Phosphoinositides and calcium signaling New aspects and diverse functions in cell regulation

Numerous circulating and locally produced hormones bind to specific cell-surface receptors and activate a variety of second-messenger pathways that evoke characteristic phenotypic responses in their target cells. One of the most ubiquitous signal transduction mechanisms is the phosphoinositide-calcium messenger system, which is activated by hormones, neurotransmitters, and growth factors. Stimulation of these receptors by their ligands causes a characteristic change in the metabolism of membrane phospholipids with production of diacylglycerol and a rapid increase in cytoplasmic Ca(2+) concentration, due to the release of stored intracellular Ca(2+) and stimulated Ca(2+) entry from the extracellular space. These intracettular signals act in concert to activate protein kinases that phosphorylate a variety of regulatory proteins. The link between phosphoinositide turnover and Ca(2+) mobilization is inositol 1,4,5-trisphosphate, the major Ca(2+)-mobilizing second messenger, which is produced from membrane phosphoinositides by activated phospholipase C enzymes. The mechanisms of ligand-regulated Ca(2+) influx and the additional regulatory role(s) of phosphoinositides and inositol phosphates are still being unfolded. This review and the following article summarize some recent developments and unsolved issues about this major signal transduction cascade that links calcium-mobilizing hormone receptors to the regulation of endocrine cell function.