AMPK is an important sensor of cellular energy levels.
Objective
The aim of these studies was to investigate whether cardiac KATP channels, which couple cellular energy metabolism to membrane excitability, are regulated by AMPK activity.
Research Design and Methods
We investigated effects of AMPK on rat ventricular KATP channels using electrophysiological and biochemical approaches
Results
Whole-cell KATP channel current was activated by metabolic inhibition; this occurred more rapidly in the presence of AICAR (an AMPK activator). AICAR had no effects on KATP channel activity recorded in the inside-out patch clamp configuration, but ZMP (the intracellular intermediate of AICAR) strongly activated KATP channels. An AMPK-mediated effect is demonstrated by the finding that ZMP had no effect on KATP 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 KATP channel subunits.
Conclusions
Our data demonstrate that the cardiac KATP 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 KATP channel opening.
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