Anesthesia Sensitivity in Mice that Lack the β3 Subunit of the γ-Aminobutyric Acid Type A Receptor

Quinlan, Joseph J.; Homanics, Gregg E.; Firestone, Leonard L.

doi:10.1097/00000542-199803000-00030

Cited by 146 publications

(59 citation statements)

References 22 publications

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“…To extend previous evidence of 6Ј tryptophan substitutions blocking alcohol inhibition of ␣2␤2 GABA A Rs (Ueno et al, 2000), we examined the effect of n-alcohols and volatile anesthetics on GABA A Rs of the same composition (␣2␤2) containing the tryptophan substitution ␣2(T6ЈW). Because GABA A Rs are implicated in immobilizing effects of n-alcohols and volatile anesthetics (Quinlan et al, 1998), we initially tested alcohol and anesthetic concentrations previously shown to produce 50% immobility (Alifimoff et al, 1989). Compared with wild-type receptors, tryptophan mutants showed greater enhancement by methanol and ethanol, but not by propanol, butanol, pentanol, hexanol, isoflurane, or chloroform (Fig.…”

Section: Resultsmentioning

confidence: 99%

The TM2 6′ Position of GABA_A Receptors Mediates Alcohol Inhibition

Johnson

Howard

Trudell

et al. 2011

J Pharmacol Exp Ther

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Ionotropic GABA A receptors (GABA A Rs), which mediate inhibitory neurotransmission in the central nervous system, are implicated in the behavioral effects of alcohol and alcoholism. Site-directed mutagenesis studies support the presence of discrete molecular sites involved in alcohol enhancement and, more recently, inhibition of GABA A Rs. We used Xenopus laevis oocytes to investigate the 6Ј position in the second transmembrane region of GABA A Rs as a site influencing alcohol inhibition. We asked whether modification of the 6Ј position by substitution with larger residues or methanethiol labeling [using methyl methanethiosulfonate (MMTS)] of a substituted cysteine, reduced GABA action and/or blocked further inhibition by alcohols. Labeling of the 6Ј position in either ␣2 or ␤2 subunits reduced responses to GABA. In addition, methanol and ethanol potentiation increased after MMTS labeling or substitution with tryptophan or methionine, consistent with elimination of an inhibitory site for these alcohols. Specific alcohols, but not the anesthetic etomidate, competed with MMTS labeling at the 6Ј position. We verified a role for the 6Ј position in previously tested ␣2␤2 as well as more physiologically relevant ␣2␤2␥2s GABA A Rs. Finally, we built a novel molecular model based on the invertebrate glutamate-gated chloride channel receptor, a GABA A R homolog, revealing that the 6Ј position residue faces the channel pore, and modification of this residue alters volume and polarity of the pore-facing cavity in this region. These results indicate that the 6Ј positions in both ␣2 and ␤2 GABA A R subunits mediate inhibition by short-chain alcohols, which is consistent with the presence of multiple counteracting sites of action for alcohols on ligand-gated ion channels.

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Section: Resultsmentioning

confidence: 99%

The TM2 6′ Position of GABA_A Receptors Mediates Alcohol Inhibition

Johnson

Howard

Trudell

et al. 2011

J Pharmacol Exp Ther

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“…In addition, deletion of another ␤ subunit, ␤ 3 , also failed to change pentobarbital sleep time (Quinlan et al, 1998). Pentobarbital has effects on a number of other ion channels (Wartenberg et al, 2001;Yamakura et al, 2001;Bachmann et al, 2002), and it is possible that these targets are more important for pentobarbital-induced loss of righting reflex than the GABA A receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Mice lacking the ␥ 2 subunit die shortly after birth (Gunther et al, 1995), whereas mice deficient the ␥ 2L (long splice variant) subunit are viable and show small increases in sleep time responses to midazolam and zolpidem, but responses to nonbenzodiazepine agents such as ethanol, etomidate, and pentobarbital are unchanged (Quinlan et al, 2000). ␤ 3 null mice (Ϫ/Ϫ) did not show any changes in sleep times after administration of pentobarbital or ethanol, but they were more resistant to etomidate and midazolam (Quinlan et al, 1998). Mice lacking the ␣ 6 subunit of the GABA A receptor, which is expressed exclusively in cerebellar granule cells, have no major phenotypic abnormalities (Jones et al, 1997).…”

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confidence: 99%

Deletion of the α1 or β2 Subunit of GABA_AReceptors Reduces Actions of Alcohol and Other Drugs

