Ca(2+)-desensitizing effect of a deletion mutation Delta K210 in cardiac troponin T that causes familial dilated cardiomyopathy.
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 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 Delta E160 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 Delta K210 in cTnT.
Morimoto
S
S
Laboratory of Clinical Pharmacology, Department of Pharmacology, Graduate School of Medicine, Kyushu University, Fukuoka 812-8582, Japan. morimoto@clipharm.med.kyushu-u.ac.jp
Lu
Q-W
QW
Harada
K
K
Takahashi-Yanaga
F
F
Minakami
R
R
Ohta
M
M
Sasaguri
T
T
Ohtsuki
I
I
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology; D011817:Rabbits; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D020107:Troponin T / Q000235:genetics* / Q000378:metabolism*
D011994:Recombinant Proteins; D020107:Troponin T; D000251:Adenosine Triphosphatases; D002118:Calcium