NEW DEVELOPMENTS IN THE MOLECULAR PHARMACOLOGY OF THE MYOINOSITOL 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 IP3 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 Ca2+ ions to move between cellular compartments. As IP3 receptors are located principally, alth ough not exclusively, in the endoplasmic reticular membrane, Ins(1,4,5 )P-3 is considered to be a second messenger that mobilizes Ca2+ from i ntracellular stores. Ca2+ store mobilization by Ins(1,4,5)P-3 can be s hown to contribute to a variety of physiological and pathophysiologica l phenomena, and therefore the IP3 receptor represents a novel, potent ial pharmacological target. In this article, Rob Wilcox and colleagues review recent developments in IP3 receptor pharmacology, with particu lar emphasis on ligand molecular recognition by this receptor-channel complex. The potential for designing non-inositol phosphate-based agon ists and antagonists is also discussed.