Abstract
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 intracellular Ca2+ reservoir and engage specific Ca2+-dependent processes, such as proliferation, migration, cytoskeletal remodeling, and gene expression. Their paralogs, Stim2, Orai2 and Orai3, support SOCE in heterologous expression systems, but their physiological role is still obscure. Ca2+ inflow in neurons has long been exclusively ascribed to voltage-operated and receptor-operated channels. Nevertheless, recent work has unveiled that Stim1–2 and Orai1-2, but not Orai3, proteins are also expressed and mediate SOCE in neurons. Herein, we survey current knowledge about the neuronal distribution of Stim and Orai proteins in rodent and human brains; we further discuss that Orai2 is the main pore-forming subunit of CRAC channels in central neurons, in which it may be activated by either Stim1 or Stim2 depending on species, brain region and physiological stimuli. We examine the functions regulated by SOCE in neurons, where this pathway is activated under resting conditions to refill the ER, control spinogenesis and regulate gene transcription. Besides, we highlighted the possibility that SOCE also controls neuronal excitation and regulate synaptic plasticity. Finally, we evaluate the involvement of Stim and Orai proteins in severe neurodegenerative and neurological disorders, such as Alzheimer’s disease and epilepsy.
Highlights
Neurons possess a highly developed Ca2+ machinery that delivers a multitude of Ca2+ signals precisely tailored at regulating specific neuronal functions (Berridge, 1998)
Ca2+ inflow from the external milieu is mediated by voltage-operated Ca2+ channels (VOCCs) or by receptoroperated channels (ROCs; Figure 1), such as the glutamate-sensitive N-methyl-D-aspartate receptors (NMDARs; Catterall, 2011; Paoletti et al, 2013)
store-operated Ca2+ entry (SOCE) is sustained by an alternative molecular machinery in mouse cerebellum: SOCE is absent in Purkinje neurons lacking Stromal interaction molecule 1 (Stim1) and Orai2, while it is not affected by Orai1 knockdown (Hartmann et al, 2014). These findings suggest that Orai2 provides the pore-forming subunit of Ca2+ release-activated Ca2+ (CRAC) channels in mouse neurons and is regulated by Stim1 in cerebellum and by Stim2 in cortex and hippocampus
Summary
Neurons possess a highly developed Ca2+ machinery that delivers a multitude of Ca2+ signals precisely tailored at regulating specific neuronal functions (Berridge, 1998). As virtually any other cell type (Clapham, 2007; Moccia et al, 2014c), neurons use both intra- and extracellular Ca2+ sources which may interact to control Ca2+-dependent processes (Berridge, 1998). Ca2+ inflow from the external milieu is mediated by voltage-operated Ca2+ channels (VOCCs) or by receptoroperated channels (ROCs; Figure 1), such as the glutamate-sensitive N-methyl-D-aspartate receptors (NMDARs; Catterall, 2011; Paoletti et al, 2013).
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