Chemical structures of selected general anaesthetics. Nitrous oxide is a molecule that exists in three resonating linear structures (although often misdrawn as a cyclical structure). For simplicity, we have drawn only one of the resonance forms.

Illustration of the general subunit topology and pentameric structure of receptors from the ligand-gated ion channel superfamily (nicotinic ACh, GABA_A, GABA_C ρ, glycine and 5-HT₃ receptors). Basic features of ligand-gated ion channel subunit topology (top panel) include an extensive extracellular N-terminal domain which binds the endogenous agonist, four putative transmembrane domains, a diverse intracellular linker between TM3 and TM4, and a short extracellular C-terminal domain. Other features not illustrated include critical disulfide linkages for some receptor subunits in the N-terminal extracellular domain and consensus phosphorylation sites for some subunits in the TM3–TM4 intracellular linker. The bottom panel depicts a schematic top view of a GABA_A αβγ receptor complex. For all ligand-gated ion channels, TM2 from each subunit (yellow) is thought to line the central ion channel pore

Location of amino acid residues within TM2 and TM3 of (a) human GABA_A α₁ [280] and (b) human GABA_A β₂ [281] receptor subunits that are critical for general anaesthetic modulation or block by the noncompetitive antagonists picrotoxinin and Zn²⁺, in addition to amino acid residues which are thought to line the ion channel pore. GABA_A α₁ and β₂ subunit isoforms are chosen since they represent the most common neuronal α and β subunit isoforms [52, 56]. The residue positions are from published studies: channel-lining residues [42, 282], volatile ethers (enflurane [219] and isoflurane [206, 219]), n-alcohols [219], picrotoxinin [283], propofol [206], trichloroethanol [227], etomidate [228, 229], loreclezole [284], barbiturate (pentobarbitone) [261] and zinc ions [285]. Note that some of the residue positions highlighted were actually first described in α- or β-subunit isoforms different from α₁ or β₂. To date, detailed three-dimensional structural information about TM2, the TM2–TM3 linker, and TM3 is lacking, so that the ordering of residues is hypothetical only. For example, the spatial interrelationship between TM2 and TM3 in a functional GABA_A receptor complex is currently unknown.

The selectivity of etomidate optical isomers for producing general anaesthesia in tadpoles mirrors the selectivity for potentiation of GABA_A receptor function. The main graph illustrates the concentration-response curves for immobility produced by etomidate stereoisomers in Rana temporaria tadpoles. Note that the in vivo potency of R(+) etomidate is approximately one order of magnitude greater than that of S(−) etomidate (also see [148]). The inset depicts electrophysiological traces from GABA responses at bovine GABA_A α₁β₂γ_2L receptors stably transfected in mouse L-cell fibroblast cells. Coapplication of R(+) etomidate produces a vastly greater enhancement of the control submaximal GABA response (C) than coapplication of S(−) etomidate. Figure from: Tomlin S. L., Jenkins A., Lieb W. R. and Franks N. P. (1998) Stereoselective effects of etomidate optical isomers on gamma-aminobutyric acid type A receptors and animals. Anesthesiology 88: 708–717. Reproduced in adapted form with permission of the authors and Lippincott-Raven Publishers, 227 East Washington Square, Philadelphia, PA 19106-3708, USA.

Specific mutations in TM2 or TM3 of the human GABA_A α₂ subunit abolish positive allosteric modulation by the volatile anaesthetic isoflurane at GABA_A α₂β₁ receptors. (A) Submaximal GABA currents in wild-type GABA_A α₂β₁ receptors are strongly enhanced (i.e. potentiated) by coapplication of clinically relevant concentrations of isoflurane. (B, C) In contrast, submaximal GABA currents in α₂(S270H)β₁ or α₂(A291W)β₁ mutant receptors are not enhanced by coapplication of isoflurane concentrations up to 1 mM. Thus, these mutant receptors are insensitive to GABA potentiation by isoflurane even at supra-anaesthetic concentrations. Individual whole-cell voltageclamp recordings from human embryonic kidney 293 cells transfected with cDNAs encoding the indicated subunit combination. Figure from: Krasowski M. D., Koltchine V. V., Rick C. E., Ye Q., Finn S. E. and Harrison N. L. (1998) Propofol and other intravenous anesthetics have sites of action on the γ-aminobutyric acid type A receptor distinct from that for isoflurane. Mol. Pharmacol. 53: 530–538. Reproduced with permission of the authors and the American Society for Pharmacology and Experimental Therapeutics, 9650 Rockville Pike, Bethesda, MD 20814-3995, USA.

Both the volatile anaesthetic halothane and the intravenous anaesthetic pentobarbitone prolong inhibitory postsynaptic currents (IPSCs) mediated by GABA_A receptors. Data were obtained from whole-cell patch-clamp recordings of rat hippocampal neurones from brain slices. Average records from whole-cell voltage-clamp recordings in hippocampal neurones of 100 individual spontaneous IPSCs for each trace show the prolongation of the decay phase of the IPSC produced by halothane and pentobarbitone. Data from halothane and pentobarbitone are from different neurones and preparations. Figure from: MacIver M. B., Tanelian D. T. and Mody I. (1991) Two mechanisms for anesthetic-induced enhancement of GABA_A-mediated neuronal inhibition. Ann. N. Y. Acad. Sci. 625: 91–96. Reproduced with permission of the authors and the Annals of the New York Academy of Sciences, 655 Madison Avenue, New York, NY 10021, USA.