Stim and Orai proteins in neuronal Ca2+ signaling and excitability

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.

Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

“…The reticular distribution of s-1R-YFP was recapitulated using a s-1R-mCh construct that was cotransfected with a green fluorescent protein-tagged STIM1. STIM1 is a sensor of Ca 21 levels in the ER and forms part of the store operated calcium entry response after Ca 21 depletion from the ER (Kraft, 2015;Moccia et al, 2015). As expected, STIM1-YFP overlapped extensively with s-1R-mCherry (s-1R-mCh; Fig.…”

Contacts between the endoplasmic reticulum and other membranes in neurons

“…Both stromal interaction molecule (STIM) and ORAi proteins, key players in SOCE, and ryanodine receptors, ER-localized Ca 2+ channels responsible for Ca 2+ -induced Ca 2+ release at the ER-PM junction in muscle (75,77), are expressed in neurons (78,79). Similarly, isoforms of junctophilin, another integral protein of the ER membrane that binds the PM in trans and functions as an accessory factor of the ryanodine receptors at muscle triads, are expressed in neurons (80)(81)(82).…”

Mesenchimal stem cells: a possible role in the pathogenesis and treatment of spondyloarthritis

“…Other studies evaluated the optimal conditions for the differentiation of MSCs to tenocytes, chondrocytes, or bone cells The results showed that mesenchymatous cell differentiation toward a tendon or bone phenotype depended on the degree of tensile loading: higher tensile loads promoted osteogenic differentiation (38). Mechanosensitive calcium permeable channels, such as the TRP channel, generate changes in intracellular calcium concentration in response to various mechanical stimuli (39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54). Activation of these channels at the level of plasma membrane of MSCs would induce intracellular calcium release and confirm the hypothesis that the mechanical tension could also activate MSCs in the pathological process that leads to the development of the SpAs (55-57).…”