New developments in the molecular pharmacology of the myo-inositol 1,4,5-trisphosphate receptor

Receptor-mediated activation of phospholipase C to generate inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] is a ubiquitous signalling pathway in mammalian systems. A family of three IP(3) receptor subtype monomers form functional tetramers, which a ct as effecters for Ins(1,4,5)P(3), providing a ligand-gated channel that allows Ca(2+) ions to move between cellular compartments. As IP(3) receptors are located principally, although not exclusively, in the endoplasmic reticular membrane, Ins(1,4,5)P(3) is considered to be a second messenger that mobilizes Ca(2+) from intracellular stores. Ca(2+) store mobilization by Ins(1,4,5)P(3) can be shown to contribute to a variety of physiological and pathophysiological phenomena, and therefore the IP(3) receptor represents a novel, potential pharmacological target. In this article, Rob Wilcox and colleagues review recent developments in IP(3) receptor pharmacology, with particular emphasis on ligand molecular recognition by this receptor-channel complex. The potential for designing non-inositol phosphate-based agonists and antagonists is also discussed.