Multiple effects of ethanol on cardiac adenylate cyclase

We characterized the effects of ethanol on the activators of adenylate cyclase complex that act through the receptor site, the stimulatory guanine nucleotide-binding regulatory protein (G(s)), or the catalytic unit. Ethanol had no effect on adenylate cyclase activity stimulated by Mn²⁺, a selective activator of the catalytic unit, whereas high concentrations of ethanol inhibited both basal and isoproterenol-stimulated adenylate cyclase. In contrast, in the presence of nonhydrolyzable GTP analogs, ethanol potentiated substantial increases in adenylate cyclase activity. In the presence of these GTP analogs, ethanol increased the V(max) without altering the affinity of adenylate cyclase for ATP. Ethanol also increased adenylate cyclase activity in membranes in which G(s) had been preactivated with isoproterenol plus a nonhydrolyzable GTP analog, suggesting that ethanol enhanced the interaction between activated G(s) and the catalytic unit. Paradoxically, the ability of cholera toxin and NAD⁺ to augment adenylate cyclase activity through an effect on G(s) was attenuated by increasing concentrations of ethanol. These results suggest that acute exposure to ethanol has multiple effects on cardiac membrane adenylate cyclase.