Multiple Non-Equivalent Interfaces Mediate Direct Activation of GABAA Receptors by Propofol

Author(s): 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 .

Journal Name: Current Neuropharmacology

Volume 14 , Issue 7 , 2016

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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.

Keywords: Activation, binding site, GABAA receptor, mutation, propofol, structure.

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Article Details

VOLUME: 14
ISSUE: 7
Year: 2016
Page: [772 - 780]
Pages: 9
DOI: 10.2174/1570159X14666160202121319
Price: $58

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