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J. Biol. Chem., Vol. 279, Issue 15, 14488-14495, April 9, 2004

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Familial Hypertrophic Cardiomyopathy Mutations from Different Functional Regions of Troponin T Result in Different Effects on the pH and Ca²+ Sensitivity of Cardiac Muscle Contraction^*

Keita Harada and James D. Potter

From the Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, Florida 33101

To understand the molecular function of troponin T (TnT) in the Ca²⁺ regulation of muscle contraction as well as the molecular pathogenesis of familial hypertrophic cardiomyopathy (FHC), eight FHC-linked TnT mutations, which are located in different functional regions of human cardiac TnT (HCTnT), were produced, and their structural and functional properties were examined. Circular dichroism spectroscopy demonstrated different secondary structures of these TnT mutants. Each of the recombinant HCTnTs was incorporated into porcine skinned fibers along with human cardiac troponin I (HCTnI) and troponin C (HCTnC), and the Ca²⁺ dependent isometric force development of these troponin-replaced fibers was determined at pH 7.0 and 6.5. All eight mutants altered the contractile properties of skinned cardiac fibers. E244D potentiated the maximum force development without changing Ca²⁺ sensitivity. In contrast, the other seven mutants increased the Ca²⁺ sensitivity of force development but not the maximal force. R92L, R92W, and R94L also decreased the change in Ca²⁺ sensitivity of force development observed on lowering the pH from 7 to 6.5, when compared with wild type TnT. The examination of additional mutants, H91Q and a double mutant H91Q/R92W, suggests that mutations in a region including residues 91–94 in HCTnT can perturb the proper response of cardiac contraction to changes in pH. These results suggest that different regions of TnT may contribute to the pathogenesis of TnT-linked FHC through different mechanisms.

Received for publication, August 25, 2003 , and in revised form, December 22, 2003.

^* This work was supported in part by National Institutes of Health Grants HL-42325 and HL-674154. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by an American Hearth Association postdoctoral fellowship (Florida/Puerto Rico affiliate).

To whom correspondence should be addressed: Dept. of Molecular and Cellular Pharmacology, University of Miami School of Medicine, 1600 N. W. 10th Ave., Miami, FL 33136. Tel.: 305-243-5874; Fax: 305-324-6024; E-mail: jdpotter{at}miami.edu.

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