Ca V 1.1 voltage-sensing domain III exclusively controls skeletal muscle excitation-contraction coupling.

Autor: Pelizzari S; Institute of Physiology, Department of Physiology and Medical Biophysics, Medical University Innsbruck, 6020, Innsbruck, Austria., Heiss MC; Institute of Physiology, Department of Physiology and Medical Biophysics, Medical University Innsbruck, 6020, Innsbruck, Austria., Fernández-Quintero ML; Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innsbruck, Austria., El Ghaleb Y; Institute of Physiology, Department of Physiology and Medical Biophysics, Medical University Innsbruck, 6020, Innsbruck, Austria., Liedl KR; Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innsbruck, Austria., Tuluc P; Department of Pharmacology and Toxicology, Center for Molecular Biosciences Innsbruck, University of Innsbruck, 6020, Innsbruck, Austria., Campiglio M; Institute of Physiology, Department of Physiology and Medical Biophysics, Medical University Innsbruck, 6020, Innsbruck, Austria., Flucher BE; Institute of Physiology, Department of Physiology and Medical Biophysics, Medical University Innsbruck, 6020, Innsbruck, Austria. bernhard.e.flucher@i-med.ac.at.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 28; Vol. 15 (1), pp. 7440. Date of Electronic Publication: 2024 Aug 28.
DOI: 10.1038/s41467-024-51809-5
Abstrakt: Skeletal muscle contractions are initiated by action potentials, which are sensed by the voltage-gated calcium channel (Ca V 1.1) and are conformationally coupled to calcium release from intracellular stores. Notably, Ca V 1.1 contains four separate voltage-sensing domains (VSDs), which activate channel gating and excitation-contraction (EC-) coupling at different voltages and with distinct kinetics. Here we show that a single VSD of Ca V 1.1 controls skeletal muscle EC-coupling. Whereas mutations in VSDs I, II and IV affect the current properties but not EC-coupling, only mutations in VSD III alter the voltage-dependence of depolarization-induced calcium release. Molecular dynamics simulations reveal comprehensive, non-canonical state transitions of VSD III in response to membrane depolarization. Identifying the voltage sensor that activates EC-coupling and detecting its unique conformational changes opens the door to unraveling the downstream events linking VSD III motion to the opening of the calcium release channel, and thus resolving the signal transduction mechanism of skeletal muscle EC-coupling.
(© 2024. The Author(s).)
Databáze: MEDLINE
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