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Mechanistic insights into volatile anesthetic modulation of K2P channels.

TitleMechanistic insights into volatile anesthetic modulation of K2P channels.
Publication TypeJournal Article
Year of Publication2020
AuthorsWague A, Joseph TT, Woll KA, Bu W, Vaidya KA, Bhanu NV, Garcia BA, Nimigean CM, Eckenhoff RG, Riegelhaupt PM
JournalElife
Volume9
Date Published2020 12 21
ISSN2050-084X
KeywordsAnesthetics, Inhalation, Animals, Binding Sites, Humans, Isoflurane, Mice, Molecular Docking Simulation, Potassium Channels, Potassium Channels, Tandem Pore Domain, Xenopus laevis, Zebrafish
Abstract

K2P potassium channels are known to be modulated by volatile anesthetic (VA) drugs and play important roles in clinically relevant effects that accompany general anesthesia. Here, we utilize a photoaffinity analog of the VA isoflurane to identify a VA-binding site in the TREK1 K2P channel. The functional importance of the identified site was validated by mutagenesis and biochemical modification. Molecular dynamics simulations of TREK1 in the presence of VA found multiple neighboring residues on TREK1 TM2, TM3, and TM4 that contribute to anesthetic binding. The identified VA-binding region contains residues that play roles in the mechanisms by which heat, mechanical stretch, and pharmacological modulators alter TREK1 channel activity and overlaps with positions found to modulate TASK K2P channel VA sensitivity. Our findings define molecular contacts that mediate VA binding to TREK1 channels and suggest a mechanistic basis to explain how K2P channels are modulated by VAs.

DOI10.7554/eLife.59839
Alternate JournalElife
PubMed ID33345771
PubMed Central IDPMC7781597
Grant ListP01 CA196539 / CA / NCI NIH HHS / United States
FAER-182483-2 / / Foundation for Anesthesia Education and Research / International
T32 GM112596 / GM / NIGMS NIH HHS / United States
P01GM055876 / GM / NIGMS NIH HHS / United States
K08 GM132781 / GM / NIGMS NIH HHS / United States
R01 AI118891 / AI / NIAID NIH HHS / United States
K08GM132781 / GM / NIGMS NIH HHS / United States