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

Diadenosine 5',5'-P¹,P⁴-tetraphosphate (Ap₄A) has been termed 'alarmone' due to its role in intracellular signaling during metabolic stress. It is not known whether Ap₄A 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 Ap₄A on K(ATP) channels. When applied to the intracellular side of patches, excised from guinea-pig ventricular myocytes, Ap₄A inhibited K(ATP) channel activity, in a reversible and concentration-dependent (half-maximal concentration ~17 μM) manner. We conclude that Ap₄A, a naturally occurring diadenosine polyphosphate, is actually an inhibitor of the myocardial K(ATP) channel.