磷化氢
心力衰竭
扩张型心肌病
心肌病
医学
内科学
错义突变
兰尼碱受体2
磷酸化
生物
内分泌学
突变
细胞生物学
钙
兰尼定受体
生物化学
基因
作者
Joachim P. Schmitt,Mitsuhiro Kamisago,Michio Asahi,Guo Hua Li,Ferhaan Ahmad,Ulrike Mende,Evangelia G. Kranias,David H. MacLennan,J G Seidman,Christine E. Seidman
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2003-02-27
卷期号:299 (5611): 1410-1413
被引量:601
标识
DOI:10.1126/science.1081578
摘要
Molecular etiologies of heart failure, an emerging cardiovascular epidemic affecting 4.7 million Americans and costing 17.8 billion health-care dollars annually, remain poorly understood. Here we report that an inherited human dilated cardiomyopathy with refractory congestive heart failure is caused by a dominant Arg → Cys missense mutation at residue 9 (R9C) in phospholamban (PLN), a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic reticular Ca 2+ –adenosine triphosphatase (SERCA2a) pump. Transgenic PLN R9C mice recapitulated human heart failure with premature death. Cellular and biochemical studies revealed that, unlike wild-type PLN, PLN R9C did not directly inhibit SERCA2a. Rather, PLN R9C trapped protein kinase A (PKA), which blocked PKA-mediated phosphorylation of wild-type PLN and in turn delayed decay of calcium transients in myocytes. These results indicate that myocellular calcium dysregulation can initiate human heart failure—a finding that may lead to therapeutic opportunities.
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