Myosin light chain phosphorylation enhances contraction of heart muscle via structural changes in both thick and thin filaments
- 9 May 2016
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 113 (21), E3039-E3047
- https://doi.org/10.1073/pnas.1602776113
Abstract
Contraction of heart muscle is triggered by calcium binding to the actin-containing thin filaments but modulated by structural changes in the myosin-containing thick filaments. We used phosphorylation of the myosin regulatory light chain (cRLC) by the cardiac isoform of its specific kinase to elucidate mechanisms of thick filament-mediated contractile regulation in demembranated trabeculae from the rat right ventricle. cRLC phosphorylation enhanced active force and its calcium sensitivity and altered thick filament structure as reported by bifunctional rhodamine probes on the cRLC: the myosin head domains became more perpendicular to the filament axis. The effects of cRLC phosphorylation on thick filament structure and its calcium sensitivity were mimicked by increasing sarcomere length or by deleting the N terminus of the cRLC. Changes in thick filament structure were highly cooperative with respect to either calcium concentration or extent of cRLC phosphorylation. Probes on unphosphorylated myosin heads reported similar structural changes when neighboring heads were phosphorylated, directly demonstrating signaling between myosin heads. Moreover probes on troponin showed that calcium sensitization by cRLC phosphorylation is mediated by the thin filament, revealing a signaling pathway between thick and thin filaments that is still present when active force is blocked by Blebbistatin. These results show that coordinated and cooperative structural changes in the thick and thin filaments are fundamental to the physiological regulation of contractility in the heart. This integrated dual-filament concept of contractile regulation may aid understanding of functional effects of mutations in the protein components of both filaments associated with heart disease.Funding Information
- British Heart Foundation (PG/12/52/29713)
- British Heart Foundation (FS/09/001/26329)
This publication has 56 references indexed in Scilit:
- A Molecular Model of Phosphorylation-Based Activation and Potentiation of Tarantula Muscle Thick FilamentsJournal of Molecular Biology, 2011
- The significance of regulatory light chain phosphorylation in cardiac physiologyArchives of Biochemistry and Biophysics, 2011
- A New State of Cardiac Myosin with Very Slow ATP Turnover: A Potential Cardioprotective Mechanism in the HeartBiophysical Journal, 2011
- Thick-Filament Strain and Interfilament Spacing in Passive Muscle: Effect of Titin-Based Passive TensionBiophysical Journal, 2011
- Myofilament length dependent activationJournal of Molecular and Cellular Cardiology, 2010
- Myosin ATP turnover rate is a mechanism involved in thermogenesis in resting skeletal muscle fibersProceedings of the National Academy of Sciences of the United States of America, 2009
- Three-Dimensional Reconstruction of Tarantula Myosin Filaments Suggests How Phosphorylation May Regulate Myosin ActivityJournal of Molecular Biology, 2008
- Conservation of the regulated structure of folded myosin 2 in species separated by at least 600 million years of independent evolutionProceedings of the National Academy of Sciences of the United States of America, 2008
- Three-dimensional structure of vertebrate cardiac muscle myosin filamentsProceedings of the National Academy of Sciences of the United States of America, 2008
- Atomic model of a myosin filament in the relaxed stateNature, 2005