|ZFIN ID: ZDB-PUB-090204-16|
A Single Serine in the Carboxyl Terminus of Cardiac Essential Myosin Light Chain-1 Controls Cardiomyocyte Contractility In Vivo
Meder, B., Laufer, C., Hassel, D., Just, S., Marquart, S., Vogel, B., Hess, A., Fishman, M.C., Katus, H.A., and Rottbauer, W.
|Source:||Circulation research 104(5): 650-659 (Journal)|
|Registered Authors:||Fishman, Mark C., Hassel, David, Hess, Alexander, Just, Steffen, Laufer, Christina, Marquart, Sabine, Meder, Benjamin, Rottbauer, Wolfgang, Vogel, Britta|
|Keywords:||zebrafish, genetics, essential cardiac myosin light chain-1, phosphorylation, myocardial contractility|
|PubMed:||19168438 Full text @ Circ. Res.|
Meder, B., Laufer, C., Hassel, D., Just, S., Marquart, S., Vogel, B., Hess, A., Fishman, M.C., Katus, H.A., and Rottbauer, W. (2009) A Single Serine in the Carboxyl Terminus of Cardiac Essential Myosin Light Chain-1 Controls Cardiomyocyte Contractility In Vivo. Circulation research. 104(5):650-659.
ABSTRACTAlthough 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.