Agonist-stimulated phosphatidylinositol 4,5-bisphosphate metabolism in the nervous system

Phosphatidylinositol 4,5-bisphosphate has recently gained prominence as the central component of a receptor transduction process which generates inositol 1,4,5-trisphosphate and diacylglycerol in stimulated cells. Both of these products of phospholipid metabolism have intracellular second messenger functions with diacylglycerol formation leading to activation of protein kinase C and inositol 1,4,5-trisphosphate stimulating Ca(2+) release from intracellular stores in the endoplasmic reticulum. There is mounting evidence that the phospholipase C which hydrolyses phosphatidylinositol 4,5-bisphosphate is coupled to activated receptors by a guanylnucleotide binding protein, analogous to Ns and Ni which couple stimulatory and inhibitory hormone receptors to adenylate cyclase. Most of the key elements of this signalling mechanism have been found in the nervous system and so too has an entirely novel and unexpected inositol phosphate ester, inositol 1,3,4,5-tetrakisphosphate, whose function is not yet known. Phosphatidylinositol 4,5-bisphosphate breakdown, detected as the accumulation of inositol phosphates in agonist-stimulated nervous tissue preparations, is a functional response that has been useful in assessing the relevance of receptors identified by radioligand binding assays, and which provides an essential link between receptor occupation and responses such as neurotransmitter release and modulation of neuronal excitability.