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Articles, Cellular/Molecular

GABA-Induced Intersubunit Conformational Movement in the GABAA Receptor α1M1-β2M3 Transmembrane Subunit Interface: Experimental Basis for Homology Modeling of an Intravenous Anesthetic Binding Site

Moez Bali, Michaela Jansen and Myles H. Akabas
Journal of Neuroscience 11 March 2009, 29 (10) 3083-3092; DOI: https://doi.org/10.1523/JNEUROSCI.6090-08.2009
Moez Bali
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Michaela Jansen
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Myles H. Akabas
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Abstract

The molecular basis of general anesthetic interactions with GABAA receptors is uncertain. An accurate homology model would facilitate studies of anesthetic action. Construction of a GABAA model based on the 4 Å resolution acetylcholine receptor structure is complicated by alignment uncertainty between the acetylcholine and GABAA receptor M3 and M4 transmembrane segments. Using disulfide crosslinking we previously established the orientation of M2 and M3 within a single GABAA subunit. The resultant model predicts that the βM3 residue β2M286, implicated in anesthetic binding, faces the adjacent α1-M1 segment and not into the β2 subunit interior as some models have suggested. To assess the proximity of β2M286 to the α1-M1 segment we expressed β2M286C and γ2 with 10 consecutive α1-M1 cysteine (Cys) mutants, α1I223C to α1L232C, in and flanking the extracellular end of α1-M1. In activated states, β2M286C formed disulfide bonds with α1Y225C and α1Q229C based on electrophysiological assays and dimers on Western blots, but not with other α1-M1 mutants. β2F289, one helical turn below β2M286, formed disulfide bonds with α1I228C, α1Q229C and α1L232C in activated states. The intervening residues, β2G287C and β2C288, did not form disulfide bonds with α1-M1 Cys mutants. We conclude that the β2-M3 residues β2M286 and β2F289 face the intersubunit interface in close proximity to α1-M1 and that channel gating induces a structural rearrangement in the transmembrane subunit interface that reduces the βM3 to αM1 separation by ∼7 Å. This supports the hypothesis that some intravenous anesthetics bind in the βM3-αM1 subunit interface consistent with azi-etomidate photoaffinity labeling.

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The Journal of Neuroscience: 29 (10)
Journal of Neuroscience
Vol. 29, Issue 10
11 Mar 2009
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GABA-Induced Intersubunit Conformational Movement in the GABAA Receptor α1M1-β2M3 Transmembrane Subunit Interface: Experimental Basis for Homology Modeling of an Intravenous Anesthetic Binding Site
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GABA-Induced Intersubunit Conformational Movement in the GABAA Receptor α1M1-β2M3 Transmembrane Subunit Interface: Experimental Basis for Homology Modeling of an Intravenous Anesthetic Binding Site
Moez Bali, Michaela Jansen, Myles H. Akabas
Journal of Neuroscience 11 March 2009, 29 (10) 3083-3092; DOI: 10.1523/JNEUROSCI.6090-08.2009

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GABA-Induced Intersubunit Conformational Movement in the GABAA Receptor α1M1-β2M3 Transmembrane Subunit Interface: Experimental Basis for Homology Modeling of an Intravenous Anesthetic Binding Site
Moez Bali, Michaela Jansen, Myles H. Akabas
Journal of Neuroscience 11 March 2009, 29 (10) 3083-3092; DOI: 10.1523/JNEUROSCI.6090-08.2009
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