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

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.
AuthorsStefania Monteleone, Andreas Lieb, Alexandra Pinggera, Giulia Negro, Julian E Fuchs, Florian Hofer, Jörg Striessnig, Petronel Tuluc, Klaus R Liedl
JournalBiophysical journal (Biophys J) Vol. 113 Issue 7 Pg. 1485-1495 (Oct 03 2017) ISSN: 1542-0086 [Electronic] United States
PMID28978442 (Publication Type: Journal Article, Validation Study)
CopyrightCopyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Calcium Channels, L-Type
  • Water
Topics
  • Adenoma (genetics, metabolism)
  • Animals
  • Calcium Channels, L-Type (chemistry, genetics, metabolism)
  • Computer Simulation
  • HEK293 Cells
  • Humans
  • Hypokalemic Periodic Paralysis (genetics, metabolism)
  • Membrane Potentials (physiology)
  • Models, Molecular
  • Mutation
  • Protein Domains
  • Protein Structure, Secondary
  • Rabbits
  • Structural Homology, Protein
  • Water (chemistry, metabolism)

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