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在一名肥厚型心肌病患者中发现的心肌肌钙蛋白C突变Leu29Gln不会改变去表皮小鼠心肌的收缩参数。

The cardiac troponin C mutation Leu29Gln found in a patient with hypertrophic cardiomyopathy does not alter contractile parameters in skinned murine myocardium.

作者信息

Neulen Axel, Stehle Robert, Pfitzer Gabriele

机构信息

Institute of Vegetative Physiology, University of Cologne, Robert-Koch-Strasse 39, 50931 Cologne, Germany.

出版信息

Basic Res Cardiol. 2009 Nov;104(6):751-60. doi: 10.1007/s00395-009-0038-y. Epub 2009 Jun 9.

DOI:10.1007/s00395-009-0038-y
PMID:19506933
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2758205/
Abstract

The present study investigates the effects of the first mutation of troponin C (hcTnC(L29Q)) found in a patient with hypertrophic cardiomyopathy (HCM) on force-pCa relations and the interplay with phosphorylation of sarcomeric PKA substrates. In triton-skinned murine cardiac fibers, the endogenous mcTnC was extracted and the fibers were subsequently reconstituted with recombinant wild-type and mutant hcTnC. Force-pCa relations of preparations containing hcTnC(L29Q) or hcTnC(WT) were similar. Incubation of fibers reconstituted with the recombinant proteins with phosphatase to dephosphorylate sarcomeric PKA substrates induced an increase in Ca2+ sensitivity, slightly more pronounced (0.04 pCa units) in hcTnC(L29Q)-containing fibers. Incubation of the dephosphorylated fibers with PKA induced significant rightward shifts of force-pCa relations of similar magnitude with both, hcTnC(L29Q) and hcTnC(WT). No significant effects of hcTnC(L29Q) on the velocity of unloaded shortening were observed. In conclusion, no major differences in contractile parameters of preparations containing hcTnC(L29Q) compared to hcTnC(WT) were observed. Therefore, it appears unlikely that hcTnC(L29Q) induces the development of HCM by affecting the regulation of Ca2+-activated force and interference with PKA-mediated modulation of the Ca2+ sensitivity of contraction.

摘要

本研究调查了在一名肥厚型心肌病（HCM）患者中发现的肌钙蛋白C的首次突变（hcTnC(L29Q)）对力-pCa关系以及与肌节蛋白激酶A（PKA）底物磷酸化相互作用的影响。在经曲拉通处理的小鼠心脏纤维中，提取内源性心肌肌钙蛋白C（mcTnC），随后用重组野生型和突变型hcTnC对纤维进行重构。含有hcTnC(L29Q)或hcTnC(WT)制剂的力-pCa关系相似。用磷酸酶孵育经重组蛋白重构的纤维以使肌节蛋白激酶A底物去磷酸化，可诱导Ca2+敏感性增加，在含有hcTnC(L29Q)的纤维中增加更为明显（0.04 pCa单位）。用蛋白激酶A孵育去磷酸化的纤维，可使含有hcTnC(L29Q)和hcTnC(WT)的制剂的力-pCa关系产生相似幅度的显著右移。未观察到hcTnC(L29Q)对无负荷缩短速度有显著影响。总之，与hcTnC(WT)相比，未观察到含有hcTnC(L29Q)的制剂在收缩参数上有重大差异。因此，hcTnC(L29Q)似乎不太可能通过影响Ca2+激活的力的调节以及干扰PKA介导的收缩Ca2+敏感性调节来诱导肥厚型心肌病的发生。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a552/2758205/658f6bad6664/395_2009_38_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a552/2758205/9a6c31965424/395_2009_38_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a552/2758205/cf30d8fb35ec/395_2009_38_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a552/2758205/22a9cc9a6ea7/395_2009_38_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a552/2758205/54c2e4ca3454/395_2009_38_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a552/2758205/658f6bad6664/395_2009_38_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a552/2758205/9a6c31965424/395_2009_38_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a552/2758205/cf30d8fb35ec/395_2009_38_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a552/2758205/22a9cc9a6ea7/395_2009_38_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a552/2758205/54c2e4ca3454/395_2009_38_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a552/2758205/658f6bad6664/395_2009_38_Fig5_HTML.jpg

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