Dualistic behavior of ATP-sensitive K⁺ channels toward intracellular nucleoside diphosphates

ATP-sensitive K⁺ (K_ATP) channels are intracellular ligandgated channels which regulate diverse cellular functions. Intracellular nucleoside diphosphates (NDPs) are essential for the physiological opening of K_ATP channels which would otherwise be permanently closed by their overt sensitivity to intracellular ATP. We find that K_ATP channels exhibit dualistic behavior toward NDPs depending on their operative condition. When channels are in the spontaneous operative condition, NDPs antagonize channel inhibition by intracellular ATP. When channels have "run down," NDPs induce channel opening but no longer antagonize intracellular ATP. The switch of the K_ATP channel response to the same ligand, i.e., NDPs, is controlled by a Mg-ATP-dependent reaction. The condition of the target protein therefore determines the effect of the ligand. This property provides a novel basis to evaluate the dynamic regulation of ion channels by their ligands.