AMP-activated protein kinase connects cellular energy metabolism to K _ATP channel function

AMPK is an important sensor of cellular energy levels. The aim of these studies was to investigate whether cardiac K _ATP channels, which couple cellular energy metabolism to membrane excitability, are regulated by AMPK activity. We investigated effects of AMPK on rat ventricular K _ATP channels using electrophysiological and biochemical approaches. Whole-cell K _ATP channel current was activated by metabolic inhibition; this occurred more rapidly in the presence of AICAR (an AMPK activator). AICAR had no effects on K _ATP channel activity recorded in the inside-out patch clamp configuration, but ZMP (the intracellular intermediate of AICAR) strongly activated K _ATP channels. An AMPK-mediated effect is demonstrated by the finding that ZMP had no effect on K _ATP channels in the presence of Compound C (an AMPK inhibitor). Recombinant AMPK activated Kir6.2/SUR2A channels in a manner that was dependent on the AMP concentration, whereas heat-inactivated AMPK was without effect. Using mass-spectrometry and co-immunoprecipitation approaches, we demonstrate that the AMPK α-subunit physically associates with K _ATP channel subunits. Our data demonstrate that the cardiac K _ATP channel function is directly regulated by AMPK activation. During metabolic stress, a small change in cellular AMP that activates AMPK can be a potential trigger for K _ATP channel opening. This article is part of a Special Issue entitled "Local Signaling in Myocytes".