Interrelationships between Ca2+ and adenylate and guanylate cyclases in the control of platelet secretion and aggregation.

Abstract

Ca2+ is a powerful inhibitor (Ki .simeq. 16 .mu.M) of basal and prostaglandin E1 (PGE1)-stimulated adenylate cyclase [ATP pyrophosphate-lyase (cyclizing); EC 4.6.1.1] activity in membranes obtained from homogenized human platelets. Ca2+ (but not the ionophore A23,187) decreased Vmax of the reaction without an effect on the Ks for ATP. Neither ATP nor PGE1 affected Ki for Ca2+. In intact platelets A23,187 induced Ca2+ influx and markedly inhibited PGE1-stimulated rise in cyclic[c]AMP levels. Guanylate cyclase [GTP pyrophosphate-lyase (cyclizing); EC 4.6.1.2] activity was mainly found in the soluble fraction (> 90%). Both soluble and membrane bound enzymes were stimulated by Mn2+ and Ca2+ and inhibited by Zn2+. Adenylate and guanylate cyclase activity were both present in the membrane fraction which contained Ca2+-activated ATPase activity, and accumulated Ca2+ from the medium in the presence of ATP and oxalate. These membranes probably originated in large part from the dense tubular system of the platelets. Concurrent inhibition of adenylate cyclase and stimulation of guanylate cyclase may facilitate the direct initiating effect of Ca2+ on platelet secretion and aggregation.