Store-Operated Calcium Channels in the Nervous System

Store-operated Ca²⁺ entry (SOCE) is a widespread mechanism of cellular Ca²⁺ signaling that arises from Ca²⁺ influx across the plasma membrane through the Orai family of calcium channels in response to depletion of intracellular Ca²⁺ stores. Orai channels are a crucial Ca²⁺ entry mechanism in both neurons and glia and are activated by a unique inside-out gating process involving interactions with the endoplasmic reticulum Ca²⁺ sensors, STIM1 and STIM2. Recent evidence indicates that SOCE is broadly found across all areas of the nervous system where its physiology and pathophysiology is only now beginning to be understood. Here, we review the growing literature on the mechanisms of SOCE in the nervous system and contributions to gene expression, neuronal excitability, synaptic plasticity, and behavior. We also explore the burgeoning links between SOCE and neurological disease and discuss therapeutic implications of targeting SOCE for brain disorders.