4.5 Article

Familial hypertrophic cardiomyopathy mutations in troponin I (K183Δ, G203S, K206Q) enhance filament sliding

期刊

PHYSIOLOGICAL GENOMICS
卷 14, 期 2, 页码 117-128

出版社

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/physiolgenomics.00101.2002

关键词

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

资金

  1. NHLBI NIH HHS [HL-63974, HL-52558, R01 HL065497] Funding Source: Medline
  2. NINDS NIH HHS [NS-08384] Funding Source: Medline

向作者/读者索取更多资源

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 K183Delta, G203S, and K206Q in cTnI affect Ca2+ regulation. All three mutants enhanced Ca2+ sensitivity and maximum speed (s(max)) of filament sliding of in vitro motility assays. Enhanced s(max) (pCa 5) was observed with rabbit skeletal and rat cardiac (alpha-MHC or beta-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.

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