Glucagon stimulates the cardiac Ca²⁺ current by activation of adenylyl cyclase and inhibition of phosphodiesterase

Abstract

GLUCAGON exerts positive inotropic and chronotropic effects in the heart^1,2. Like its glycogenolytic effect in liver cells³, the cardiac effects of glucagon are often correlated with adenylyl cyclase stimulation^2,4–7. Therefore, cyclic AMP-dependent phosphorylation of L-type Ca²⁺ channels^8–10 might be involved in the inotropic effect of glucagon. There have been no reports, however, of the effects of glucagon on the cardiac Ca²⁺ current (I_Ca). Also, the physiological effects of glucagon could involve mechanisms other than stimulation of adenylyl cyclase^11,12. Here we show that glucagon enhances I_Ca in frog and rat ventricular myocytes. The effect of glucagon in rats resulted from a stimulation of adenylyl cyclase. In frogs, however, the effect of glucagon on I_Ca was smaller and occurred at a concentration tenfold lower than in rats, and adenylyl cyclase was not modified. In addition, cAMP potentiated the effect of glucagon on I_Ca in frog ventricle, which correlated with the observed inhibition by glucagon of low-K_m cAMP phosphodiesterase activity. Therefore, this is an example of a hormone that affects cardiac function in a similar way to a variety of synthetic cardiotonic compounds, such as milrinone and Ro-20-1724 (ref. 13). Inhibition of phosphodiesterase activity by glucagon may be essential in animals in which glucagon increases cardiac contractility but does not effectively stimulate adenylyl cyclase^7,14,15.