A single serine in the carboxyl terminus of cardiac essential myosin light chain-1 controls cardiomyocyte contractility in vivo
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Meder, Benjamin, Laufer, Christina, Hassel, David, Just, Steffen, Marquart, Sabine, Vogel, Britta, Hess, Alexander, Fishman, Mark, Katus, Hugo A and Rottbauer, Wolfgang (2009) A single serine in the carboxyl terminus of cardiac essential myosin light chain-1 controls cardiomyocyte contractility in vivo. Circulation Research, 104 (5). pp. 650-659. ISSN 1524-4571
Abstract
Although it is well known that mutations in the cardiac essential myosin light chain-1 (cmlc-1) gene can cause hypertrophic cardiomyopathy, the precise in vivo structural and functional roles of cMLC-1 in the heart are only poorly understood. We have isolated the zebrafish mutant lazy susan (laz), which displays severely reduced contractility of both heart chambers. By positional cloning, we identified a nonsense mutation within the zebrafish cmlc-1 gene to be responsible for the laz phenotype, leading to expression of a carboxyl-terminally truncated cMLC-1. Whereas complete loss of cMLC-1 leads to cardiac acontractility attributable to impaired cardiac sarcomerogenesis, expression of a carboxyl-terminally truncated cMLC-1 in laz mutant hearts is sufficient for normal cardiac sarcomerogenesis but severely impairs cardiac contractility in a cell-autonomous fashion. Whereas overexpression of wild-type cMLC-1 restores contractility of laz mutant cardiomyocytes, overexpression of phosphorylation site serine 195-deficient cMLC-1 (cMLC-1(S195A)) does not reconstitute cardiac contractility in laz mutant cardiomyocytes. By contrast, introduction of a phosphomimetic amino acid on position 195 (cMLC-1(S195D)) rescues cardiomyocyte contractility, demonstrating for the first time an essential role of the carboxyl terminus and especially of serine 195 of cMLC-1 in the regulation of cardiac contractility.
| Item Type: | Article |
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| Additional Information: | Author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used |
| Keywords: | zebrafish; genetics; essential cardiac myosin light chain-1; phosphorylation; myocardial contractility |
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| Date Deposited: | 22 Feb 2010 11:50 |
| Last Modified: | 22 Feb 2010 11:50 |
| URI: | https://oak.novartis.com/id/eprint/1794 |