William U. Primrose

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)P3] is a ubiquitous signalling pathway in mammalian systems. A family of three IP3 receptor subtype monomers form functional tetramers, which act as effectors for Ins(1,4,5)P3, providing a ligand-gated channel that allows Ca2+ ions to move between cellular compartments. As IP3 receptors are located principally, although not exclusively, in the endoplasmic reticular membrane, Ins(1,4,5)P3 is considered to be a second messenger that mobilizes Ca2+ from intracellular stores. Ca2+ store mobilization by Ins(1,4,5)P3 can be shown to contribute to a variety of physiological and pathophysiological phenomena, and therefore the IP3 receptor represents a novel, potential pharmacological target. In this article, Rob Wilcox and colleagues review recent developments in IP3 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.

NMR and IR Studies of the Effect of Calcium on the Binding of Inhibitors to Phospholipase A2

The phospholipases A2 are a ubiqiuitous family of Ca2+-dependent enzymes which catalyse the hydrolysis of fatty acids from phospholipids [1]. Subsequent metabolism results in the formation of leukotrienes and prostaglandins, which play a major role in the inflammatory response. There is thus a strong interest in the design of compounds which may inhibit enzymes of this class for use as drugs. In order to be able to do this efectively it is necessary to have a detailed knowledge of both the mode of substrate binding to the enzyme and the catalytic mechanism.