Ca 2+-desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy

Sachio Morimoto, Q. W. Lu, K. Harada, F. Takahashi-Yanaga, Reiko Minakami, M. Ohta, Toshiyuki Sasaguri, I. Ohtsuki

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Abstract

A deletion mutation ΔK210 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 Ca 2+-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 Ca 2+ 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 Ca 2+ concentrations required for the activation of ATPase. In contrast, a deletion mutation ΔE160 in cTnT that causes familial hypertrophic cardiomyopathy (HCM) decreased the free Ca 2+ 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 Ca 2- sensitivity of cardiac muscle contraction in opposite directions. The present study strongly suggests that Ca 2+ desensitization of force generation in sarcomere is a primary mechanism for the pathogenesis of DCM associated with the deletion mutation ΔK210 in cTnT.

Original languageEnglish
Pages (from-to)913-918
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number2
DOIs
Publication statusPublished - Jan 22 2002

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Troponin T
Sequence Deletion
Myocardium
Hypertrophic Cardiomyopathy
Dilated Cardiomyopathy
Muscle Contraction
Mutation
Familial Hypertrophic Cardiomyopathy
Sarcomeres
Familial dilated cardiomyopathy
Myofibrils
Cardiomyopathies
Adenosine Triphosphatases
Rabbits

All Science Journal Classification (ASJC) codes

  • General

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Ca 2+-desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy. / Morimoto, Sachio; Lu, Q. W.; Harada, K.; Takahashi-Yanaga, F.; Minakami, Reiko; Ohta, M.; Sasaguri, Toshiyuki; Ohtsuki, I.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 2, 22.01.2002, p. 913-918.

Research output: Contribution to journalArticle

Morimoto, Sachio ; Lu, Q. W. ; Harada, K. ; Takahashi-Yanaga, F. ; Minakami, Reiko ; Ohta, M. ; Sasaguri, Toshiyuki ; Ohtsuki, I. / Ca 2+-desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy. In: Proceedings of the National Academy of Sciences of the United States of America. 2002 ; Vol. 99, No. 2. pp. 913-918.
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