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Although little is known about local movements within the GABA-binding site, a recent structural model of the GABA<jats:sub>A<\/jats:sub>receptor (GABA<jats:sub>A<\/jats:sub>R) ligand-binding domain predicts that \u03b2<jats:sub>2<\/jats:sub>Glu<jats:sup>155<\/jats:sup>is a key residue for direct interactions with the neurotransmitter (Cromer et al., 2002). To elucidate the role of the \u03b2<jats:sub>2<\/jats:sub>Ile<jats:sup>154<\/jats:sup>-Asp<jats:sup>163<\/jats:sup>region in GABA<jats:sub>A<\/jats:sub>R activation, each residue was individually mutated to cysteine and coexpressed with wild-type \u03b1<jats:sub>1<\/jats:sub>subunits in<jats:italic>Xenopus laevis<\/jats:italic>oocytes. Seven mutations increased the GABA EC<jats:sub>50<\/jats:sub>value (8- to 3400-fold), whereas three mutations (E155C, S156C, and G158C) also significantly increased the 2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl) pyridazinium (SR-95531)<jats:italic>K<\/jats:italic><jats:sub>I<\/jats:sub>value. GABA, SR-95531, and pentobarbital slowed<jats:italic>N-<\/jats:italic>biotinylaminoethyl methanethiosulfonate modification of T160C and D163C, indicating that \u03b2<jats:sub>2<\/jats:sub>Thr<jats:sup>160<\/jats:sup>and \u03b2<jats:sub>2<\/jats:sub>Asp<jats:sup>163<\/jats:sup>are located in or near the GABA-binding site and that this region undergoes structural rearrangements during channel gating. Cysteine substitution of \u03b2<jats:sub>2<\/jats:sub>Glu<jats:sup>155<\/jats:sup>resulted in spontaneously open GABA<jats:sub>A<\/jats:sub>Rs and differentially decreased the GABA, piperidine-4-sulfonic acid (partial agonist), and SR-95531 sensitivities, indicating that the mutation perturbs ligand binding as well as channel gating. Tethering thiol-reactive groups onto \u03b2<jats:sub>2<\/jats:sub>E155C closed the spontaneously open channels, suggesting that \u03b2<jats:sub>2<\/jats:sub>Glu<jats:sup>155<\/jats:sup>is a control element involved in coupling ligand binding to channel gating. Structural modeling suggests that the \u03b2<jats:sub>2<\/jats:sub>Ile<jats:sup>154<\/jats:sup>-Asp<jats:sup>163<\/jats:sup>region is a protein hinge that forms a network of interconnections that couples binding site movements to the cascade of events leading to channel opening.<\/jats:p>","DOI":"10.1523\/jneurosci.3746-04.2004","type":"journal-article","created":{"date-parts":[[2004,12,15]],"date-time":"2004-12-15T21:09:50Z","timestamp":1103144990000},"page":"11226-11235","source":"Crossref","is-referenced-by-count":72,"title":["Mutation of Glutamate 155 of the GABA<sub>A<\/sub>Receptor \u03b2<sub>2<\/sub>Subunit Produces a Spontaneously Open Channel: A Trigger for Channel Activation"],"prefix":"10.1523","volume":"24","author":[{"given":"J. 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