Mechanisms involved in calcium-mobilizing agonist responses.

Many hormones and neurotransmitters exert their biological effects by increasing the levels of Ca2+ and 1,2-diacylglycerol in their target cells. Major agonists that act in this way are epinephrine and norepinephrine, acetylcholine, vasopressin, cholecystokinin, and angiotensin II. These and other Ca2+-mobilizing agonists may also produce effects that are not mediated by Ca2+ or diacylglycerol, but involve separate receptors and an increase or decrease in cyclic AMP. The general mechanisms by which Ca2+-mobilizing agonists induce their physiological responses are depicted in Fig. 12. These responses appear to involve an initial mobilization of Ca2+ from endoplasmic reticulum and perhaps other intracellular Ca2+ stores, followed by alterations in the flux of Ca2+ across the plasma membrane. The Ca2+ changes are consistently associated with increased turnover of cellular phosphoinositides. The most rapid response is breakdown of phosphatidylinositol 4,5-P2 in the plasma membrane, and there is much evidence that this involves a guanine-nucleotide-binding regulatory protein similar to those involved in the regulation of adenylate cyclase. Myo-inositol 1,4,5-P3 produced by phosphatidylinositol 4,5-P2 breakdown rapidly releases Ca2+ from endoplasmic reticulum, and it is likely that it is the long-sought second message for the Ca2+-dependent hormones. 1,2-Diacylglycerol, the other product of phosphatidylinositol 4,5-P2 breakdown, also acts as a second message in that it activates protein kinase C, a Ca2+-phospholipid-dependent protein kinase, by lowering its requirement for Ca2+. The cellular substrates for protein kinase C and its role in the different physiological responses to the Ca2+-mediated agonists are currently being defined. The major intracellular target for Ca2+ is the Ca2+-dependent regulatory protein calmodulin. This binds Ca2+ with high affinity, and the resulting complex interacts with a variety of enzymes and other cellular proteins, modifying their activities. A major target is the multifunctional calmodulin-dependent protein kinase that phosphorylates and alters the activities of many proteins, for example, glycogen synthase and tyrosine hydroxylase. Calcium ions may also stimulate calmodulin-dependent protein kinases that are more specific, such as phosphorylase kinase and myosin light-chain kinase. Other important Ca2+-calmodulin targets are the microtubule-associated proteins, but it is likely that many more will be found.(ABSTRACT TRUNCATED AT 400 WORDS)