Stress tolerance of the heart requires high-fidelity metabolic sensing by ATP-sensitive potassium (KATP) channels that adjust a membrane potential-dependent functions to match cellular energetic demand. Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac KATP channel. These missense and frameshift mutations mapped to evolutionarily conserved domains adjacent to the catalytic ATPase pocket within SUR2A. Mutant SUR2A proteins showed aberrant redistribution of conformations in the intrinsic ATP hydrolytic cycle, translating into abnormal KATP channel phenotypes with compromised metabolic signal decoding. Defective catalysis-mediated pore regulation is thus a mechanism for channel dysfunction and susceptibility to dilated cardiomyopathy.
Bibliographical noteFunding Information:
We thank J. Bryan, Y. Kurachi and S. Seino for KATP channel clones; B. Schwappach for constructs used in trafficking studies; and T.P. Burghardt and A.J. Caride for technical advice. This work was supported by the US National Institutes of Health, American Heart Association, Miami Heart Research Institute, Marriott Foundation, Siragusa Foundation, University of Minnesota Supercomputing Institute, Mayo-Dubai Healthcare City Research Project and Mayo Foundation. A.T. is an Established Investigator of the American Heart Association.