Isoflurane Is a Potent Modulator of Extrasynaptic GABA<sub>A</sub>Receptors in the Thalamus

Fan, Jia; Yue, Minerva; Chandra, Dev; Homanics, Gregg E.; Goldstein, Peter A.; Harrison, Neil L.

doi:10.1124/jpet.107.134569

Cited by 52 publications

(48 citation statements)

References 54 publications

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“…In each case, that concentration was 5-10-fold higher than the EC 50 typically reported for the anesthetic potentiation of GABA A responses and closer to the EC 50 reported for direct anesthetic gating of the GABA A R in the absence of GABA (24,25,27,28). However, concentrations of etomidate up to 100 M produce a progressive decrease in GABA EC 50 without any evidence of saturation (32), and the Figs.…”

Section: Discussionsupporting

confidence: 64%

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Numerous Classes of General Anesthetics Inhibit Etomidate Binding to γ-Aminobutyric Acid Type A (GABAA) Receptors

Chiara

Cohen

et al. 2010

Journal of Biological Chemistry

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Enhancement of ␥-aminobutyric acid type A receptor (GABA A R)-mediated inhibition is a property of most general anesthetics and a candidate for a molecular mechanism of anesthesia. Intravenous anesthetics, including etomidate, propofol, barbiturates, and neuroactive steroids, as well as volatile anesthetics and long-chain alcohols, all enhance GABA A R function at anesthetic concentrations. The implied existence of a receptor site for anesthetics on the GABA A R protein was supported by identification, using photoaffinity labeling, of a binding site for etomidate within the GABA A R transmembrane domain at the ␤-␣ subunit interface; the etomidate analog Inhibition by barbiturates, which was pharmacologically specific and stereospecific, and by propofol was only partial, consistent with allosteric interactions, whereas isoflurane inhibition was nearly complete, apparently competitive. Protein sequencing showed that propofol inhibited to the same extent the photolabeling of ␣1Met-236 and ␤Met-286. These results indicate that several classes of general anesthetics modulate etomidate binding to the GABA A R: isoflurane binds directly to the site with millimolar affinity, whereas propofol and barbiturates inhibit binding but do not bind in a mutually exclusive manner with etomidate. ␥-Aminobutyric acid type A receptors (GABA A Rs) 3 are major mediators of brain inhibitory neurotransmission and participate in most circuits and behavioral pathways relevant to normal and pathological function. Their regulation may underlie many psychiatric/neurological disorders. GABA A Rs are subject to modulation by endogenous neurosteroids, as well as myriad clinically important central nervous system drugs, including general anesthetics, benzodiazepines, and ethanol (1-3). The mechanism of GABA A R modulation by these different classes of drugs is of major interest, including the localization of their binding sites in the receptor.Each GABA A R is made up of five homologous subunits that associate around a central axis that forms the ion channel. Each subunit consists of a large extracellular N-terminal domain, a transmembrane domain made up of a loose bundle of four transmembrane ␣-helices, and a cytoplasmic domain made up of the amino acids located in the primary structure between the M3 and M4 helices. In an ␣ 2 ␤ 2 ␥ GABA A R, the neurotransmitter-binding sites are located in the extracellular domain at the interfaces between the ␤ and ␣ subunits, two sites per receptor, whereas the benzodiazepine sites are at an equivalent position at the ␣-␥ subunit interface, one per receptor (4).Most general anesthetics enhance GABA A R responses in vitro at concentrations that produce immobilization in vivo, suggesting a link between the GABA A R and anesthesia (5, 6). The expression of receptors containing chimeric subunits combining sequences from subunits conferring different anesthetic sensitivities led to the identification of two residues that determine the sensitivity of the GABA A R to volatile agents and alcohols (7). These residue...

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Section: Discussionsupporting

confidence: 64%

“…5B), a concentration within a factor of 2 of that enhancing [ 3 H]muscimol binding (Fig. 2C) but ϳ5-fold higher than the electrophysiological EC 50 for GABA A R potentiation (27,28). In contrast, neither ethanol at a concentration as high as 170 mM (Fig.…”

Section: Numerous Chemical Classes Of General Anesthetics Modulate [ mentioning

confidence: 86%

Numerous Classes of General Anesthetics Inhibit Etomidate Binding to γ-Aminobutyric Acid Type A (GABAA) Receptors

Chiara

Cohen

et al. 2010

Journal of Biological Chemistry

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“…transmission via pre-and postsynaptic mechanisms (MacIver et al, 1996;Nishikawa and MacIver, 2000), enhances inhibitory GABAergic transmission (Verbny et al, 2005;Jia et al, 2008) and hyperpolarizes neurons by an increase in K + leak conductance (Berg-Johnsen and Langmoen, 1990;Ries and Puil, 1999). Isoflurane can hypothetically suppress the CAP by inhibiting glutamatergic synaptic transmission between hair cells and spiral ganglion cells, or by increasing efferent GABAergic input (Puel, 1995).…”

Section: Discussionmentioning

confidence: 97%

Effects of isoflurane on auditory evoked potentials in the cochlea and brainstem of guinea pigs

