General anaesthetic action at transmitter-gated inhibitory amino acid receptors

doi:10.1016/S0165-6147(99)01405-4

Trends in Pharmacological Sciences

Volume 20, Issue 12, 1 December 1999, Pages 496-502

https://doi.org/10.1016/S0165-6147(99)01405-4 Get rights and content

Abstract

Research within the past decade has provided compelling evidence that anaesthetics can act directly as allosteric modulators of transmitter-gated ion channels. Recent comparative studies of the effects of general anaesthetics across a structurally homologous family of inhibitory amino acid receptors that includes mammalian GABA_A, glycine and Drosophila RDL GABA receptors have provided new insights into the structural basis of anaesthetic action at transmitter-gated channels. In this article, the differential effects of general anaesthetics across inhibitory amino acid receptors and the potential relevance of such actions to general anaesthesia will be discussed.

Section snippets

GABA_A receptor diversity

GABA is the major inhibitory neurotransmitter in the higher centres of the CNS and mediates fast synaptic transmission via the activation of an anion channel intrinsic to the GABA_A receptor. Multiple isoforms of the GABA_A receptor exist as a pentameric complex drawn, in mammals, from α(1–6)-, β(1–3)-, γ(1–3)-, δ(1)-, ϵ(1)- and θ(1)-subunit isoforms10, 11. In addition, a peripheral π-subunit and three ρ(1–3)-subunits are known¹⁰. The majority of GABA_A receptors are thought to assemble as

β-subunits

The subunit composition of the GABA_A receptor determines the allosteric effects of some general anaesthetics but few generalizations can be made at present. A contribution of the β-subunit to anaesthetic binding at the GABA_A receptor is suggested by studies conducted using homo-oligomeric assemblies of β₁- or β₃-subunits. The largely GABA-insensitive, and in most studies spontaneously open, channels formed by β-subunit homo-oligomers are apparently activated by pentobarbitone, propofol,

Effects of anaesthetics at mammalian and invertebrate homo-oligomeric GABA receptors

Receptors formed from GABA ρ-subunits represent a subtype of the GABA_A receptor [recently classified as GABA_A0r (Ref. 10)]. Such receptors, and their endogenous counterparts, display a characteristic pharmacology that includes insensitivity to most intravenous general anaesthetic agents at concentrations used in surgery40, 41, 42 (Table 1). Exceptions are steroidal agents, such as alphaxalone, which produce a modest potentiation of currents mediated by homo-oligomeric assemblies of the

Glycine receptor diversity

Glycine contributes to fast inhibitory synaptic transmission within the brainstem and spinal cord via the activation of anion-selective, strychnine-sensitive, glycine receptors⁴⁹. The glycine receptor is a pentameric complex that is assembled from α(1–4)- and β(1)-subunits. The predominant receptor isoform in adults consists of α1- and β-subunits with the stoichiometry 3α.2β (Ref. 49). In recombinant systems, homo-oligomeric assemblies of α-subunit function efficiently. Indeed, the embryonic

Influence of amino acid residues within TM2 and TM3

Structural elements that influence the differential effects of general anaesthetics across inhibitory amino acid receptors have recently been elucidated. Using chimeric constructs of GABA_A receptor β1- and β2-subunits, Wingrove et al.⁵⁴ and Belelli et al.²⁵ found that the region of the polypeptide distal to the N-terminal extracellular domain is the major determinant of the differential effects of loreclezole and etomidate at hetero-oligomeric GABA_A receptors, incorporating β1-subunits rather

Concluding remarks

It is a tantalizing prospect that the recent appreciation of the role of individual amino acids in anaesthetic action in vitro might be exploited to create animals engineered to express receptors indifferent to certain anaesthetic agents, yet otherwise normal. Indeed, generation of null-allelle mice lacking specific receptor subunits has already initiated an assessment of how anaesthetic action in the whole animal is affected by the ablation of specific receptor isoforms65, 66. The feasibility

Acknowledgements

Work in the authors’ laboratory was supported by the MRC, MRC-ROPA scheme Organon Teknika, EC Biomedicine and Health Grant BMH4-CT97-2359 and the Royal College of Anaesthetists.

