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Biophys J. 2017 Oct 3;113(7):1485-1495. doi: 10.1016/j.bpj.2017.08.010.

Mechanisms Responsible for ω-Pore Currents in Cav Calcium Channel Voltage-Sensing Domains.

Author information

1
Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innsbruck, Austria.
2
Department of Pharmacology and Toxicology, Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria; Institute of Neurology, University College London, London, United Kingdom.
3
Department of Pharmacology and Toxicology, Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria; Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
4
Department of Pharmacology and Toxicology, Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.
5
Department of Pharmacology and Toxicology, Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria. Electronic address: petronel.tuluc@uibk.ac.at.
6
Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innsbruck, Austria. Electronic address: klaus.liedl@uibk.ac.at.

Abstract

Mutations of positively charged amino acids in the S4 transmembrane segment of a voltage-gated ion channel form ion-conducting pathways through the voltage-sensing domain, named ω-current. Here, we used structure modeling and MD simulations to predict pathogenic ω-currents in CaV1.1 and CaV1.3 Ca2+ channels bearing several S4 charge mutations. Our modeling predicts that mutations of CaV1.1-R1 (R528H/G, R897S) or CaV1.1-R2 (R900S, R1239H) linked to hypokalemic periodic paralysis type 1 and of CaV1.3-R3 (R990H) identified in aldosterone-producing adenomas conducts ω-currents in resting state, but not during voltage-sensing domain activation. The mechanism responsible for the ω-current and its amplitude depend on the number of charges in S4, the position of the mutated S4 charge and countercharges, and the nature of the replacing amino acid. Functional characterization validates the modeling prediction showing that CaV1.3-R990H channels conduct ω-currents at hyperpolarizing potentials, but not upon membrane depolarization compared with wild-type channels.

PMID:
28978442
PMCID:
PMC5627182
DOI:
10.1016/j.bpj.2017.08.010
[Indexed for MEDLINE]
Free PMC Article

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