文章基本信息

标题：Ca2+-desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy
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作者：S. Morimoto ; Q.-W. Lu ; K. Harada 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2002
卷号：99
期号：2
页码：913-918
DOI：10.1073/pnas.022628899
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：A deletion mutation {Delta}K210 in cardiac troponin T (cTnT) was recently found to cause familial dilated cardiomyopathy (DCM). To explore the effect of this mutation on cardiac muscle contraction under physiological conditions, we determined the Ca2+-activated force generation in permeabilized rabbit cardiac muscle fibers into which the mutant and wild-type cTnTs were incorporated by using our TnT exchange technique. The free Ca2+ concentrations required for the force generation were higher in the mutant cTnT-exchanged fibers than in the wild-type cTnT-exchanged ones, with no statistically significant differences in maximal force-generating capability and cooperativity. Exchanging the mutant cTnT into isolated cardiac myofibrils also increased the free Ca2+ concentrations required for the activation of ATPase. In contrast, a deletion mutation {Delta}E160 in cTnT that causes familial hypertrophic cardiomyopathy (HCM) decreased the free Ca2+ concentrations required for force generation, just as in the case of the other HCM-causing mutations in cTnT. The results indicate that cTnT mutations found in the two distinct forms of cardiomyopathy (i.e., HCM and DCM) change the Ca2+ sensitivity of cardiac muscle contraction in opposite directions. The present study strongly suggests that Ca2+ desensitization of force generation in sarcomere is a primary mechanism for the pathogenesis of DCM associated with the deletion mutation {Delta}K210 in cTnT.