Glossary

Chemical name

F3:: 1-chloro-1,2,2-triflurocyclobutane

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We investigated the effects of nitrous oxide (N₂O) on glycinergic inhibitory whole-cell and synaptic responses using a “synapse bouton preparation,” dissociated mechanically from rat spinal sacral dorsal commissural nucleus (SDCN) neurons. This technique can evaluate pure single- or multi-synaptic responses from native functional nerve endings and enable us to accurately quantify how N₂O influences pre- and postsynaptic transmission. We found that 70 % N₂O enhanced exogenous glycine-induced whole-cell currents (I_Gly) at glycine concentrations lower than 3 × 10^–5 M, but did not affect I_Gly at glycine concentrations higher than 10^–4 M. N₂O did not affect the amplitude and 1/e decay-time of both spontaneous and miniature glycinergic inhibitory postsynaptic currents recorded in the absence and presence of tetrodotoxin (sIPSCs and mIPSCs, respectively). The decrease in frequency induced by N₂O was observed in sIPSCs but not in mIPSCs, which was recorded in the presence of both tetrodotoxin and Cd²⁺, which block voltage-gated Na⁺ and Ca²⁺ channels, respectively. N₂O also decreased the amplitude and increased the failure rate and paired-pulse ratio of action potential-evoked glycinergic inhibitory postsynaptic currents. N₂O slightly decreased the Ba²⁺ currents mediated by voltage-gated Ca²⁺ channels in SDCN neurons. We found that N₂O suppresses glycinergic responses at synaptic levels with presynaptic effect having much more predominant role. The difference between glycinergic whole-cell and synaptic responses suggests that extrasynaptic responses seriously modulate whole-cell currents. Our results strongly suggest that these responses may thus in part explain analgesic effects of N₂O via marked glutamatergic inhibition by glycinergic responses in the spinal cord.
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Citation Excerpt :
More simply, for intravenous anaesthetic agents potency is described by the dose that produces a loss of eyelash reflex, loss of verbal command or object drop (typically a water-filled syringe).1 If we accept the premise that anaesthesia results from a depression of central nervous system activity two main target processes can be proposed: enhancement of inhibitory transmission via an interaction with GABAA receptors1,2 and inhibition of excitatory transmission via an interaction with N-methyl-d-aspartate (NMDA) glutamate receptors.1 The vast majority of anaesthetic agents can be demonstrated to interact with one of these targets and these are covered in more detail below.
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Role of GABA A receptor subtypes in the behavioural effects of intravenous general anaesthetics
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Citation Excerpt :
A methionine (M) residue occupies the equivalent position of the Drosophila invertebrate GABA subunit.41 Mutation to β2N265M not only abolished the actions of etomidate, but additionally reduced the effects of propofol.9 42 43 Considering the long-held view that general anaesthetics act in a non-specific way to disrupt the neuronal membrane, these findings, at least for etomidate, were surprising.
Since the introduction of general anaesthetics into clinical practice, researchers have been mystified as to how these chemically disparate drugs act to produce their dramatic effects on central nervous system function and behaviour. Scientific advances, particularly during the last 25 years, have now begun to reveal the molecular mechanisms underpinning their behavioural effects. For certain i.v. general anaesthetics, such as etomidate and propofol, a persuasive case can now be made that the GABA_A receptor, a major inhibitory receptor in the mammalian central nervous system, is an important target. Advances in molecular pharmacology and in genetic manipulation of rodent genes reveal that different subtypes of the GABA_A receptor are responsible for mediating particular aspects of the anaesthetic behavioural repertoire. Such studies provide a better understanding of the neuronal circuitry involved in the various anaesthetic-induced behaviours and, in the future, may result in the development of novel therapeutics with a reduced propensity for side-effects.
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Based on the diverse array of anaesthetic structures, a single anaesthetic target site seems unlikely. With the knowledge that anaesthesia likely results from central nervous system depression, it can be hypothesized that anaesthesia results from either enhanced inhibitory transmission or reduced excitatory transmission. Two main targets have been extensively described: GABA_A receptors and N-methyl-d-aspartate (NMDA) glutamate receptors. On γ-aminobutyric acid (GABA) binding to GABA_A receptors, an influx of Cl⁻ results to produce hyperpolarization. With the exception of ketamine, xenon and nitrous oxide, all anaesthetic agents potentiate GABA-mediated conductance. On binding of the main excitatory transmitter glutamate, NMDA receptors gate an influx of Ca²⁺ and Na⁺. Ketamine, xenon and nitrous oxide inhibit this ion movement to depress excitatory transmission.
Effects of propofol on glycinergic neurotransmission in a single spinal nerve synapse preparation
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The effects of the intravenous anesthetic, propofol, on glycinergic transmission and on glycine receptor-mediated whole-cell currents (I_Gly) were examined in the substantia gelatinosa (SG) neuronal cell body, mechanically dissociated from the rat spinal cord. This “synaptic bouton” preparation, which retains functional native nerve endings, allowed us to evaluate glycinergic inhibitory postsynaptic currents (IPSCs) and whole-cell currents in a preparation in which experimental solution could rapidly access synaptic terminals. Synaptic IPSCs were measured as spontaneous (s) and evoked (e) IPSCs. The eIPSCs were elicited by applying paired-pulse focal electrical stimulation, while I_Gly was evoked by a bath application of glycine. A concentration-dependent enhancement of I_Gly was observed for ≥10 µM propofol. Propofol (≥3 µM) significantly increased the frequency of sIPSCs and prolonged the decay time without altering the current amplitude. However, propofol (≥3 µM) also significantly increased the mean amplitude of eIPSCs and decreased the failure rate (Rf). A decrease in the paired-pulse ratio (PPR) was noted at higher concentrations (≥10 µM). The decay time of eIPSCs was prolonged only at the maximum concentration tested (30 µM). Propofol thus acts at both presynaptic glycine release machinery and postsynaptic glycine receptors. At clinically relevant concentrations (<1 μM) there was no effect on I_Gly, sIPSCs or eIPSCs suggesting that at anesthetic doses propofol does not affect inhibitory glycinergic synapses in the spinal cord.

