The Role of the GABAA Receptor/Chloride Channel Complex in Anesthesia

Tanelian, Darrell L.; Kosek, Peter; Módy, István; Maclver, M. B.

doi:10.1097/00000542-199304000-00020

Cited by 339 publications

(118 citation statements)

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“…Con-versely, the loreclezole site is affected only by the P subunit, being dependent on the presence of fl2 or 113 . Other anaesthetic compounds such as propofol, halothane and enflurane as well as the neuroactive steroids such as alphaxalone have been shown to act by enhancing the GABA-induced chloride current (Tanelian et al, 1993;Keane & Biziere, 1987;Wakamori et al, 1991;Lin et al, 1992). Some of these compounds, propofol and neurosteroids for example, also produce direct activation of the receptor at high concentrations (Tanelian et al, 1983;Keane & Biziere, 1987;Hara et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…It is now generally accepted that a common feature of general anaesthetic agents is positive modulation of the inhibitory function of the neurotransmitter yaminobutyric acid (GABA) through GABAA receptors (Olsen, 1988;Tanelian et al, 1993;Franks & Lieb, 1994;Zimmerman et al, 1994). Electrophysiological and neurochemical studies have shown that general anaesthetic agents can have three mechanisms of action, namely (i) a potentiation of the GABA response (Evans, 1979;Study & Barker, 1981;Lin et al, 1992), (ii) a direct activation of GABAA receptors (Robertson, 1989;Franks & Lieb, 1994) and (iii) at high concentrations, a block of the GABA chloride channel (Schwartz et al, 1986;Peters et al, 1988;Robertson, 1989).…”

Section: Introductionmentioning

confidence: 99%

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Barbiturate interactions at the human GABA_A receptor: dependence on receptor subunit combination

Thompson

Whiting

Wafford

1996

British J Pharmacology

170

114

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1 Human GABAA receptors containing different and subunits with a y2s subunit were expressed in Xenopus oocytes and the effects of pentobarbitone on these subunit combinations were examined by electrophysiological recording of GABA currents with the two-electrode voltage-clamp method. 2 Pentobarbitone has previously been shown to have three actions on GABAA receptors: a potentiation of GABA responses, a direct activation of GABAA receptors and, at high concentrations, a block of the GABA chloride channel. In this study pentobarbitone activity consisted of the above mentioned three components on all the subunit combinations tested. However, the affinities and efficacies varied with receptor subtype. 3 Potentiation of GABA by pentobarbitone occurred over the same concentration-range for all the subunits with affinities in the range of 20-35 tiM. The degree of potentiation obtained, however, varied from 236% of GABA EC20 on al/#2y2s to 536% on a6fl2y2s.4 Examination of the direct effect of pentobarbitone revealed that the type of a subunit present determines both the degree of affinity and efficacy obtained. Receptors containing an cc6 subunit produced maximum direct responses to pentobarbitone larger than that obtainable with maximum GABA (150% to 170% of maximum GABA). The maximum direct pentobarbitone response obtainable with other a subunits ranged between 45% of maximum GABA for ac5f2y2s to 82% for a2/32y2s. The affinity of the direct action of pentobarbitone on a6/32y2s was 58 tiM compared to affinities for the other subunits ranging from 139 pM on a2fl2y2s to 528 gM on ac5f2y2s.5 The type of subunit present did not influence the direct action of pentobarbitone to the same extent as the a subunit. There were no significant differences between affinity or efficacy on oocytes expressing a6 and y2s with /31, /32 or P3. Affinities and efficacies on oocytes expressing al and y2s with PI, /2 or /3 were significantly different with pentobarbitone having a higher affinity and efficacy on al/33y2s followed by al/32y2s and then al/3ly2s. 6 The direct effect of pentobarbitone was blocked by picrotoxin but not by competitive antagonists, such as bicuculline or SR95531, indicating that the direct agonist activity of pentobarbitone was not mediated via the GABA binding site. 7 For the first time the influence of the various a and subunits on the effects of pentobarbitone were demonstrated. The results indicate that GABAA receptors containing a6 subunits have both a higher affinity and efficacy for direct activation by pentobarbitone, and reveal that pentobarbitone binds to more than one site on the GABAA receptor, and these are dependent on receptor subunit composition.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Barbiturate interactions at the human GABA_A receptor: dependence on receptor subunit combination

Thompson

Whiting

Wafford

1996

British J Pharmacology

170

114

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“…Electrophysiological data on inhibitory postsynaptic currents (i.p.s.cs) and potentials (i.p.s.ps) have also given equivocal results, with volatile anaesthetics being shown both to prolong i.p.s.cs (Gage & Robertson, 1985;Mody et al, 1991) and inhibit i.p.s.ps (Yoshimura et al, 1985;Fujiwara et al, 1988;El-Beheiry & Puil, 1989) (Jones et al, 1992), dorsal root ganglia (Nakahiro et al, 1989) and nucleus tractus solitarius (Wakamori et al, 1991). These recent voltage-clamp results add to the growing evidence (Tanelian et al, 1993;Franks & Lieb, 1994) that the GABAA receptor channel is an important target for volatile general anaesthetics.…”

Section: Introductionmentioning

confidence: 90%

Stereoselective and non‐stereoselective actions of isoflurane on the GABA_A receptor

