Structure and function of inositol trisphosphate receptors.

Abstract

Inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) is a soluble intracellular messenger formed rapidly after activation of a variety of cell-surface receptors that stimulate phosphoinositidase C activity. The initial response to Ins(1,4,5)P3 is a rapid Ca2+ efflux from nonmitochondrial intracellular stores which are probably specialized subcompartments of the endoplasmic reticulum, although their exact identities remain unknown. This initial response is followed by more complex Ca2+ signals: regenerative Ca2+ waves propagate across the cell, repetitive Ca2+ spikes occur, and stimulated Ca2+ entry across the plasma membrane contributes to the sustained Ca2+ signal. The mechanisms underlying these complex Ca2+ signals are unknown, although Ins(1,4,5)P3 is clearly involved. The intracellular receptor that mediates Ins(1,4,5)P3-stimulated Ca2+ mobilization has been purified and functionally reconstituted, and its amino acid sequence deduced from its cDNA sequence. These studies demonstrate that the Ins(1,4,5)P3 receptor has an integral Ca2+ channel separated from the Ins(1,4,5)P3 binding site by a long stretch of residues some of which form binding sites for allosteric regulators, and some of which are substrates for phosphorylation. In this review, we discuss the ligand recognition characteristics of Ins(1,4,5)P3 receptors, and their functional properties in their native environment and after purification, and we relate these properties to what is known of the structure of the receptor. In addition to regulation by Ins(1,4,5)P3, the Ins(1,4,5)P3 receptor is subject to many additional regulatory influences which include Ca2+, adenine nucleotides, pH and phosphorylation by protein kinases. Many of the functional and structural characteristics of the Ins(1,4,5)P3 receptor show striking similarities to another intracellular Ca2+ channel, the ryanodine receptor. These properties of the Ins(1,4,5)P3 are discussed, and their possible roles in contributing to the complex Ca2+ signals evoked by extracellular stimuli are considered.