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Modulation of GABAA receptors by benzodiazepines (BZDs) is believed to involve two distinct steps: a recognition step in which BZDs bind and a conformational transition step in which the affinity of the receptor for GABA changes. Previously, using γ2/α1 chimeric subunits (χ), we demonstrated that although the N-terminal 167 γ2 amino acid residues confer high-affinity BZD binding, other γ2domains couple BZD binding to potentiation of the GABA-mediated Cl− current (IGABA). To determine which γ2 regions couple binding to potentiation, we generated χs with longer N-terminal γ2 segments for voltage-clamp experiments in Xenopus oocytes. Chimeras containing greater than the N-terminal 167 γ2 residues showed incremental gains in maximal potentiation for diazepam enhancement ofIGABA. Residues in γ2199–236, γ2224–236 (pre-M1), and particularly γ2257–297 (M2 and surrounding loops) are important for BZD potentiation. For several positive BZD modulators tested, the same regions restored potentiation of IGABA. In contrast, β-carboline inverse-agonism was unaltered in chimeric receptors, suggesting that structural determinants for positive and negative BZD allosteric modulation are different. Dissection of the γ2257–297 domain revealed that three residues in concert, γ2T281, γ2I282 (M2 channel vestibule), and γ2S291 (M2–M3 loop) are necessary to impart full BZD potentiation to chimeric receptors. Thus, these residues participate in coupling distant BZD-binding events to conformational changes in the GABAA receptor. The location of these novel residues provides insight into the mechanisms underlying allosteric coupling for other members of the ligand-gated ion channel superfamily.

the journal of neuroscience/the journal of neuroscience

Identification of Transduction Elements for Benzodiazepine Modulation of the GABA<sub>A</sub>Receptor: Three Residues Are Required for Allosteric Coupling

Identification of Transduction Elements for Benzodiazepine Modulation of the GABAAReceptor: Three Residues Are Required for Allosteric Coupling

Identification of Transduction Elements for Benzodiazepine Modulation of the GABA_AReceptor: Three Residues Are Required for Allosteric Coupling