Dynamic sensitivity of ATP-sensitive K+ channels to ATP

ATP and MgADP regulate K-ATP channel activity and hence potentially couple cellular metabolism to membrane electrical activity in various cell types. Using recombinant K-ATP channels that lack sensitivity to MgADP, expressed in COSm6 cells, we demonstrate that similar on-cell activity can be observe d with widely varying apparent submembrane [ATP] ([ATP](sub)). Metabolic in hibition leads to a biphasic change in the channel activity; activity first increases, presumably in response to a fast decrease in [ATP](sub), and th en declines. The secondary decrease in channel activity reflects a marked i ncrease in ATP sensitivity and is correlated with a fall in polyphosphoinos itides (PPIs), including phosphatidylinositol. 4,5-bisphosphate, probed usi ng equilibrium labeling of cells with [H-3]myo-inositol. Both ATP sensitivi ty and PPIs rapidly recover following removal of metabolic inhibition, and in both cases recovery is blocked by wortmannin. These data are consistent with metabolism having a dual effect on K-ATP channel activity: rapid activ ation of channels because of relief of ATP inhibition and much slower reduc tion of channel activity mediated by a fall in PPIs. These two mechanisms c onstitute a feedback system that will tend to render K-ATP channel activity transiently responsive to a change in [ATP](sub) over a wide range of stea dy state concentrations.