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Construction of a GABAA receptor homology model based on the acetylcholine (ACh) receptor structure is complicated by the low sequence similarity between GABAA and ACh M3 transmembrane segments that creates significant uncertainty in their alignment. We determined the orientation of the GABAA M2 and M3 transmembrane segments using disulfide cross-linking. The M2 residues alpha1M266 (11') and alpha1T267 (12') were mutated to cysteine in either wild type or single M3 cysteine mutant (alpha1V297C, alpha1A300C to alpha1A305C) backgrounds. We assayed spontaneous and induced disulfide bond formation. Reduction with DTT significantly potentiated GABA-induced currents in alpha1T267C-L301C and alpha1T267C-F304C. Copper phenanthroline-induced oxidation inhibited GABA-induced currents in these mutants and in alpha1T267C-A305C. Intrasubunit disulfide bonds formed between these Cys pairs, implying that the alpha-carbon separation was at most 5.6 A. The reactive alpha1M3 residues (L301, F304, A305) lie on the same face of an alpha-helix. The unresponsive ones (A300, I302, E303) lie on the opposite face. In the resting state, the reactive side of alpha1M3 faces M2-alpha1T267. In conjunction with the ACh structure, our data indicate that alignment of GABAA and ACh M3 requires a single gap in the GABAA M2-M3 loop. In the presence of GABA, oxidation of alpha1T267C-L301C and alpha1T267C-F304C had no effect, but oxidation of alpha1T267C-A305C caused a significant increase in spontaneous channel opening. We infer that, as the channel opens, the distance and/or orientation between M2-alpha1T267 and M3-alpha1A305 changes such that the disulfide bond stabilizes the open state. This begins to define the conformational motion that M2 undergoes during channel opening.

State-Dependent Cross-Linking of the M2 and M3 Segments: Functional Basis for the Alignment of GABAAand Acetylcholine Receptor M3 Segments

State-Dependent Cross-Linking of the M2 and M3 Segments: Functional Basis for the Alignment of GABA_Aand Acetylcholine Receptor M3 Segments