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J. Biol. Chem., Vol. 279, Issue 5, 3535-3542, January 30, 2004

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Familial Hypertrophic Cardiomyopathy-linked Alterations in Ca²⁺ Binding of Human Cardiac Myosin Regulatory Light Chain Affect Cardiac Muscle Contraction^*

Danuta Szczesna-Cordary, Georgianna Guzman, Shuk-Shin Ng, and Jiaju Zhao

From the Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, Florida 33136

The ventricular isoform of human cardiac regulatory light chain (HCRLC) has been shown to be one of the sarcomeric proteins associated with familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disease characterized by left ventricular and/or septal hypertrophy, myofibrillar disarray, and sudden cardiac death. Our recent studies have demonstrated that the properties of isolated HCRLC could be significantly altered by the FHC mutations and that their detrimental effects depend upon the specific position of the missense mutation. This report reveals that the Ca²⁺ sensitivity of myofibrillar ATPase activity and steady-state force development are also likely to change with the location of the specific FHC HCRLC mutation. The largest effect was seen for the two FHC mutations, N47K and R58Q, located directly in or near the single Ca²⁺-Mg²⁺ binding site of HCRLC, which demonstrated no Ca²⁺ binding compared with wild-type and other FHC mutants (A13T, F18L, E22K, P95A). These two mutants when reconstituted in porcine cardiac muscle preparations increased Ca²⁺ sensitivity of myofibrillar ATPase activity and force development. These results suggest the importance of the intact Ca²⁺ binding site of HCRLC in the regulation of cardiac muscle contraction and imply its possible role in the regulatory light chain-linked pathogenesis of FHC.

Received for publication, July 3, 2003 , and in revised form, September 2, 2003.

^* This work was supported by National Institutes of Health Grant HL071778 and American Heart Association Grant-in-aid 0355384B (to D. S.-C.). 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.

To whom correspondence should be addressed: Dept. of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Rm. 6113, Rosenstiel Medical Sciences Building R-189, 1600 N. W. 10th Ave., Miami, FL 33136. Tel.: 305-243-2908; Fax: 305-243-4555; E-mail: dszczesna{at}med.miami.edu.

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