Activation of Cardiac Adenylate Cyclase: Hormonal Modification of the Magnesium Ion Requirement

Histamine and epinephrine stimulate the activity of guinea pig heart adenylate cyclase [ATP pyrophosphate-lyase (cyclizing) EC 4.6.1.1], in part, by decreasing the requirement for Mg2+as an activator. This effect may represent an increase in affinity for Mg2+and/or a decrease in sensitivity of the enzyme towards inhibition by free ATP. Both of these inotropic hormones also increase maximum velocity. Pretreatment of the membrane-bound enzyme with EDTA, to remove available divalent cations, almost eliminates persistent stimulation by guanyl-5′-yl imidodiphosphate [Gpp(NH)p]. Addition of Mg2+to the preincubation medium restores the capacity of Gpp(NH)p to acutely activate the enzyme. These results indicate that Mg2+interacts with the nucleotide (GTP) regulatory site. Persistent stimulation of the enzyme by either Gpp(NH)p or fluoride ion also involves a decrease in the requirement for Mg2+and an increase in maximum velocity.