A rich conformational palette underlies human CaV2.1-channel availability
Abstract Depolarization-evoked opening of CaV2.1 (P/Q-type) Ca2+-channels triggers neurotransmitter release, while voltage-dependent inactivation (VDI) limits channel availability to open, contributing to synaptic plasticity. The mechanism of CaV2.1 response to voltage is unclear. Using voltage-clam...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58884-2 |
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| author | Kaiqian Wang Michelle Nilsson Marina Angelini Riccardo Olcese Fredrik Elinder Antonios Pantazis |
| author_facet | Kaiqian Wang Michelle Nilsson Marina Angelini Riccardo Olcese Fredrik Elinder Antonios Pantazis |
| author_sort | Kaiqian Wang |
| collection | DOAJ |
| description | Abstract Depolarization-evoked opening of CaV2.1 (P/Q-type) Ca2+-channels triggers neurotransmitter release, while voltage-dependent inactivation (VDI) limits channel availability to open, contributing to synaptic plasticity. The mechanism of CaV2.1 response to voltage is unclear. Using voltage-clamp fluorometry and kinetic modeling, we optically track and physically characterize the structural dynamics of the four CaV2.1 voltage-sensor domains (VSDs). The VSDs are differentially sensitive to voltage changes, both brief and long-lived. VSD-I seems to directly drive opening and convert between two modes of function, associated with VDI. VSD-II is apparently voltage-insensitive. VSD-III and VSD-IV sense more negative voltages and undergo voltage-dependent conversion uncorrelated with VDI. Auxiliary β-subunits regulate VSD-I-to-pore coupling and VSD conversion kinetics. Hence, the central role of CaV2.1 channels in synaptic release, and their contribution to plasticity, memory formation and learning, can arise from the voltage-dependent conformational changes of VSD-I. |
| format | Article |
| id | doaj-art-06a04025cd134b358f7b566d5e8cfd34 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-06a04025cd134b358f7b566d5e8cfd342025-08-20T02:20:25ZengNature PortfolioNature Communications2041-17232025-04-0116111310.1038/s41467-025-58884-2A rich conformational palette underlies human CaV2.1-channel availabilityKaiqian Wang0Michelle Nilsson1Marina Angelini2Riccardo Olcese3Fredrik Elinder4Antonios Pantazis5Division of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Linköping UniversityDivision of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Linköping UniversityDepartment of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of CaliforniaDepartment of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of CaliforniaDivision of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Linköping UniversityDivision of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Linköping UniversityAbstract Depolarization-evoked opening of CaV2.1 (P/Q-type) Ca2+-channels triggers neurotransmitter release, while voltage-dependent inactivation (VDI) limits channel availability to open, contributing to synaptic plasticity. The mechanism of CaV2.1 response to voltage is unclear. Using voltage-clamp fluorometry and kinetic modeling, we optically track and physically characterize the structural dynamics of the four CaV2.1 voltage-sensor domains (VSDs). The VSDs are differentially sensitive to voltage changes, both brief and long-lived. VSD-I seems to directly drive opening and convert between two modes of function, associated with VDI. VSD-II is apparently voltage-insensitive. VSD-III and VSD-IV sense more negative voltages and undergo voltage-dependent conversion uncorrelated with VDI. Auxiliary β-subunits regulate VSD-I-to-pore coupling and VSD conversion kinetics. Hence, the central role of CaV2.1 channels in synaptic release, and their contribution to plasticity, memory formation and learning, can arise from the voltage-dependent conformational changes of VSD-I.https://doi.org/10.1038/s41467-025-58884-2 |
| spellingShingle | Kaiqian Wang Michelle Nilsson Marina Angelini Riccardo Olcese Fredrik Elinder Antonios Pantazis A rich conformational palette underlies human CaV2.1-channel availability Nature Communications |
| title | A rich conformational palette underlies human CaV2.1-channel availability |
| title_full | A rich conformational palette underlies human CaV2.1-channel availability |
| title_fullStr | A rich conformational palette underlies human CaV2.1-channel availability |
| title_full_unstemmed | A rich conformational palette underlies human CaV2.1-channel availability |
| title_short | A rich conformational palette underlies human CaV2.1-channel availability |
| title_sort | rich conformational palette underlies human cav2 1 channel availability |
| url | https://doi.org/10.1038/s41467-025-58884-2 |
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