Target Molecules of STIM Proteins in the Central Nervous System

Abstract

Stromal interaction molecules (STIMs), including STIM1 and STIM2, are single-pass transmembrane proteins that are located predominantly in the endoplasmic reticulum (ER). They serve as calcium ion (Ca2+) sensors within the ER. In the central nervous system (CNS), they are involved mainly in Orai-mediated store-operated Ca2+ entry (SOCE). The key molecular components of the SOCE pathway are well-characterized, but the molecular mechanisms that underlie the regulation of this pathway need further investigation. Numerous intracellular target proteins that are located in the plasma membrane, ER, cytoskeleton, and cytoplasm have been reported to play essential roles in concert with STIMs, such as conformational changes in STIMs, their translocation, the stabilization of their interactions with Orai, and the activation of other channels. The present review focuses on numerous regulators, such as Homer, SOCE-associated regulatory factor (SARAF), septin, synaptopodin, golli proteins, partner of STIM1 (POST), and transcription factors and proteasome inhibitors that regulate STIM-Orai interactions in the CNS. Further we describe novel roles of STIMs in mediating Ca2+ influx via other than Orai pathways, including TRPC channels, VGCCs, AMPA and NMDA receptors, and group I metabotropic glutamate receptors. This review also summarizes recent findings on additional molecular targets of STIM proteins including SERCA, IP3Rs, end-binding proteins (EB), presenilin, and CaMKII. Dysregulation of the SOCE-associated toolkit, including STIMs, contributes to the development of neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, and Huntington's disease), traumatic brain injury, epilepsy, and stroke. Emerging evidence points to the role of STIM proteins and several of their molecular effectors and regulators in neuronal and glial physiology and pathology, suggesting their potential application for future therapeutic strategies.

AaTs-1: A Tetrapeptide from Androctonus australis Scorpion Venom, Inhibiting U87 Glioblastoma Cells Proliferation by p53 and FPRL-1 Up-Regulations

“…The SOCE process, whereby calcium influx across the plasma membrane, is related to the IP3 receptor (IP3R) leading to its activation in response to depletion of intracellular calcium stores of the endoplasmic reticulum (ER) [55]. Our results showed that the blocking of FPRL by AaTs-1 reduced SOCE by acting both on SOC (store operated channels), an effect observed near IC 50 for AaTs-1, and for higher AaTs-1 concentrations on ER release and most likely on the stromal interaction molecules STIMs (the reticular protein partners connected to SOC) [56]. Both concentrations SOCE were reduced, which could explain the AaTs-1 effect on cell proliferation.…”

DrosophilaSPG12 ortholog, reticulon-like 1, governs presynaptic ER organization and Ca2+dynamics

“…The lowered cytosolic Ca 2+ fluxes in Rtnl1 mutants (Fig. 5) might potentially be explained by disruption of ER-PM contacts that contain STIM (Serwach & Gruszczynska-Biegala, 2020). However, the lack of any decrease in resting Ca 2+ levels in any compartment in Rtnl1 mutants does not provide any evidence for a defect in SOCE.…”

Junctophilins: Key Membrane Tethers in Muscles and Neurons

“…ER calcium sensor STIM1 senses the drop in calcium concentration and relocalizes to ER–PM contacts, where it activates PM-localized calcium channel Orai1 to allow the entry of extracellular calcium. Sarco/ER calcium transport ATPase (SERCA) pumps then take up the calcium into the ER ( Serwach and Gruszczynska-biegala, 2020 ).…”