ITPR2 encodes an inositol 1,4,5-trisphosphate-gated calcium channel that mediates calcium release from the endoplasmic reticulum (ER) to the cytoplasm, functioning as a key regulator of intracellular calcium signaling 1. The channel exists in distinct conformational states, transitioning from a 'parked' closed state to active 'drive' mode upon ligand binding, enabling calcium flux essential for cellular processes 2. ITPR2 localizes to mitochondria-associated ER membranes (MAMs) where it forms complexes with Grp75 and VDAC1, facilitating ER-mitochondrial calcium transfer critical for bioenergetics and cellular homeostasis 2. Functionally, ITPR2-mediated calcium signaling regulates astrocytic ATP release, which modulates antidepressant-like effects in depression models 3, and controls cellular senescence and aging through ER-mitochondrial contacts 1. Disease relevance includes genetic associations with congenital vertebral malformation, where ITPR2 variants show large effect sizes in spine development 4, and Kashin-Beck disease, where SNP rs11048526 increases osteoarthropathy risk 5. Clinically, ITPR2 degradation by neutrophil elastase regulates hepatocyte calcium signaling in alcohol-associated hepatitis 6, suggesting therapeutic potential for modulating this pathway in liver disease and aging-related pathologies.