Mechanistic insights into volatile anesthetic modulation of K2P channels. Academic Article uri icon

Overview

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.

publication date

  • December 21, 2020

Research

keywords

  • Anesthetics, Inhalation
  • Potassium Channels, Tandem Pore Domain

Identity

PubMed Central ID

  • PMC7781597

Scopus Document Identifier

  • 85099317839

Digital Object Identifier (DOI)

  • 10.1016/s0896-6273(01)00503-7

PubMed ID

  • 33345771

Additional Document Info

volume

  • 9