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

Overview

Journal Biophys J

Publisher Cell Press

Specialty Biophysics

Date 2017 Oct 6

PMID 28978442

Citations 13

Authors

Stefania Monteleone

Andreas Lieb

Alexandra Pinggera

Giulia Negro

Julian E Fuchs

Florian Hofer

Jorg Striessnig

Petronel Tuluc

Klaus R Liedl

Affiliations

Soon will be listed here.

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 Ca1.1 and Ca1.3 Ca channels bearing several S4 charge mutations. Our modeling predicts that mutations of Ca1.1-R1 (R528H/G, R897S) or Ca1.1-R2 (R900S, R1239H) linked to hypokalemic periodic paralysis type 1 and of Ca1.3-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 Ca1.3-R990H channels conduct ω-currents at hyperpolarizing potentials, but not upon membrane depolarization compared with wild-type channels.

Citing Articles

Periodic paralysis.

Cannon S Handb Clin Neurol. 2024; 203:39-58.

PMID: 39174253 PMC: 11556526. DOI: 10.1016/B978-0-323-90820-7.00002-1.

Anionic omega currents from single countercharge mutants in the voltage-sensing domain of Ci-VSP.

Shen R, Roux B, Perozo E J Gen Physiol. 2023; 156(1).

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Characterization of two pathological gating-charge substitutions in Cav1.4 L-type calcium channels.

Heigl T, Netzer M, Zanetti L, Ganglberger M, Fernandez-Quintero M, Koschak A Channels (Austin). 2023; 17(1):2192360.

PMID: 36943941 PMC: 10038055. DOI: 10.1080/19336950.2023.2192360.

Ortner N Handb Exp Pharmacol. 2023; 279:183-225.

PMID: 36592224 DOI: 10.1007/164_2022_626.

Gating pore currents occur in CaV1.1 domain III mutants associated with HypoPP.

Wu F, Quinonez M, Cannon S J Gen Physiol. 2021; 153(11).

PMID: 34463712 PMC: 8563280. DOI: 10.1085/jgp.202112946.

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