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.