate endothelial SOCE in the vascular tree from multiple species (e.g., human, mouse, rat, and bovine). We propose that three distinct currents can mediate SOCE in vascular endothelial cells: (1) the Ca²⁺-selective Ca²⁺-release activated Ca²⁺ current (ICRAC), which is mediated by STIM1 and Orai1; (2) the store-operated non-selective current (ISOC), which is mediated by STIM1, TRPC1, and TRPC4; and (3) the moderately Ca²⁺-selective, ICRAC-like current, which is mediated by STIM1, TRPC1, TRPC4, and Orai1.
