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Cellular/Molecular GABA-Induced Intersubunit Conformational Movement in
 

Summary: Cellular/Molecular
GABA-Induced Intersubunit Conformational Movement in
the GABAA Receptor 1M1- 2M3 Transmembrane Subunit
Interface: Experimental Basis for Homology Modeling of an
Intravenous Anesthetic Binding Site
Moez Bali,1 Michaela Jansen,1 and Myles H. Akabas1,2,3
Departments of 1Physiology and Biophysics, 2Neuroscience, and 1Medicine, Albert Einstein College of Medicine of Yeshiva University, Bronx,
New York 10461
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 resolution acetylcholine receptor structure is complicated
by alignment uncertainty between the acetylcholine and GABAA receptor M3 and M4 transmembrane segments. Using disulfide
crosslinkingwepreviouslyestablishedtheorientationofM2andM3withinasingleGABAA subunit.Theresultantmodelpredictsthatthe
M3 residue 2M286, implicated in anesthetic binding, faces the adjacent 1-M1 segment and not into the 2 subunit interior as some
models have suggested. To assess the proximity of 2M286 to the 1-M1 segment we expressed 2M286C and 2 with 10 consecutive
1-M1cysteine(Cys)mutants, 1I223Cto 1L232C,inandflankingtheextracellularendof 1-M1.Inactivatedstates, 2M286Cformed
disulfidebondswith 1Y225Cand 1Q229CbasedonelectrophysiologicalassaysanddimersonWesternblots,butnotwithother 1-M1
mutants. 2F289, one helical turn below 2M286, formed disulfide bonds with 1I228C, 1Q229C and 1L232C in activated states. The
interveningresidues, 2G287Cand 2C288,didnotformdisulfidebondswith 1-M1Cysmutants.Weconcludethatthe 2-M3residues
2M286 and 2F289 face the intersubunit interface in close proximity to 1-M1 and that channel gating induces a structural rearrange-
ment in the transmembrane subunit interface that reduces the M3 to M1 separation by 7 . This supports the hypothesis that some

  

Source: Akabas, Myles - Department of Physiology and Biophysics, Albert Einstein College of Medicine, Yeshiva University

 

Collections: Biology and Medicine