Inositol 1,4,5-trisphosphate-gated calcium channel ITPR1

ITPR1 encodes inositol 1,4,5-trisphosphate-gated calcium channel, a key regulator of calcium release from the endoplasmic reticulum. Upon ligand binding, the channel undergoes conformational changes to release calcium ions across the ER membrane. Released cytoplasmic calcium triggers apoptosis through CAMK2 activation and participates in mitochondrial calcium-dependent apoptosis via the HSPA9–ITPR1–VDAC1 complex (UniProt: Q14643). ITPR1 is also involved in epithelial electrolyte secretion and regulates calcium oscillations during fertilization and egg activation.

ITPR1 mutations cause several cerebellar disorders, including spinocerebellar ataxias 15 and 29 (SCA15, SCA29) and Gillespie syndrome, which present with progressive ataxia, cerebellar atrophy, and variable cognitive and motor symptoms (UniProt: Q14643).

ITPR1 is downregulated in Alzheimer's disease brain tissue. Chaparral AD proteomics data from post-mortem AD brain compared to age-matched controls show ITPR1 reduced by a mean log2 fold-change of −0.5951 (Chaparral AD proteomics). This downregulation may reflect impaired ER-to-mitochondrial calcium signaling and apoptotic regulation in AD pathogenesis.