IP 3 receptor mutations and brain diseases in human and rodents

The inositol 1,4,5‐trisphosphate receptor ( IP 3 R) is a huge Ca 2+ channel that is localized at the endoplasmic reticulum. The IP 3 R releases Ca 2+ from the endoplasmic reticulum upon binding to IP 3 , which is produced by various extracellular stimuli through phospholipase C activation. All vertebrate organisms have three subtypes of IP 3 R genes, which have distinct properties of IP 3 ‐binding and Ca 2+ sensitivity, and are differently regulated by phosphorylation and by their associated proteins. Each cell type expresses the three subtypes of IP 3 R in a distinct proportion, which is important for creating and maintaining spatially and temporally appropriate intracellular Ca 2+ level patterns for the regulation of specific physiological phenomena. Of the three types of IP 3 Rs, the type 1 receptor ( IP 3 R1) is dominantly expressed in the brain and is important for brain function. Recent emerging evidence suggests that abnormal Ca 2+ signals from the IP 3 R1 are closely associated with human brain pathology. In this review, we focus on the recent advances in our knowledge of the regulation of IP 3 R1 and its functional implication in human brain diseases, as revealed by IP 3 R mutation studies and analysis of human disease‐associated genes. This article is part of the mini review series “60th Anniversary of the Japanese Society for Neurochemistry” .