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Physiol. Genomics 14: 117-128, 2003. First published May 20, 2003; doi:10.1152/physiolgenomics.00101.2002
1094-8341/03 $5.00
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Received 6 August 2002; accepted in final form 13 May 2003.
Physiological Genomics 14:117-128 (2003)
1094-8341/03 $5.00 © 2003 American Physiological Society

Familial hypertrophic cardiomyopathy mutations in troponin I (K183{Delta}, G203S, K206Q) enhance filament sliding1

Jan Köhler 1, Ying Chen 2, Bernhard Brenner 1, Albert M. Gordon 3, Theresia Kraft 1, Donald A. Martyn 4, Michael Regnier 4, Anthony J. Rivera 4, Chien-Kao Wang 3,4 and P. Bryant Chase 5

1 Molekular- und Zellphysiologie, Medizinische Hochschule, D-30625 Hannover, Germany
2 Departments of Radiology
3 Physiology and Biophysics
4 Bioengineering, University of Washington, Seattle, Washington
5 Department of Biological Science, Florida State University, Tallahassee, Florida 32306-4370

A major cause of familial hypertrophic cardiomyopathy (FHC) is dominant mutations in cardiac sarcomeric genes. Linkage studies identified FHC-related mutations in the COOH terminus of cardiac troponin I (cTnI), a region with unknown function in Ca2+ regulation of the heart. Using in vitro assays with recombinant rat troponin subunits, we tested the hypothesis that mutations K183{Delta}, G203S, and K206Q in cTnI affect Ca2+ regulation. All three mutants enhanced Ca2+ sensitivity and maximum speed (smax) of filament sliding of in vitro motility assays. Enhanced smax (pCa 5) was observed with rabbit skeletal and rat cardiac ({alpha}-MHC or ß-MHC) heavy meromyosin (HMM). We developed a passive exchange method for replacing endogenous cTn in permeabilized rat cardiac trabeculae. Ca2+ sensitivity and maximum isometric force did not differ between preparations exchanged with cTn(cTnI,K206Q) or wild-type cTn. In both trabeculae and motility assays, there was no loss of inhibition at pCa 9. These results are consistent with COOH terminus of TnI modulating actomyosin kinetics during unloaded sliding, but not during isometric force generation, and implicate enhanced cross-bridge cycling in the cTnI-related pathway(s) to hypertrophy.

heart; calcium regulation; systole; in vitro motility; troponin exchange




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