Volatile anesthetics gate a chloride current in postnatal rat hippocampal neurons

Yang, Jay; Isenberg, Keith; Zorumski, Charles F.

doi:10.1096/fasebj.6.3.1740240

Cited by 45 publications

(17 citation statements)

References 20 publications

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“…2A) indicates the presence of a persistent background current in this neuron, consistent with the reports of tonic inhibition in thalamocortical relay neurons (Belelli et al, 2005;Cope et al, 2005;Jia et al, 2005;Chandra et al, 2006;Bright et al, 2007). Isoflurane is able to directly activate GABA A -Rs (Yang et al, 1992; see also Fig. 5), as well as potentiate the action of GABA at these receptors (Jones and Harrison, 1993; see also Fig.…”

Section: Resultssupporting

confidence: 85%

Isoflurane Is a Potent Modulator of Extrasynaptic GABAA Receptors in the Thalamus

Fan

Yue²,

Chandra³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

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Volatile anesthetics are used clinically to produce analgesia, amnesia, unconsciousness, blunted autonomic responsiveness, and immobility. Previous work has shown that the volatile anesthetic isoflurane, at concentrations that produce unconsciousness (250 -500 M), enhances fast synaptic inhibition in the brain mediated by GABA A receptors (GABA A -Rs). In addition, isoflurane causes sedation at concentrations lower than those required to produce unconsciousness or analgesia. In this study, we found that isoflurane, at low concentrations (25-85 M) associated with its sedative actions, elicits a sustained current associated with a conductance increase in thalamocortical neurons in the mouse ventrobasal (VB) nucleus. These isoflurane-evoked currents reversed polarity close to the Cl Ϫ equilibrium potential and were totally blocked by the GABA A -R antagonist gabazine. Isoflurane (25-250 M) produced no sustained current in VB neurons from GABA A -R ␣ 4 -subunit knockout (Gabra4 Ϫ/Ϫ ) mice, although 250 M isoflurane enhanced synaptic inhibition in VB neurons from both wild-type and Gabra4Ϫ/Ϫ mice. These data indicate an obligatory requirement for ␣ 4 -subunit expression in the generation of the isoflurane-activated current. In addition, isoflurane directly activated ␣ 4 ␤ 2 ␦ GABA A -Rs expressed in human embryonic kidney 293 cells, and it was more potent at ␣ 4 ␤ 2 ␦ than at ␣ 1 ␤ 2 ␥ 2 receptors (the presumptive extrasynaptic and synaptic GABA A -R subtypes in VB neurons). We conclude that the extrasynaptic GABA A -Rs of thalamocortical neurons are sensitive to low concentrations of isoflurane. In view of the crucial role of the thalamus in sensory processing, sleep, and cognition, the modulation of these extrasynaptic GABA A -Rs by isoflurane may contribute to the sedation and hypnosis associated with low doses of this anesthetic agent.

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Section: Resultssupporting

confidence: 85%

Isoflurane Is a Potent Modulator of Extrasynaptic GABAA Receptors in the Thalamus

Fan

Yue²,

Chandra³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

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“…This 'direct activation' of GABA A α 2 β 1 and glycine α 1 receptors by iso-flurothyl was not an artifact of potentiation of responses to residual GABA or glycine in the bath, since direct activation by iso-flurothyl was observed even when no GABA or glycine was present anywhere in the perfusion system. The maximal degree of direct activation by iso-flurothyl at GABA A α 2 β 1 and glycine α 1 receptors was approximately 10% of the maximal responses to agonist, consistent with previous reports of direct activation by ether anesthetics at GABA A and glycine receptors (Downie et al, 1996;Krasowski et al, 1998a;Wakamori et al, 1991;Yang et al, 1992). Fig.…”

Section: Contrasting Modulation Of Wild-type Gaba a Glycine And Gasupporting

confidence: 91%

Differential modulatory actions of the volatile convulsant flurothyl and its anesthetic isomer at inhibitory ligand-gated ion channels

Krasowski

2000

Neuropharmacology

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A challenge for theories of general anesthesia is the existence of compounds predicted to be anesthetics but which, instead, do not produce anesthesia and often elicit other behavioral effects such as convulsions. This study focused on flurothyl (bis[2,2,2-trifluoroethyl] ether), a potent volatile convulsant, and its anesthetic isomer, 'iso-flurothyl' (1,1,1,3,3,3-hexafluoro-2-methoxypropane). The effects of flurothyl and iso-flurothyl were studied using the whole-cell patch-clamp technique on agonist activated chloride currents in human GABA A , glycine, and GABA c ρ 1 receptors expressed in HEK 293 cells. GABA A and glycine receptors are promising molecular targets for the actions of inhaled ether general anesthetics. Flurothyl acted as a non-competitive antagonist at GABA A α 2 β 1 and α 2 β 1 γ 2s receptors, but had no effect at glycine α 1 receptors. Flurothyl had biphasic actions on GABA responses at GABA C ρ 1 receptors. In contrast, iso-flurothyl enhanced ('potentiated') submaximal agonist responses at GABA A and glycine receptors, but had no effect on GABA responses at GABA C ρ 1 receptors. Point mutations in GABA A and glycine receptor subunits, which have been previously shown to abolish potentiation of agonist responses by the ether anesthetics enflurane and isoflurane, also ablated potentiation of agonist responses by iso-flurothyl. These same mutations in the GABA A receptor had only modest effects on the inhibitory actions of flurothyl. GABA A receptors with mutations conferring insensitivity to antagonism by picrotoxin were still inhibited by flurothyl, suggesting that picrotoxin and flurothyl antagonize GABA responses by distinct sites or mechanisms of action. In summary, antagonism of GABA A receptors is likely to account for the convulsant effects of flurothyl, while the general anesthetic actions of iso-flurothyl, like those of other ether anesthetics, may be related to positive modulation of GABA A and/or glycine receptors.

