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 beta-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 beta-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. (C) 1997 Elsevier Science Inc.