Spatial localization of SOCE channels and its modulators regulate neuronal physiology and contributes to pathology

Ca²⁺ function as second messenger and changes in cytosolic Ca²⁺ levels dictate neuronal physiology. Although several Ca²⁺ entry channels are present in neuronal cells, release of Ca²⁺ from intracellular endoplasmic reticulum (ER) stores modulates store-operated Ca²⁺ entry (SOCE) that restore ER Ca²⁺ levels and maintains Ca²⁺ homeostasis in organelles such as: mitochondria, Golgi apparatus, lysosomes and associated vesicles, and nucleus. Members of the Orai and canonical TRPC channels that are gated by ER Ca²⁺ sensor STIM1 induces SOCE in neuronal and associated cells. Similarly, mitochondrial Ca²⁺ uniporter is essential for mitochondrial Ca²⁺ uptake; whereas two-pore Ca²⁺ channels and the mucolipin are essential for lysosomal functions. Interestingly, spatiotemporal compartmentalization of Ca²⁺ in various organelle modulate diverse and opposing functions. Thus, interplay between organelle Ca²⁺ and Ca²⁺ influx provide the spatial resolution that is imperative for executing the precise neuronal responses and alterations in Ca²⁺ signaling leads to neuronal loss.