The molecular transition that confers voltage dependence to muscle contraction
Abstract What is the molecular origin of voltage dependence in skeletal muscle excitation-contraction? Cholinergic transmission to the muscle fiber triggers action potentials, which are sensed by voltage-gated L-type calcium channels (CaV1.1). In turn, the conformational changes in CaV1.1 propagate...
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| Format: | Article |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59649-7 |
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| author | Marina Angelini Nicoletta Savalli Federica Steccanella Savana Maxfield Serena Pozzi Marino DiFranco Stephen C. Cannon Antonios Pantazis Riccardo Olcese |
| author_facet | Marina Angelini Nicoletta Savalli Federica Steccanella Savana Maxfield Serena Pozzi Marino DiFranco Stephen C. Cannon Antonios Pantazis Riccardo Olcese |
| author_sort | Marina Angelini |
| collection | DOAJ |
| description | Abstract What is the molecular origin of voltage dependence in skeletal muscle excitation-contraction? Cholinergic transmission to the muscle fiber triggers action potentials, which are sensed by voltage-gated L-type calcium channels (CaV1.1). In turn, the conformational changes in CaV1.1 propagate to and activate intracellular ryanodine receptors (RyR1), causing Ca2+ release and contraction. The CaV1.1 channel has four voltage-sensing domains (VSD-I to -IV) with diverse voltage-sensing properties, so the identity of VSD(s) responsible for conferring voltage dependence to RyR1 opening, is unknown. Using voltage-clamp fluorometry, we show that only VSD-III possesses kinetic, voltage-dependent and pharmacological properties consistent with skeletal-muscle excitability and Ca2+ release. We propose that the earliest voltage-dependent event in the excitation-contraction process is the structural rearrangement of VSD-III that propagates to RyR1 to initiate Ca2+ release and contraction. |
| format | Article |
| id | doaj-art-72f9196f117e4464a2ca49b0dc67225a |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-72f9196f117e4464a2ca49b0dc67225a2025-08-20T01:53:14ZengNature PortfolioNature Communications2041-17232025-05-0116111010.1038/s41467-025-59649-7The molecular transition that confers voltage dependence to muscle contractionMarina Angelini0Nicoletta Savalli1Federica Steccanella2Savana Maxfield3Serena Pozzi4Marino DiFranco5Stephen C. Cannon6Antonios Pantazis7Riccardo Olcese8Division of Molecular Medicine, Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine, University of California Los AngelesDivision of Molecular Medicine, Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine, University of California Los AngelesDivision of Molecular Medicine, Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine, University of California Los AngelesDivision of Molecular Medicine, Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine, University of California Los AngelesDivision of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Linköping UniversityDepartment of Physiology, David Geffen School of Medicine, University of California Los AngelesDepartment of Physiology, David Geffen School of Medicine, University of California Los AngelesDivision of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Linköping UniversityDivision of Molecular Medicine, Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine, University of California Los AngelesAbstract What is the molecular origin of voltage dependence in skeletal muscle excitation-contraction? Cholinergic transmission to the muscle fiber triggers action potentials, which are sensed by voltage-gated L-type calcium channels (CaV1.1). In turn, the conformational changes in CaV1.1 propagate to and activate intracellular ryanodine receptors (RyR1), causing Ca2+ release and contraction. The CaV1.1 channel has four voltage-sensing domains (VSD-I to -IV) with diverse voltage-sensing properties, so the identity of VSD(s) responsible for conferring voltage dependence to RyR1 opening, is unknown. Using voltage-clamp fluorometry, we show that only VSD-III possesses kinetic, voltage-dependent and pharmacological properties consistent with skeletal-muscle excitability and Ca2+ release. We propose that the earliest voltage-dependent event in the excitation-contraction process is the structural rearrangement of VSD-III that propagates to RyR1 to initiate Ca2+ release and contraction.https://doi.org/10.1038/s41467-025-59649-7 |
| spellingShingle | Marina Angelini Nicoletta Savalli Federica Steccanella Savana Maxfield Serena Pozzi Marino DiFranco Stephen C. Cannon Antonios Pantazis Riccardo Olcese The molecular transition that confers voltage dependence to muscle contraction Nature Communications |
| title | The molecular transition that confers voltage dependence to muscle contraction |
| title_full | The molecular transition that confers voltage dependence to muscle contraction |
| title_fullStr | The molecular transition that confers voltage dependence to muscle contraction |
| title_full_unstemmed | The molecular transition that confers voltage dependence to muscle contraction |
| title_short | The molecular transition that confers voltage dependence to muscle contraction |
| title_sort | molecular transition that confers voltage dependence to muscle contraction |
| url | https://doi.org/10.1038/s41467-025-59649-7 |
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