Structure and function of inositol 1,4,5-trisphosphate receptors

Abstract

The InsP₃R is an intracellular calcium release channel that forms an important component of the InsP₃ signalling pathway and is ubiquitously expressed in multicellular organisms. Molecular studies have identified three separate genes in mammals that code for the three isoforms of InsP₃Rs. These three isoforms are shown to have different ligand affinities and modulatory properties. These differences are presently thought to generate the heterogeneity required in calcium dynamics to regulate processes as diverse as secretion, synaptic plasticity, immune responses in T cells and fertilization events in sea urchin eggs. The understanding of these processes mandates an understanding of the single channel properties of the three isoforms as well as splice variants that are expressed in a tissue-specific manner. Recent single channel studies aimed at understanding the functional properties of the InsP₃Rs using point mutants in the channel have uncovered important residues that affect the calcium dependence and ion selectivity of the channel. Genetic studies using knockouts of the mammalian InsP₃Rs appear inadequate to relate the channel function to the physiological behaviour at an animal level most likely due to compensation by other isoforms of the channel. In this scenario, study of InsP₃R in Drosophila melanogaster, that encodes a single gene for InsP₃R should prove useful in correlating single channel properties of the channel with phenotypes of the whole organism.