ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating. Nat Genet 2004 Apr;36(4):382-7
Date
03/23/2004Pubmed ID
15034580Pubmed Central ID
PMC1995438DOI
10.1038/ng1329Scopus ID
2-s2.0-12144290256 (requires institutional sign-in at Scopus site) 310 CitationsAbstract
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.
Author List
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, Terzic AMESH terms used to index this publication - Major topics in bold
ATP-Binding Cassette TransportersAdult
Amino Acid Sequence
Animals
Cardiomyopathy, Dilated
Catalysis
Female
Humans
Ion Channel Gating
Male
Middle Aged
Molecular Sequence Data
Mutation
Potassium Channels
Potassium Channels, Inwardly Rectifying
Receptors, Drug
Sequence Homology, Amino Acid
Sulfonylurea Receptors
