ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating
ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating
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DOI：
10.1038/ng1329
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发表时间：
2004-04-01
期刊：
影响因子：
30.8
通讯作者：
Terzic, A
中科院分区：
文献类型：
--
作者：
Bienengraeber, M;Olson, TM;Terzic, A
心脏的应激耐受需要通过ATP敏感性钾（K-ATP）通道的高保真代谢传感，所述通道调节膜电位依赖性功能以匹配细胞能量需求。对特发性扩张型心肌病所致心力衰竭和心律紊乱患者的基因组DNA进行扫描，发现ABCC 9中有两个突变，ABCC 9编码心脏K-ATP通道的调节性SUR 2A亚基。这些错义和移码突变映射到邻近SUR 2A内催化ATP酶口袋的进化保守结构域。突变体SUR 2A蛋白在固有ATP水解循环中表现出异常的构象再分布，转化为异常的K-ATP通道表型，代谢信号解码受损。因此，有缺陷的催化介导的孔调节是通道功能障碍和扩张型心肌病易感性的机制。
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.