STIM-Orai signaling in neurons: integrating calcium dynamics and synaptic plasticity

Precise regulation of intracellular calcium signaling is essential for neuronal function and depends on tightly coordinated molecular mechanisms. Among them, endoplasmic reticulum-plasma membrane (ER-PM) junctions form dynamic signaling microdomains that support store-operated calcium entry (SOCE), lipid transfer, phosphoinositide signaling, and ion channel regulation. Within this context, stromal interaction molecules STIM1 and STIM2 act as ER calcium sensors with distinct activation properties. STIM1 is recruited during substantial ER calcium depletion and strong neuronal activity, whereas STIM2 responds to subtle calcium fluctuations and supports basal calcium homeostasis. Upon ER calcium depletion, STIM proteins undergo conformational rearrangement, oligomerization, and translocation to ER-PM junctions, where they engage Orai calcium channels to trigger calcium influx and restore ER calcium balance. Although originally characterized in non-excitable cells, the STIM-Orai signaling axis is now recognized as an important regulator of neuronal calcium dynamics. This system exhibits considerable molecular diversity, with multiple STIM and Orai isoforms and splice variants differing in activation thresholds, subcellular localization, and signaling properties. Consequently, neuronal SOCE is not a uniform calcium entry pathway but contributes to specialized functions across dendrites, dendritic spines, and presynaptic compartments. Beyond classical SOCE, STIM proteins also function as multifunctional organizers of ER architecture and ER-PM junctions, linking calcium homeostasis to dendritic spine morphology, receptor trafficking, neurotransmitter release, and synaptic plasticity. Despite significant progress in this field, a comprehensive comparative understanding of the isoform-specific roles of STIM and Orai proteins in neuronal compartments remains limited. This review summarizes current knowledge regarding the functions of STIM1, STIM2, and Orai1-3 in dendrites and synapses, emphasizing their distinct contributions to calcium homeostasis, local signaling microdomains, and activity-dependent versus homeostatic forms of synaptic plasticity. By integrating evidence from genetic, biochemical, and in vivo studies, this review further highlights region-specific and context-dependent effects, unresolved controversies regarding the physiological roles of STIM and Orai, and the consequences of their dysregulation for neuronal function.