Ca2+-desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy

被引:131
作者
Morimoto, S [1 ]
Lu, QW
Harada, K
Takahashi-Yanaga, F
Minakami, R
Ohta, M
Sasaguri, T
Ohtsuki, I
机构
[1] Kyushu Univ, Lab Clin Pharmacol, Dept Pharmacol, Grad Sch Med, Fukuoka 8128582, Japan
[2] Kyushu Univ, Sch Hlth Sci, Fukuoka 8128582, Japan
关键词
D O I
10.1073/pnas.022628899
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
A deletion mutation DeltaK210 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 DeltaE160 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 DCAA) 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 DeltaK210 in cTnT.
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页码:913 / 918
页数:6
相关论文
共 47 条
[1]  
CHANDRA M, 2001, AM J PHYSIOL, V280, pH1653
[2]   The X-linked gene G4.5 is responsible for different infantile dilated cardiomyopathies [J].
DAdamo, P ;
Fassone, L ;
Gedeon, A ;
Janssen, EAM ;
Bione, S ;
Bolhuis, PA ;
Barth, PG ;
Wilson, M ;
Haan, E ;
Orstavik, KH ;
Patton, MA ;
Green, AJ ;
Zammarchi, E ;
Donati, MA ;
Toniolo, D .
AMERICAN JOURNAL OF HUMAN GENETICS, 1997, 61 (04) :862-867
[3]   IDIOPATHIC DILATED CARDIOMYOPATHY [J].
DEC, GW ;
FUSTER, V .
NEW ENGLAND JOURNAL OF MEDICINE, 1994, 331 (23) :1564-1575
[4]  
Ebashi S, 1968, Prog Biophys Mol Biol, V18, P123, DOI 10.1016/0079-6107(68)90023-0
[5]   Altered regulatory properties of human cardiac troponin I mutants that cause hypertrophic cardiomyopathy [J].
Elliott, K ;
Watkins, H ;
Redwood, CS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (29) :22069-22074
[6]  
GILBERT EM, 1994, HEART, P1609
[7]   Functional consequences of the deletion mutation ΔGlu160 in human cardiac troponin T [J].
Harada, K ;
Takahashi-Yanaga, F ;
Minakami, R ;
Morimoto, S ;
Ohtsuki, I .
JOURNAL OF BIOCHEMISTRY, 2000, 127 (02) :263-268
[8]   EFFECT OF REMOVAL AND RECONSTITUTION OF TROPONIN-C AND TROPONIN-I ON THE CA2+-ACTIVATED TENSION DEVELOPMENT OF SINGLE GLYCERINATED RABBIT SKELETAL-MUSCLE FIBERS [J].
HATAKENAKA, M ;
OHTSUKI, I .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1992, 205 (03) :985-993
[9]   REPLACEMENT OF 3 TROPONIN COMPONENTS WITH CARDIAC TROPONIN COMPONENTS WITHIN SINGLE GLYCERINATED SKELETAL-MUSCLE FIBERS [J].
HATAKENAKA, M ;
OHTSUKI, I .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1991, 181 (03) :1022-1027
[10]   Plasticity in skeletal cardiac, and smooth muscle -: Invited review:: Pathophysiology of cardiac muscle contraction and relaxation as a result of alterations in thin filament regulation [J].
Hernandez, OM ;
Housmans, PR ;
Potter, JD .
JOURNAL OF APPLIED PHYSIOLOGY, 2001, 90 (03) :1125-1136