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(Circulation Research. 2009;104:650.)
© 2009 American Heart Association, Inc.

Cellular Biology

A Single Serine in the Carboxyl Terminus of Cardiac Essential Myosin Light Chain-1 Controls Cardiomyocyte Contractility In Vivo

Benjamin Meder^*, Christina Laufer^*, David Hassel^*, Steffen Just, Sabine Marquart, Britta Vogel, Alexander Hess, Mark C. Fishman, Hugo A. Katus, Wolfgang Rottbauer

From the Department of Medicine III (B.M., C.L., D.H., S.J., S.M., B.V., A.H., H.A.K., W.R.), University of Heidelberg, Germany; and Novartis Institutes for BioMedical Research (M.C.F.), Cambridge, Mass.

Correspondence to Wolfgang Rottbauer, Department of Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. E-mail wolfgang.rottbauer{at}med.uni-heidelberg.de

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.

Key Words: zebrafish • genetics • essential cardiac myosin light chain-1 • phosphorylation • myocardial contractility