Functional and structural models of GABAA receptor interactions with etomidate.

Panel A: A side-on ribbon depiction of a structural homology model for α1β3γ2L GABAA receptors based on the glutamate-gated chloride channel (GluCl) from Caenorhabditis elegans [20]. Both the extracellular domains and transmembrane domains are shown in relation to membrane lipids. Subunits are color-coded (α1 = blue; β3 = yellow; γ2L = green). βN265 and other residues involved in etomidate and propofol binding are depicted as red stick structures in one of two β+/α− transmembrane interfacial sites. Panel B: A view of the transmembrane domains from the extracellular space shows the structure of each subunit’s four-helix bundle and the arrangement of subunits around the central chloride channel (grey circle). Residues in one interfacial anesthetic site are depicted as red stick structures. Panel C: A close-up view of one β+/α− transmembrane inter-subunit etomidate binding site in the homology model. Helix backbones are depicted as solid cylinders. The βN265 residue and six anesthetic contact residues identified by photolabeling or cysteine modification/protection are highlighted as labeled space-filling structures. Panel D: A Monod-Wyman-Changeux two-state (inactive = R; active = O) equilibrium co-agonist scheme with two equivalent orthosteric agonist (GABA; G) sites and two equivalent allosteric agonist (etomidate; E) sites is depicted [1]. For simplicity, states with only one occupied agonist site are omitted. The model is defined by five equilibrium parameters (see Eq. 3, methods): L0 is a basal gating equilibrium (C/O); KG and KE are dissociation constants for respectively, GABA and etomidate binding to inactive receptors; c and d quantify the binding affinity ratios for respectively, GABA and etomidate to active vs. inactive receptors. Maximal agonist efficacies for GABA and etomidate are respectively, (1+L0c2)−1 and (1+L0d2)−1.