2010

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“…The residual tonic currents suggest the possible contribution of the ␣ 4 ␤ 3 ␦ subtype or an unknown subunit compensation induced by gene knockout. Thalamic extrasynaptic GABA A -Rs have also been implicated in the action of hypnotics and anesthetics (Belelli et al, 2005;Cope et al, 2005;Chandra et al, 2006;Jia et al, 2008a).…”

Section: Discussionmentioning

confidence: 99%

Ethanol Modulates Synaptic and Extrasynaptic GABA_A Receptors in the Thalamus

Fan

Chandra²,

Homanics³

et al. 2008

J Pharmacol Exp Ther

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Drinking alcohol is associated with the disturbance of normal sleep rhythms, and insomnia is a major factor in alcoholic relapse. The thalamus is a brain structure that plays a pivotal role in sleep regulation and rhythmicity. A number of studies have implicated GABA A receptors (GABA A -Rs) in the anxiolytic, amnestic, sedative, and anesthetic effects of ethanol. In the present study, we examined the effects of ethanol on both synaptic and extrasynaptic GABA A -Rs of relay neurons in the thalamus. We found that ethanol (Ն50 mM) elicits a sustained current in thalamocortical relay neurons from the mouse ventrobasal thalamus, and this current is associated with a decrease in neuronal excitability and firing rate in response to depolarization. The steady current induced by ethanol was totally abolished by gabazine and was absent in relay neurons from GABA A -R ␣ 4 subunit knockout mice, indicating that the effect of ethanol is to enhance tonic GABA-mediated inhibition. Ethanol (50 mM) enhanced the amplitude of tonic inhibition by nearly 50%. On the other hand, ethanol had no effect on spontaneous or evoked inhibitory postsynaptic currents (IPSCs) at 50 mM but did prolong IPSCs at 100 mM. Ethanol had no effect on the paired-pulse depression ratio, suggesting that the release of GABA from presynaptic terminals is insensitive to ethanol. We conclude that ethanol, at moderate (50 mM) but not low (10 mM) concentrations, can inhibit thalamocortical relay neurons and that this occurs mainly via the actions of ethanol at extrasynaptic GABA A -Rs containing GABA A -R ␣ 4 subunits.Drinking alcohol can promote the onset of sleep, but it can also disrupt the normal sleep pattern, increase nocturnal awakenings, and reduce sleep quality (Drummond et al., 1998). Sleep disturbance caused by chronic alcohol can play a role in the progression of alcoholism, and poor sleep quality is often cited as a factor in alcoholic relapse (Brower et al., 1998;Brower, 2001). Inhibition in the thalamus plays an important role in the normal regulation of sleep cycles (Steriade, 2000;Huguenard and McCormick, 2007;Jia et al., 2007) and may, therefore, be involved in both the sedative effects of acute alcohol and in the development of alcoholism.The inhibitory neurotransmitter GABA has long been implicated in the anxiolytic, amnestic, sedative, and anesthetic effects of alcohol. A large number of studies have investigated the interactions of alcohol with GABA A receptors (GABA A -Rs). The standard forms of recombinant GABA A -Rs that are found at GABAergic synapses (␣ 1 ␤␥ 2 and ␣ 2 ␤␥ 2 subtypes) are modulated only by Ͼ60 mM ethanol (Sigel et al., 1993;Mihic et al., 1997). Most investigators have failed to observe direct postsynaptic actions of alcohol (Ͻ60 mM) on GABA-mediated inhibitory postsynaptic currents (IPSCs) in brain slices, except at high levels (Ariwodola and Weiner, 2004;Weiner and Valenzuela, 2006). In several brain areas, however, ethanol has been shown to facilitate synaptic inhibition by a presynaptic mechanism, for example...

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Isoflurane Is a Potent Modulator of Extrasynaptic GABA_AReceptors in the Thalamus

Cited by 52 publications

References 54 publications

Numerous Classes of General Anesthetics Inhibit Etomidate Binding to γ-Aminobutyric Acid Type A (GABAA) Receptors

Numerous Classes of General Anesthetics Inhibit Etomidate Binding to γ-Aminobutyric Acid Type A (GABAA) Receptors

Effects of isoflurane on auditory evoked potentials in the cochlea and brainstem of guinea pigs

Ethanol Modulates Synaptic and Extrasynaptic GABA_A Receptors in the Thalamus

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Isoflurane Is a Potent Modulator of Extrasynaptic GABAAReceptors in the Thalamus

Cited by 52 publications

References 54 publications

Numerous Classes of General Anesthetics Inhibit Etomidate Binding to γ-Aminobutyric Acid Type A (GABAA) Receptors

Numerous Classes of General Anesthetics Inhibit Etomidate Binding to γ-Aminobutyric Acid Type A (GABAA) Receptors

Effects of isoflurane on auditory evoked potentials in the cochlea and brainstem of guinea pigs

Ethanol Modulates Synaptic and Extrasynaptic GABAA Receptors in the Thalamus

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Isoflurane Is a Potent Modulator of Extrasynaptic GABA_AReceptors in the Thalamus

Ethanol Modulates Synaptic and Extrasynaptic GABA_A Receptors in the Thalamus