Department of Anesthesiology

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Voltage-dependent C-type inactivation in a constitutively open K+ channel.

TitleVoltage-dependent C-type inactivation in a constitutively open K+ channel.
Publication TypeJournal Article
Year of Publication2008
AuthorsPanaghie G, Purtell K, Tai K-K, Abbott GW
JournalBiophys J
Volume95
Issue6
Pagination2759-78
Date Published2008 Sep 15
ISSN1542-0086
KeywordsAmino Acid Sequence, Animals, Cell Membrane Permeability, Electric Conductivity, Extracellular Space, Humans, Ion Channel Gating, KCNQ1 Potassium Channel, Kinetics, Molecular Sequence Data, Mutant Proteins, Mutation, Porosity, Protein Structure, Tertiary, Substrate Specificity, Xenopus laevis
Abstract

Most voltage-gated potassium (Kv) channels undergo C-type inactivation during sustained depolarization. The voltage dependence and other mechanistic aspects of this process are debated, and difficult to elucidate because of concomitant voltage-dependent activation. Here, we demonstrate that MinK-KCNQ1 (I(Ks)) channels with an S6-domain mutation, F340W in KCNQ1, exhibit constitutive activation but voltage-dependent C-type inactivation. F340W-I(Ks) inactivation was sensitive to extracellular cation concentration and species, and it altered ion selectivity, suggestive of pore constriction. The rate and extent of F340W-I(Ks) inactivation and recovery from inactivation were voltage-dependent with physiologic intracellular ion concentrations, and in the absence or presence of external K(+), with an estimated gating charge, z(i), of approximately 1. Finally, double-mutant channels with a single S4 charge neutralization (R231A,F340W-I(Ks)) exhibited constitutive C-type inactivation. The results suggest that F340W-I(Ks) channels exhibit voltage-dependent C-type inactivation involving S4, without the necessity for voltage-dependent opening, allosteric coupling to voltage-dependent S6 transitions occurring during channel opening, or voltage-dependent changes in ion occupancy. The data also identify F340 as a critical hub for KCNQ1 gating processes and their modulation by MinK, and present a unique system for further mechanistic studies of the role of coupling of C-type inactivation to S4 movement, without contamination from voltage-dependent activation.

DOI10.1529/biophysj.108.133678
Alternate JournalBiophys. J.
PubMed ID18567635
PubMed Central IDPMC2527255
Grant ListR01 HL079275 / HL / NHLBI NIH HHS / United States
R01 HL079275 / HL / NHLBI NIH HHS / United States