Multiple non-equivalent interfaces mediate direct activation of GABAA receptors by propofol

Megan M. Eaton, Allison L. Germann, Ruby Arora, Lily Q. Cao, Xiaoyi Gao, Daniel J. Shin, Albert Wu, David C. Chiara, Jonathan B. Cohen, Joe Henry Steinbach, Alex S. Evers, Gustav Akk

Research output: Contribution to journalReview article

17 Scopus citations

Abstract

Background: Propofol is a sedative agent that at clinical concentrations acts by allosterically activating or potentiating the γ-aminobutyric acid type A (GABAA) receptor. Mutational, modeling, and photolabeling studies with propofol and its analogues have identified potential interaction sites in the transmembrane domain of the receptor. At the "+ " of the β subunit, in the β-α interface, meta-azipropofol labels the M286 residue in the third transmembrane domain. Substitution of this residue with tryptophan results in loss of potentiation by propofol. At the "-" side of the β subunit, in the α-β interface (or β-β interface, in the case of homomeric β receptors), ortho-propofol diazirine labels the H267 residue in the second transmembrane domain. Structural modeling indicates that the β(H267) residue lines a cavity that docks propofol with favorable interaction energy. Method: We used two-electrode voltage clamp to determine the functional effects of mutations to the "+" and "- " sides of the β subunit on activation of the α1β3 GABAA receptor by propofol. Results: We found that while the individual mutations had a small effect, the combination of the M286W mutation with tryptophan mutations of selected residues at the α-β interface leads to strong reduction in gating efficacy for propofol. Conclusion: We conclude that α1β3 GABAA receptors can be activated by propofol interactions with the β-β, α-β, and β-α interfaces, where distinct, non-equivalent regions control channel gating. Any interface can mediate activation, hence substitutions at all interfaces are required for loss of activation by propofol.

Original languageEnglish
Pages (from-to)772-780
Number of pages9
JournalCurrent Neuropharmacology
Volume14
Issue number7
DOIs
StatePublished - Oct 1 2016

Keywords

  • Activation
  • Binding site
  • GABAA receptor
  • Mutation
  • Propofol
  • Structure

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    Eaton, M. M., Germann, A. L., Arora, R., Cao, L. Q., Gao, X., Shin, D. J., Wu, A., Chiara, D. C., Cohen, J. B., Steinbach, J. H., Evers, A. S., & Akk, G. (2016). Multiple non-equivalent interfaces mediate direct activation of GABAA receptors by propofol. Current Neuropharmacology, 14(7), 772-780. https://doi.org/10.2174/1570159X14666160202121319