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Functional heterogeneity of the four voltage sensors of a human L-type calcium channel
Division of Molecular Medicine, Department of Anesthesiology, University of California, Los Angeles, CA 90095, USA.
Division of Molecular Medicine, Department of Anesthesiology, University of California, Los Angeles, CA 90095, USA.
dPET, Spokane, WA 99223, USA.
Centro Interdisciplinario de Neurociencias de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile.
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2014 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, no 51, p. 18381-18386Article in journal (Refereed) Published
Abstract [en]

Excitation-evoked Ca(2+) influx is the fastest and most ubiquitous chemical trigger for cellular processes, including neurotransmitter release, muscle contraction, and gene expression. The voltage dependence and timing of Ca(2+) entry are thought to be functions of voltage-gated calcium (CaV) channels composed of a central pore regulated by four nonidentical voltage-sensing domains (VSDs I-IV). Currently, the individual voltage dependence and the contribution to pore opening of each VSD remain largely unknown. Using an optical approach (voltage-clamp fluorometry) to track the movement of the individual voltage sensors, we discovered that the four VSDs of CaV1.2 channels undergo voltage-evoked conformational rearrangements, each exhibiting distinct voltage- and time-dependent properties over a wide range of potentials and kinetics. The voltage dependence and fast kinetic components in the activation of VSDs II and III were compatible with the ionic current properties, suggesting that these voltage sensors are involved in CaV1.2 activation. This view is supported by an obligatory model, in which activation of VSDs II and III is necessary to open the pore. When these data were interpreted in view of an allosteric model, where pore opening is intrinsically independent but biased by VSD activation, VSDs II and III were each found to supply ∼50 meV (∼2 kT), amounting to ∼85% of the total energy, toward stabilizing the open state, with a smaller contribution from VSD I (∼16 meV). VSD IV did not appear to participate in channel opening.

Place, publisher, year, edition, pages
Washington, DC, United States: National Academy of Sciences , 2014. Vol. 111, no 51, p. 18381-18386
Keywords [en]
Ca2+ entry, CaV1.2, allostery, fluorometry, gating mechanism
National Category
Bioinformatics and Systems Biology
Identifiers
URN: urn:nbn:se:liu:diva-151619DOI: 10.1073/pnas.1411127112ISI: 000346767200072PubMedID: 25489110Scopus ID: 2-s2.0-84919935344OAI: oai:DiVA.org:liu-151619DiVA, id: diva2:1251675
Available from: 2018-09-27 Created: 2018-09-27 Last updated: 2018-10-04Bibliographically approved

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Pantazis, AntoniosSavalli, NicolettaSigg, DanielNeely, AlanOlcese, Riccardo
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