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.