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.

Keywords: Ca2+ channels; SOCE components; STIM; STIM regulators and effectors; calcium signaling; central nervous system; glutamate receptors; store-operated calcium entry (SOCE).

Figure 1

STIM activation and coupling with Orai1 in a mechanism of SOCE. Activation of STIM dimers is initiated by low Ca²⁺ concentration in the ER. STIMs oligomerize and migrate to ER–PM junctions where they activate SOC channels (e.g., Orai1) causing Ca²⁺ influx from the extracellular milieu to the cytoplasm and then refilling ER Ca²⁺ stores. SAM sterile alpha motif, TMD transmembrane domain, CC coiled-coil, SOAR STIM–Orai-activating region.

Figure 2

Impact of Ca²⁺ overload on STIM expression level and SOCE in the development of CNS disorders. In hypoxic/ischemic neuronal injury, TBI, epilepsy, PD, and HD Ca²⁺ overload is associated with increased STIM expression level and SOCE and thus decreased ER Ca²⁺ level. Contrary, in AD Ca²⁺ overload results in decreased STIM expression level and SOCE and thus increased ER Ca²⁺ level. SOCE blockage and STIM downregulation seem to be neuroprotective in hypoxic/ischemic neuronal brain injury, epilepsy, TBI, HD, and PD, while in AD increased expression level of STIMs and SOCE enhancement appear to be neuroprotective.

Figure 3

Schematic overview of key regulators and effectors of STIM proteins in the CNS. Negative regulators (—|): SARAF prevents STIM1 activation and inhibits the STIM1-Orai association. SARAF silencing increases TRPC1-mediated Ca²⁺ entry. The PS1–γ-secretase complex cleaves the STIM1 transmembrane domain. Homer1a dissociates the STIM1-Orai1 complex. Lower dSEPT7 expression increases the amount of dSTIM-dOrai clusters. Positive regulators (→): The glutamate-mediated activation of mGluRs results in Ca²⁺ release from ER stores via IP₃Rs and activates STIM-Orai coupling. EB3 forms complexes with STIM2, which promotes the formation of mushroom spines in hippocampal neurons. SEPT1/4 regulates the number of ER-PM junctions and enhances STIM1-Orai1 interactions. The STIM1-POST complex binds to SERCA and promotes ER Ca²⁺ refilling. Golli proteins interact with STIM1 and TRPC1 and thus enhance SOCE. SP interacts with STIM and Orai and determines synaptic plasticity. Positive effectors (+): STIM proteins increase Ca²⁺ influx via Orai, TRPC, and AMPARs. STIM2-mediated SOCE activates CaMKII and thus stabilizes mushroom spines. Negative effectors (–): STIM proteins decrease Ca²⁺ influx via L-type VGCCs and NMDARs.