Hall

Lieb

Franks

1994

British J Pharmacology

107

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1 Acutely dissociated cerebellar Purkinje neurones from 8-14 day old rats were studied under voltage clamp in the whole-cell patch-clamp configuration. Cl-currents induced by bath application of Ty-aminobutyric acid (GABA) were measured (using symmetrical Cl-solutions) at both low (2 JM) non-desensitizing and high (300 JM) desensitizing concentrations of GABA.2 At 2 JM GABA, the bicuculline-sensitive Cl-currents were potentiated by racemic isoflurane and both of its optical isomers. Isoflurane had no effect on membrane current in the absence of GABA. The dose-response data for potentiation by racemic isoflurane could be fitted with a Hill equation with an EC50 = 320 ± 20 gM isoflurane and a Hill coefficient of h = 2.7 ± 0.4 (means ± s.e.mean).3 The potentiations produced by the optical isomers of isoflurane at 2 JM GABA were stereoselective at moderate and high anaesthetic concentrations. The maximum stereoselectivity, about two fold, occurred at the ECm concentration for general anaesthesia (310I1M isoflurane), with S( + )-isoflurane being more effective than R(-)-isoflurane. At sub-anaesthetic concentrations, the stereoselectivity was less marked and vanished at the lowest concentration used (77JM isoflurane).4 The sustained residual current remaining after exposure of neurones to a desensitizing concentration of GABA (300JM) was inhibited non-stereoselectively, but only at high concentrations of isoflurane.The ratio of inhibitions by S(+)-and R(-)-isoflurane (mean ± s.e.mean) was 1.14 ± 0.21 at 770 JM isoflurane. At the EC50 concentration for general anaesthesia, however, the inhibition was barely significant. 5 The above results are discussed in relation to the possible role of the GABAA receptor channel in general anaesthesia.

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“…It is becoming widely accepted that this effect contributes importantly to the production of "anesthesia" (Tanelian et al, 1993;Franks and Lieb, 1994).…”

Section: Abstract: Gaba; Halothane; Taurine; Synaptic Inhibition; Anmentioning

confidence: 99%

Effects of Halothane on GABA_AReceptor Kinetics: Evidence for Slowed Agonist Unbinding

Li¹,

Pearce

2000

J. Neurosci.

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Many anesthetics, including the volatile agent halothane, prolong the decay of GABA A receptor-mediated IPSCs at central synapses. This effect is thought to be a major factor in the production of anesthesia. A variety of different kinetic mechanisms have been proposed for several intravenous agents, but for volatile agents the kinetic mechanisms underlying this change remain unknown. To address this question, we used rapid solution exchange techniques to apply GABA to recombinant GABA A receptors (␣ 1 ␤ 2 ␥ 2s ) expressed in HEK 293 cells, in the absence and presence of halothane. To differentiate between different microscopic kinetic steps that may be altered by the anesthetic, we studied a variety of measures, including peak concentration-response characteristics, macroscopic desensitization, recovery from desensitization, maximal current activation rates, and responses to the low-affinity agonist taurine. Experimentally observed alterations were compared with predictions based on a kinetic scheme that incorporated two agonist binding steps, and open and desensitized states. We found that, in addition to slowing deactivation after a brief pulse of GABA, halothane increased agonist sensitivity and slowed recovery from desensitization but did not alter macroscopic desensitization or maximal activation rate and only slightly slowed rapid deactivation after taurine application. This pattern of responses was found to be consistent with a reduction in the microscopic agonist unbinding rate (k off ) but not with changes in channel gating steps, such as the channel opening rate (␤), closing rate (␣), or microscopic desensitization. We conclude that halothane slows IPSC decay by slowing dissociation of agonist from the receptor. Key words: GABA; halothane; taurine; synaptic inhibition; anesthetics; receptor kineticsThe activity of ligand-gated ion channels can be described in kinetic terms by defining transition rates between individual metastable states of the receptor. Drug action can then be viewed as altering the transition rates between these states, under the assumption that drug binding does not introduce new transitions to the kinetic scheme. Using this approach to study pharmacological modulation of the GABA A receptor, it has been proposed that barbiturates alter transition rates between agonist-bound closed states (Macdonald et al., 1989a;Macdonald and Olsen, 1994), neurosteroids decrease the exit rate from the desensitized state of the receptor (Zhu and Vicini, 1997), and benzodiazepines increase the agonist binding rate (Rogers et al., 1994) or decrease agonist unbinding rate and accelerate desensitization (Mellor and Randall, 1997). In addition, it has been proposed that dephosphorylation of the GABA A receptor reduces the agonist unbinding rate, slowing deactivation and prolonging inhibitory currents (Jones and Westbrook, 1997).The volatile anesthetic halothane prolongs GABA A receptormediated IPSCs (Gage and Robertson, 1985;Mody et al., 1991;Jones and Harrison, 1993;Pearce, 1996), as do a great number o...

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The Role of the GABAA Receptor/Chloride Channel Complex in Anesthesia

Cited by 339 publications

References 0 publications

Barbiturate interactions at the human GABA_A receptor: dependence on receptor subunit combination

Barbiturate interactions at the human GABA_A receptor: dependence on receptor subunit combination

Stereoselective and non‐stereoselective actions of isoflurane on the GABA_A receptor

Effects of Halothane on GABA_AReceptor Kinetics: Evidence for Slowed Agonist Unbinding

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The Role of the GABAA Receptor/Chloride Channel Complex in Anesthesia

Cited by 339 publications

References 0 publications

Barbiturate interactions at the human GABAA receptor: dependence on receptor subunit combination

Barbiturate interactions at the human GABAA receptor: dependence on receptor subunit combination

Stereoselective and non‐stereoselective actions of isoflurane on the GABAA receptor

Effects of Halothane on GABAAReceptor Kinetics: Evidence for Slowed Agonist Unbinding

Contact Info

Product

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About

Barbiturate interactions at the human GABA_A receptor: dependence on receptor subunit combination

Barbiturate interactions at the human GABA_A receptor: dependence on receptor subunit combination

Stereoselective and non‐stereoselective actions of isoflurane on the GABA_A receptor

Effects of Halothane on GABA_AReceptor Kinetics: Evidence for Slowed Agonist Unbinding