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DOI	10.1073/pnas.2023706118
	Stress-dependent activation of myosin in the heart requires thin filament activation and thick filament mechanosensing
	Park-Holohan S.-J.; Brunello E.; Kampourakis T.; Rees M.; Irving M.; Fusi L.
发表日期	2021
ISSN	00278424
卷号	118 期号:16
英文摘要	Myosin-based regulation in the heart muscle modulates the number of myosin motors available for interaction with calcium-regulated thin filaments, but the signaling pathways mediating the stronger contraction triggered by stretch between heartbeats or by phosphorylation of the myosin regulatory light chain (RLC) remain unclear. Here, we used RLC probes in demembranated cardiac trabeculae to investigate the molecular structural basis of these regulatory pathways. We show that in relaxed trabeculae at near-physiological temperature and filament lattice spacing, the RLC-lobe orientations are consistent with a subset of myosin motors being folded onto the filament surface in the interacting-heads motif seen in isolated filaments. The folded conformation of myosin is disrupted by cooling relaxed trabeculae, similar to the effect induced by maximal calcium activation. Stretch or increased RLC phosphorylation in the physiological range have almost no effect on RLC conformation at a calcium concentration corresponding to that between beats. These results indicate that in near-physiological conditions, the folded myosin motors are not directly switched on by RLC phosphorylation or by the titin-based passive tension at longer sarcomere lengths in the absence of thin filament activation. However, at the higher calcium concentrations that activate the thin filaments, stretch produces a delayed activation of folded myosin motors and force increase that is potentiated by RLC phosphorylation. We conclude that the increased contractility of the heart induced by RLC phosphorylation and stretch can be explained by a calcium-dependent interfilament signaling pathway involving both thin filament sensitization and thick filament mechanosensing. © This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
英文关键词	Heart muscle; Muscle regulation; Myosin motor; Myosin-binding protein C
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179827
作者单位	Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, British Heart Foundation Centre of Research Excellence, King's College London, London, SE1 1UL, United Kingdom
推荐引用方式 GB/T 7714	Park-Holohan S.-J.,Brunello E.,Kampourakis T.,et al. Stress-dependent activation of myosin in the heart requires thin filament activation and thick filament mechanosensing[J],2021,118(16).
APA	Park-Holohan S.-J.,Brunello E.,Kampourakis T.,Rees M.,Irving M.,&Fusi L..(2021).Stress-dependent activation of myosin in the heart requires thin filament activation and thick filament mechanosensing.Proceedings of the National Academy of Sciences of the United States of America,118(16).
MLA	Park-Holohan S.-J.,et al."Stress-dependent activation of myosin in the heart requires thin filament activation and thick filament mechanosensing".Proceedings of the National Academy of Sciences of the United States of America 118.16(2021).