IP3 receptor mutations and brain diseases in human and rodents

Abstract

The inositol 1,4,5-trisphosphate receptor (IP₃ R) is a huge Ca²⁺ channel that is localized at the endoplasmic reticulum. The IP₃ R releases Ca²⁺ from the endoplasmic reticulum upon binding to IP₃ , which is produced by various extracellular stimuli through phospholipase C activation. All vertebrate organisms have three subtypes of IP₃ R genes, which have distinct properties of IP₃ -binding and Ca²⁺ sensitivity, and are differently regulated by phosphorylation and by their associated proteins. Each cell type expresses the three subtypes of IP₃ R in a distinct proportion, which is important for creating and maintaining spatially and temporally appropriate intracellular Ca²⁺ level patterns for the regulation of specific physiological phenomena. Of the three types of IP₃ Rs, the type 1 receptor (IP₃ R1) is dominantly expressed in the brain and is important for brain function. Recent emerging evidence suggests that abnormal Ca²⁺ signals from the IP₃ R1 are closely associated with human brain pathology. In this review, we focus on the recent advances in our knowledge of the regulation of IP₃ R1 and its functional implication in human brain diseases, as revealed by IP₃ 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".

Keywords: Purkinje cell; calcium; disease; endoplasmic reticulum.