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Trends in Pharmacological Sciences

ReviewGeneral anaesthetic action at transmitter-gated inhibitory amino acid receptors

Abstract

Section snippets

GABAA receptor diversity

β-subunits

Effects of anaesthetics at mammalian and invertebrate homo-oligomeric GABA receptors

Glycine receptor diversity

Influence of amino acid residues within TM2 and TM3

Concluding remarks

Acknowledgements

Glossary

Chemical name

Trends Pharmacol. Sci.

Neuropharmacology

Trends Pharmacol. Sci.

Brain Res.

Neuron

Neuron

Trends Neurosci.

Trends Neurosci.

Pharmacol. Ther.

J. Biol. Chem.

J. Biol. Chem.

Br. J. Anaesth.

Anesth. Analg.

Anesth. Analg.

Nature

FASEB J.

Anesthesiology

Cell. Mol. Life Sci.

Pharmacol. Rev.

Proc. Natl. Acad. Sci. U. S. A.

Br. J. Pharmacol.

Br. J. Pharmacol.

Nat. Med.

Nature

Anesthesiology

Anesthesiology

Mol. Pharmacol.

J. Pharmacol. Exp. Ther.

Anesthesiology

Mol. Pharmacol.

Mol. Pharmacol.

Eur. J. Neurosci.

Mol. Pharmacol.

Proc. Natl. Acad. Sci. U. S. A.

Review
General anaesthetic action at transmitter-gated inhibitory amino acid receptors

GABA_A receptor diversity