Blednov

Jung

Alva

et al. 2003

J Pharmacol Exp Ther

114

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Enhancement of the activation of GABA A receptors is a common feature of many sedative and hypnotic drugs, and it is probable that the GABA A receptor complex is a molecular target for these drugs in the mammalian central nervous system. We set out to elucidate the role of the two predominant (␣ 1 and ␤ 2 ) subunits of GABA A receptor in sedative drug action by studying mice lacking these two subunits. Both ␣ 1 (Ϫ/Ϫ) and ␤ 2 (Ϫ/Ϫ) null mutant mice showed markedly decreased sleep time induced by nonselective benzodiazepine, flurazepam, and GABA A agonist, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol. The sleep time induced by the ␤-selective drug etomidate was decreased only in ␤ 2 (Ϫ/Ϫ) knockout mice. In contrast, ␣ 1 (Ϫ/Ϫ) mice were more resistant to the ␣ 1 -selective drug zolpidem than ␤ 2 (Ϫ/Ϫ) or wild-type animals. Knockout mice of both strains were similar to wild-type mice in their responses to pentobarbital. The duration of loss of the righting reflex produced by ethanol was decreased in male mice for both null alleles compared with wild-type mice, but there were no differences in ethanol-induced sleep time in mutant females. Deletion of either the ␣ 1 or ␤ 2 subunits reduced the muscimolstimulated 36 Cl Ϫ influx in cortical microsacs suggesting that these mutant mice have reduced number of functional brain GABA A receptors. Our results show that removal of either ␣ 1 or ␤ 2 subunits of GABA A receptors produce strong and selective decreases in hypnotic effects of different drugs. Overall, these data confirm the crucial role of the GABA A receptor in mechanisms mediating sedative/hypnotic effects.

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“…However, subsequent testing with other neuronal depressants put into doubt whether the genes being selected specifically modulated anesthetic action (20). Knockout mice thus far have not revealed a predominant effect of any one gene on VA sensitivity (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Most notably, the knocking out of GABA A receptor subunits produced no or only small changes in VA sensitivity (21,23,25).…”

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confidence: 99%

Nitrous oxide (N ₂ O) requires the N -methyl- d -aspartate receptor for its action in Caenorhabditis elegans

Nägele

Metz

Crowder

2004

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

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Nitrous oxide (N2O, also known as laughing gas) and volatile anesthetics (VAs), the original and still most widely used general anesthetics, produce anesthesia by ill-defined mechanisms. Electrophysiological experiments in vertebrate neurons have suggested that N 2O and VAs may act by distinct mechanisms; N2O antagonizes the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, whereas VAs alter the function of a variety of other synaptic proteins. However, no genetic or pharmacological experiments have demonstrated that any of these in vitro actions are responsible for the behavioral effects of either class of anesthetics. By using genetic tools in Caenorhabditis elegans, we tested whether the action of N 2 O requires the NMDA receptor in vivo and whether its mechanism is shared by VAs. Distinct from the action of VAs, N 2O produced behavioral defects highly specific and characteristic of that produced by loss-of-function mutations in both NMDA and non-NMDA glutamate receptors. A null mutant of nmr-1, which encodes a C. elegans NMDA receptor, was completely resistant to the behavioral effects of N 2O, whereas a non-NMDA receptor-null mutant was normally sensitive. The N 2O-resistant nmr-1(null) mutant was not resistant to VAs. Likewise, VA-resistant mutants had wild-type sensitivity to N 2O. Thus, the behavioral effects of N 2O require the NMDA receptor NMR-1, consistent with the hypothesis formed from vertebrate electrophysiological data that a major target of N 2O is the NMDA receptor.

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Anesthesia Sensitivity in Mice that Lack the β3 Subunit of the γ-Aminobutyric Acid Type A Receptor

Cited by 146 publications

References 22 publications

The TM2 6′ Position of GABA_A Receptors Mediates Alcohol Inhibition

The TM2 6′ Position of GABA_A Receptors Mediates Alcohol Inhibition

Deletion of the α1 or β2 Subunit of GABA_AReceptors Reduces Actions of Alcohol and Other Drugs

Nitrous oxide (N ₂ O) requires the N -methyl- d -aspartate receptor for its action in Caenorhabditis elegans

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Anesthesia Sensitivity in Mice that Lack the β3 Subunit of the γ-Aminobutyric Acid Type A Receptor

Cited by 146 publications

References 22 publications

The TM2 6′ Position of GABAA Receptors Mediates Alcohol Inhibition

The TM2 6′ Position of GABAA Receptors Mediates Alcohol Inhibition

Deletion of the α1 or β2 Subunit of GABAAReceptors Reduces Actions of Alcohol and Other Drugs

Nitrous oxide (N 2 O) requires the N -methyl- d -aspartate receptor for its action in Caenorhabditis elegans

Contact Info

Product

Resources

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The TM2 6′ Position of GABA_A Receptors Mediates Alcohol Inhibition

The TM2 6′ Position of GABA_A Receptors Mediates Alcohol Inhibition

Deletion of the α1 or β2 Subunit of GABA_AReceptors Reduces Actions of Alcohol and Other Drugs

Nitrous oxide (N ₂ O) requires the N -methyl- d -aspartate receptor for its action in Caenorhabditis elegans