Diadenosine tetraphosphate-induced inhibition of ATP-sensitive K+ channels in patches excised from ventricular myocytes

Diadenosine 5',5 ''-P-1,P-4-tetraphosphate (Ap(4)A) has been termed 'alarmone' due to its role in intracellular signaling during metabolic stress. It is not known whether Ap,A could modulate ATP-sensitive K+ (K-ATP) channels, a family of channels regulated by the metabolic status of a cell. We applied the single-channel patch-clamp technique to measure the effect of Ap(4)A on K-ATP channels. When applied to the intracellular side of patches, excised from guinea-pig ventricular myocytes, Ap(4)A inhibited K-ATP channel activity, in a reversible and concentration-dependent (half-maximal concentration similar to 17 mu M) manner. We conclude that Ap(4)A, a naturally occurring diadenosine polyphosphate, is actually an inhibitor of the myocardial K-ATP channel.