Store-Operated Calcium Channels in Physiological and Pathological States of the Nervous System

Zhang, Isis; Hu, Huijuan

doi:10.3389/fncel.2020.600758

Cited by 26 publications

(19 citation statements)

References 167 publications

(275 reference statements)

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“…SOCE plays an important role in the nerve terminals where α-syn is present in high concentrations (77). Upon Ca 2+ depletion of ER, Ca 2+ -selective store-operated channels (SOCs) are assembled by interaction between ER Ca 2+ -sensing STIM1/2 proteins and plasma membrane-associated ORAI1/2/3 proteins, which together form the PM Ca 2+ release-activated Ca 2+ (CRAC) channels, thereby allowing restoration of ER Ca 2+ stores by influx from the extracellular space (78). In addition to ORAI proteins, the transient receptor potential canonical channels (TRPC) have also been suggested to participate in CRAC channel formation (78,79).…”

Section: Ryrmentioning

confidence: 99%

“…By inducing Ca 2+ influx into the cytoplasm and ER as a consequence of ER Ca 2+ depletion, SOCE plays an important role in maintaining neuronal Ca 2+ homeostasis, and SOCE has been linked to a multitude of biological processes, including transcription, exocytosis, and metabolism (78). The α-syn aggregate dependent activation of SERCA that increases ER Ca 2+ levels holds potential for disturbing SOCE (21).…”

Section: Ryrmentioning

confidence: 99%

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Endoplasmic Reticulum-Based Calcium Dysfunctions in Synucleinopathies

2021

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Neuronal calcium dyshomeostasis has been associated to Parkinson's disease (PD) development based on epidemiological studies on users of calcium channel antagonists and clinical trials are currently conducted exploring the hypothesis of increased calcium influx into neuronal cytosol as basic premise. We reported in 2018 an opposite hypothesis based on the demonstration that α-synuclein aggregates stimulate the endoplasmic reticulum (ER) calcium pump SERCA and demonstrated in cell models the existence of an α-synuclein-aggregate dependent neuronal state wherein cytosolic calcium is decreased due to an increased pumping of calcium into the ER. Inhibiting the SERCA pump protected both neurons and an α-synuclein transgenic C. elegans model. This models two cellular states that could contribute to development of PD. First the prolonged state with reduced cytosolic calcium that could deregulate multiple signaling pathways. Second the disease ER state with increased calcium concentration. We will discuss our hypothesis in the light of recent papers. First, a mechanistic study describing how variation in the Inositol-1,4,5-triphosphate (IP3) kinase B (ITPKB) may explain GWAS studies identifying the ITPKB gene as a protective factor toward PD. Here it was demonstrated that how increased ITPKB activity reduces influx of ER calcium to mitochondria via contact between IP3-receptors and the mitochondrial calcium uniporter complex in ER-mitochondria contact, known as mitochondria-associated membranes (MAMs). Secondly, it was demonstrated that astrocytes derived from PD patients contain α-synuclein accumulations. A recent study has demonstrated how human astrocytes derived from a few PD patients carrying the LRRK2-2019S mutation express more α-synuclein than control astrocytes, release more calcium from ER upon ryanodine receptor (RyR) stimulation, show changes in ER calcium channels and exhibit a decreased maximal and spare respiration indicating altered mitochondrial function in PD astrocytes. Here, we summarize the previous findings focusing the effect of α-synuclein to SERCA, RyR, IP3R, MCU subunits and other MAM-related channels. We also consider how the SOCE-related events could contribute to the development of PD.

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Section: Ryrmentioning

confidence: 99%

Section: Ryrmentioning

confidence: 99%

Endoplasmic Reticulum-Based Calcium Dysfunctions in Synucleinopathies

2021

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“…The role of SOCs in abnormal Ca 2+ handling in DMD has been investigated, and targeting of SOCs to restore Ca 2+ homeostasis for DMD therapies has been discussed previously [ 18 , 54 ]. While Orai1 and STIM1 are major components of SOCs, other Ca 2+ channels, such as TRPC1, TRPV, and TRPM7, also contribute to SOC activity [ 55 , 56 ]. In this study, siRNA-mediated knockdown experiments revealed that Orai1 and STIM1 are the most prominent candidates for SOCs regulating Ca 2+ overload in DMD.…”

Section: Discussionmentioning

confidence: 99%

Orai1–STIM1 Regulates Increased Ca2+ Mobilization, Leading to Contractile Duchenne Muscular Dystrophy Phenotypes in Patient-Derived Induced Pluripotent Stem Cells

