Mechanistic insights into volatile anesthetic modulation of K2P channels

• Published in: eLife Vol. 9
• Main Authors: Wague, Aboubacar, Joseph, Thomas T, Woll, Kellie A, Bu, Weiming, Vaidya, Kiran A, Bhanu, Natarajan V, Garcia, Benjamin A, Nimigean, Crina M, Eckenhoff, Roderic G, Riegelhaupt, Paul M
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 21.12.2020; eLife Sciences Publications, Ltd; eLife Sciences Publications Ltd
• Subjects: Anesthesia; anesthetic; Anesthetics, Inhalation - metabolism; Anesthetics, Inhalation - pharmacology; Animals; Binding Sites; Biochemistry and Chemical Biology; Humans; isoflurane; Isoflurane - pharmacology; K2P; Mice; Molecular Docking Simulation; Molecular dynamics; Potassium Channels - drug effects; Potassium Channels - metabolism; Potassium Channels, Tandem Pore Domain - drug effects; Potassium Channels, Tandem Pore Domain - metabolism; Structural Biology and Molecular Biophysics; TREK1; Xenopus laevis; Zebrafish; mouse; anesthetic; chemical biology; biochemistry; xenopus; K2P; structural biology; TREK1; zebrafish; isoflurane; molecular biophysics
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.59839

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.