The distinct role of the four voltage sensors of the skeletal CaV1.1 channel in voltage-dependent activation

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dc.contributor.authorSavalli, Nicoletta
dc.contributor.authorSteccanella, Federica
dc.contributor.authorWier, Julian
dc.contributor.authorWu, Fenfen
dc.contributor.authorQuinonez, Marbella
dc.contributor.authorDifranco, Marino
dc.contributor.authorNeely, Alan
dc.contributor.authorCannon, Stephen C.
dc.contributor.authorOlcese, Riccardo
dc.date.accessioned2022-11-30T02:46:56Z
dc.date.available2022-11-30T02:46:56Z
dc.date.issued2021
dc.description.abstractInitiation of skeletal muscle contraction is triggered by rapid activation of RYR1 channels in response to sarcolemmal depolarization. RYR1 is intracellular and has no voltage-sensing structures, but it is coupled with the voltage-sensing apparatus of CaV1.1 channels to inherit voltage sensitivity. Using an opto-electrophysiological approach, we resolved the excitation-driven molecular events controlling both CaV1.1 and RYR1 activations, reported as fluorescence changes. We discovered that each of the four human CaV1.1 voltage-sensing domains (VSDs) exhibits unique biophysical properties: VSD-I time-dependent properties were similar to ionic current activation kinetics, suggesting a critical role of this voltage sensor in CaV1.1 activation; VSD-II, VSD-III, and VSD-IV displayed faster activation, compatible with kinetics of sarcoplasmic reticulum Ca2+ release. The prominent role of VSD-I in governing CaV1.1 activation was also confirmed using a naturally occurring, charge-neutralizing mutation in VSD-I (R174W). This mutation abolished CaV1.1 current at physiological membrane potentials by impairing VSD-I activation without affecting the other VSDs. Using a structurally relevant allosteric model of CaV activation, which accounted for both time- and voltage-dependent properties of CaV1.1, to predict VSD-pore coupling energies, we found that VSD-I contributed the most energy (~75 meV or ∼3 kT) toward the stabilization of the open states of the channel, with smaller (VSD-IV) or negligible (VSDs II and III) energetic contribution from the other voltage sensors (<25 meV or ∼1 kT). This study settles the longstanding question of how CaV1.1, a slowly activating channel, can trigger RYR1 rapid activation, and reveals a new mechanism for voltage-dependent activation in ion channels, whereby pore opening of human CaV1.1 channels is primarily driven by the activation of one voltage sensor, a mechanism distinct from that of all other voltage-gated channels.en_ES
dc.facultadFacultad de Cienciasen_ES
dc.file.nameSavalli_Dis2021.pdf
dc.identifier.doihttps://doi.org/10.1085/jgp.202112915
dc.identifier.urihttp://repositoriobibliotecas.uv.cl/handle/uvscl/7535
dc.languageen
dc.publisherRockefeller University Press
dc.rightsThis article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
dc.sourceJournal of General Physiology (JGP)
dc.subjectEXCITATION-CONTRACTION COUPLINGen_ES
dc.titleThe distinct role of the four voltage sensors of the skeletal CaV1.1 channel in voltage-dependent activation
dc.typeArticulo
uv.departamentoCentro Interdisciplinario de Neurociencia de Valparaiso

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