Uchimura

Sakurai

2021

Biomedicines

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Ca2+ overload is one of the factors leading to Duchenne muscular dystrophy (DMD) pathogenesis. However, the molecular targets of dystrophin deficiency-dependent Ca2+ overload and the correlation between Ca2+ overload and contractile DMD phenotypes in in vitro human models remain largely elusive. In this study, we utilized DMD patient-derived induced pluripotent stem cells (iPSCs) to differentiate myotubes using doxycycline-inducible MyoD overexpression, and searched for a target molecule that mediates dystrophin deficiency-dependent Ca2+ overload using commercially available chemicals and siRNAs. We found that several store-operated Ca2+ channel (SOC) inhibitors effectively prevented Ca2+ overload and identified that STIM1–Orai1 is a molecular target of SOCs. These findings were further confirmed by demonstrating that STIM1–Orai1 inhibitors, CM4620, AnCoA4, and GSK797A, prevented Ca2+ overload in dystrophic myotubes. Finally, we evaluated CM4620, AnCoA4, and GSK7975A activities using a previously reported model recapitulating a muscle fatigue-like decline in contractile performance in DMD. All three chemicals ameliorated the decline in contractile performance, indicating that modulating STIM1–Orai1-mediated Ca2+ overload is effective in rescuing contractile phenotypes. In conclusion, SOCs are major contributors to dystrophin deficiency-dependent Ca2+ overload through STIM1–Orai1 as molecular mediators. Modulating STIM1–Orai1 activity was effective in ameliorating the decline in contractile performance in DMD.

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“…However, different cell distribution as well as potentially different functions of STIM1 and STIM2 may also be contributing factors. For example, STIM2 has been implicated in regulating basal neuronal Ca 2+ levels, whereas it has been suggested that STIM1 is an important regulator of mGluR1-mediated Ca 2+ signaling ( Zhang and Hu, 2020 ). Similar to the cardiomyocyte studies, targeting the balance between STIM1 and STIM2 levels should be explored in more detail.…”

Section: Stim/orai In Neurodegenerationmentioning

confidence: 99%

STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases

2022

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Tight spatiotemporal regulation of intracellular Ca2+ plays a critical role in regulating diverse cellular functions including cell survival, metabolism, and transcription. As a result, eukaryotic cells have developed a wide variety of mechanisms for controlling Ca2+ influx and efflux across the plasma membrane as well as Ca2+ release and uptake from intracellular stores. The STIM and Orai protein families comprising of STIM1, STIM2, Orai1, Orai2, and Orai3, are evolutionarily highly conserved proteins that are core components of all mammalian Ca2+ signaling systems. STIM1 and Orai1 are considered key players in the regulation of Store Operated Calcium Entry (SOCE), where release of Ca2+ from intracellular stores such as the Endoplasmic/Sarcoplasmic reticulum (ER/SR) triggers Ca2+ influx across the plasma membrane. SOCE, which has been widely characterized in non-excitable cells, plays a central role in Ca2+-dependent transcriptional regulation. In addition to their role in Ca2+ signaling, STIM1 and Orai1 have been shown to contribute to the regulation of metabolism and mitochondrial function. STIM and Orai proteins are also subject to redox modifications, which influence their activities. Considering their ubiquitous expression, there has been increasing interest in the roles of STIM and Orai proteins in excitable cells such as neurons and myocytes. While controversy remains as to the importance of SOCE in excitable cells, STIM1 and Orai1 are essential for cellular homeostasis and their disruption is linked to various diseases associated with aging such as cardiovascular disease and neurodegeneration. The recent identification of splice variants for most STIM and Orai isoforms while complicating our understanding of their function, may also provide insight into some of the current contradictions on their roles. Therefore, the goal of this review is to describe our current understanding of the molecular regulation of STIM and Orai proteins and their roles in normal physiology and diseases of aging, with a particular focus on heart disease and neurodegeneration.

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Store-Operated Calcium Channels in Physiological and Pathological States of the Nervous System

Cited by 26 publications

References 167 publications

Endoplasmic Reticulum-Based Calcium Dysfunctions in Synucleinopathies

Endoplasmic Reticulum-Based Calcium Dysfunctions in Synucleinopathies

Orai1–STIM1 Regulates Increased Ca2+ Mobilization, Leading to Contractile Duchenne Muscular Dystrophy Phenotypes in Patient-Derived Induced Pluripotent Stem Cells

STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases

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