Intracellular diadenosine polyphosphates. A novel family of inhibitory ligands of the ATP-sensitive K⁺ channel

Intracellular diadenosine polyphosphates (Ap(n)A) are signal molecules that alert the cell under stress conditions. Herein, we review evidence that has recently identified a novel target for Ap(n)A, namely the ATP-sensitive K⁺ (K(ATP)) channel. These channels are abundant in pancreatic β-cells and cardiac myocytes where they are essential in coupling the cellular metabolic state with membrane excitability. The potency and efficacy of Ap(n)A to inhibit K(ATP) channel activity were first described in cardiac K(ATP) channels, and appear similar to those of intracellular ATP, the primary ligand of K(ATP) channels. Also, the inhibitory ligand action of Ap(n)A is dependent upon the operative condition of K(ATP) channels and the presence of nucleotide diphosphates. In addition to a direct antagonism of channel opening, an indirect effect of Ap(n)A on K(ATP) channel activity has been associated with inhibition of adenylate kinase, a catalytic system believed essential for the regulation of channel opening. At present, the precise role for Ap(n)A-induced K(ATP) channel inhibition remains to be established. Yet, it is known that, under glucose challenge of pancreatic β-cells, intracellular concentrations of Ap(n)A do increase to micromolar levels necessary to block K(ATP) channels, leading to insulin secretion. Thus, the Ap(n)A mediated K(ATP) channel gating represents a previously unrecognized pathway of channel regulation.