1. ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating.
- Author
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Bienengraeber M, Olson TM, Selivanov VA, Kathmann EC, O'Cochlain F, Gao F, Karger AB, Ballew JD, Hodgson DM, Zingman LV, Pang YP, Alekseev AE, and Terzic A
- Subjects
- Adult, Amino Acid Sequence, Animals, Catalysis, Female, Humans, Male, Middle Aged, Molecular Sequence Data, Sequence Homology, Amino Acid, Sulfonylurea Receptors, ATP-Binding Cassette Transporters genetics, Cardiomyopathy, Dilated genetics, Ion Channel Gating genetics, Mutation, Potassium Channels genetics, Potassium Channels, Inwardly Rectifying, Receptors, Drug genetics
- Abstract
Stress tolerance of the heart requires high-fidelity metabolic sensing by ATP-sensitive potassium (K(ATP)) channels that adjust 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 K(ATP) 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 K(ATP) channel phenotypes with compromised metabolic signal decoding. Defective catalysis-mediated pore regulation is thus a mechanism for channel dysfunction and susceptibility to dilated cardiomyopathy.
- Published
- 2004
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