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“…Numerous other compounds with general anaesthetic properties potentiate the actions of GABA and at higher doses directly activate GABAA receptors. These agents include anaesthetic barbiturates (Macdonald et al, 1986), anaesthetic steroids (Cottrell et al, 1987;Harrison et al, 1987), etomidate (Robertson, 1989), chlormethiazole (Hales & Lambert, 1992) and volatile agents (Jones et al, 1992;Yang et al, 1992). The anticonvulsant and anxiolytic benzodiazepines are also potent potentiators of GABA-evoked responses, but are unable to activate directly GABAA receptors in the absence of GABA.…”

Section: Discussionmentioning

confidence: 99%

Potentiation, activation and blockade of GABA_A receptors of clonal murine hypothalamic GT1‐7 neurones by propofol

Adodra

Hales

1995

British J Pharmacology

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1 The actions of GABA and the intravenous general anaesthetic propofol (2,6-diisopropylphenol) on GABAA receptors of self-replicating GT1-7 hypothalamic neurones were investigated by the patch clamp technique. 2 GABA (1 gM-1 mM) dose-dependently activated inward currents with an EC50 of 27 gM, recorded from whole cells voltage-clamped at -60 mV. GABA (100 gM)-activated currents reversed at the Clequilibrium potential. 3 Propofol (0.1-100 tiM) dose-dependently potentiated GABA (100 IM)-evoked currents with an EC50 of 5 gM. 4 In the absence of GABA, propofol (10 UM-1 mM) activated small inward currents with a reversal potential similar to the Cl-equilibrium potential. The peak current amplitudes activated by propofol were only 31% of those activated by GABA in the same cells.5 Like GABA (100 kM)-activated currents, propofol (100 gM)-activated currents were inhibited by the GABAA receptor antagonist, bicuculline (10 gM) and were abolished by Zn2+ (100 pM). 6 Propofol (10, 30 and 100 gM) dose-dependently activated currents in the absence of GABA.However, the peak amplitude of currents activated by propofol declined with concentrations > 100 MM. The cessation of application of a high dose of propofol (1 mM) was associated with a current 'surge'. 7 The surge current, seen after application of propofol (1 mM), had a reversal potential similar to the Cl-equilibrium potential. The ratio between peak current amplitude in the presence of propofol (1 mM) and surge current amplitude after propofol application, were not dependent on holding potential. Thus, it is unlikely that the surge current represents reversal of a voltage-dependent block of GABAA receptors by propofol. 8 The amplitude of the surge current exceeded the amplitude of the initial propofol (1 mM)-evoked current following brief applications, but declined after prolonged applications of the drug. 9 The observed modulatory actions of propofol may be due to separate potentiation, activation and inhibitory sites for this anaesthetic agent on GT1-7 cell GABAA receptors.

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Volatile anesthetics gate a chloride current in postnatal rat hippocampal neurons

Cited by 45 publications

References 20 publications

Isoflurane Is a Potent Modulator of Extrasynaptic GABAA Receptors in the Thalamus

Isoflurane Is a Potent Modulator of Extrasynaptic GABAA Receptors in the Thalamus

Differential modulatory actions of the volatile convulsant flurothyl and its anesthetic isomer at inhibitory ligand-gated ion channels

Potentiation, activation and blockade of GABA_A receptors of clonal murine hypothalamic GT1‐7 neurones by propofol

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Volatile anesthetics gate a chloride current in postnatal rat hippocampal neurons

Cited by 45 publications

References 20 publications

Isoflurane Is a Potent Modulator of Extrasynaptic GABAA Receptors in the Thalamus

Isoflurane Is a Potent Modulator of Extrasynaptic GABAA Receptors in the Thalamus

Differential modulatory actions of the volatile convulsant flurothyl and its anesthetic isomer at inhibitory ligand-gated ion channels

Potentiation, activation and blockade of GABAA receptors of clonal murine hypothalamic GT1‐7 neurones by propofol

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Potentiation, activation and blockade of GABA_A receptors of clonal murine hypothalamic GT1‐7 neurones by propofol