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, G203S, K206Q) enhance filament sliding
1 Molekular-und Zellphysiologie, Medizinische Hochschule, Hannover, Germany
2 Department of Radiology, University of Washington, Seattle, WA, USA
3 Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA
4 Department of Bioengineering, University of Washington, Seattle, WA, USA
5 Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA; Department of Bioengineering, University of Washington, Seattle, WA, USA
6 Department of Biological Science, Florida State University, Tallahassee, FL, USA
* To whom correspondence should be addressed. E-mail: chase{at}bio.fsu.edu.
A major cause of familial hypertrophic cardiomyopathy (FHC) is dominant mutations in cardiac sarcomeric genes. Linkage studies identified FHC-related mutations in cardiac troponin I's (cTnI) C-terminus, 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
, 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 (
-MHC or 
-MHC) 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 WT cTn. In both trabeculae and motility assays, there was no loss of inhibition at pCa 9. These results are consistent with TnI's C-terminus 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.
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