Angiotensin II receptors and mechanisms of action in adrenal glomerulosa cells

The plasma-membrane receptors, coupling mechanisms, and effector enzymes that mediate target-cell activation by angiotensin II (All) have been characterized in rat and bovine adrenal glomerulosa cells. The All holoreceptor is a glycoprotein of Mr∼125,000 under non-denaturing conditions. Photoaffinity labeling of All receptors with azido-AII derivatives has shown size heterogeneity among the All binding sites between species and target tissues, with Mr values of 55,000 to 79,000. Such variations in molecular size probably reflect differences in carbohydrate content of the individual receptor sites. The adrenal All receptor, like that in other tissues, is coupled to the inhibitory guanine nucleotide inhibitory protein (N i). However, studies with pertussis toxin have shown that stimulation of aldosterone production by All is not mediated by N i but by a pertussis-insensitive nucleotide regulatory protein of unidentified nature. Although N i is not involved in the stimulatory action of All on steroidogenesis, it does mediate the inhibitory effects of high concentrations of All upon aldosterone production. The actions of All on adrenal cortical function are thus regulated by at least two guanine nucleotide regulatory proteins that are selectively activated by increasing All concentrations. The principal effector enzyme in All action is phospholipase C, which is rapidly stimulated in rat and bovine glomerulosa after All receptor activation. All-induced breakdown of phosphatidylinositol bisphosphate (PIP 2) and phosphatidylinositol phosphate (PIP) leads to formation of inositol 1,4,5-trisphosphate IP 3) and inositol 1,4-bisphosphate (IP 2). These are metabolized predominantly to inositol-4-monophosphate, which serves as a marker of polyphosphoinositide breakdown, whereas inositol-1-phosphate is largely derived from phosphatidylinositol hydrolysis. The All-stimulated glomerulosa cell also produces inositol 1,3,4-trisphosphate, a biologically inactive IP 3 isomer formed from Ins-l,4,5-trisphosphate via inositol tetrakisphosphate (IP 4) during ligand activation in several calcium-dependent target cells. The Ins-l,4,5-P3 formed during All action binds with high affinity to specific intracellular reeceptors that have been characterized in the bovine adrenal gland and other All target tissues, and may represent the sites through which (IP 3) causes calcium mobilization during the initiation of cellular responses.