Inhibition of β-adrenergic signaling by intracellular AMP is independent of cell-surface adenosine receptors in rat cardiac cells

We report a novel action of intracellular adenosine monophosphate (AMP) to inhibit β-adrenergic signaling in isolated rat ventricular myocytes. Extracellular application of adenosine or AMP suppressed isoproterenol (Iso)-induced prolongation of action potential duration (APD). This effect was completely abolished by an A1-receptor antagonist, DPCPX. Intracellular application of AMP, but not adenosine, attenuated Iso-induced APD prolongation. Iso-induced increases in the L-type Ca2+ current (ICa,L) were also inhibited by intracellular AMP. These inhibitory effects were not affected by either DPCPX or glibenclamide. In vitro, AMP directly inhibited PKA activity via binding to its regulatory subunit. These results suggest that intracellular AMP attenuates β-adrenergic signaling by directly inhibiting PKA activity, independently of A1-purinergic receptor.