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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online December 3, 2002 as doi:10.1096/fj.02-0611fje. |
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* Institute of Pharmacology and Toxicology, and
Institute of Laboratory Animal Science, University of Zürich, CH-8057 Zürich, Switzerland; and
Department of Anesthesiology, University of Tübingen, D-72076 Tübingen, Germany
2Correspondence: Institute of Pharmacology and Toxicology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. E-mail: rudolph{at}pharma.unizh.ch
SPECIFIC AIM
General anesthetics are widely used in clinical practice. In vitro, amino acid residues have been identified within 
-aminobutyric acid type A (GABAA) receptor subunits, which are critical for modulating general anesthetic actions; however, the functional relevance of these target sites in mediating essential components of the general anesthetic state in vivo, like immobility and hypnosis, is unknown at this time. Using gene targeting technology, we generated mice harboring a point mutation at one of these identified sites (N265M) located in the second transmembrane region of the ß3 subunit of the GABAA receptor. In these mice, behavioral responses to a variety of intravenous (i.v.) and volatile anesthetics were assessed, with the aim of demonstrating whether this residue (N265) within the GABAA receptor ß3 subunit is a critical target site mediating general anesthetic responses in vivo.
PRINCIPAL FINDINGS
1. ß3(N265M) knock-in mice are grossly normal and exhibit normal expression of GABAA receptors
A "knock-in" gene targeting approach was used to introduce the ß3(N265M) point mutation into the germline of mice. A targeting vector containing the desired point mutation in exon 8 of the GABAA receptor ß3 subunit gene and a loxP-flanked neomycin resistance marker (neo) in intron 8 was constructed and electroporated into R1 embryonic stem cells. Chimeric mice were bred to EIIa-cre mice on the 129/SvJ background, efficiently eliminating the neo cassette from the germline, and further backcrossed on the 129/SvJ background. Offspring of F2 heterozygote matings showed a normal Mendelian ratio, suggesting no embryonic lethality in the mutants.
Immunoblotting and immunohistochemical analysis revealed no major changes in either the expression levels or distribution patterns of the mutant ß3 subunit and the other major GABAA receptor subunits (ß2, 
1, 2, 3, and 2) compared with wild-type mice. Likewise, biochemical assays revealed no difference in either the affinity or number of benzodiazepine binding sites in wild-type and mutant mice. No differences between genotypes were observed in either motor activity levels or responsiveness to a noxious thermal stimulus as determined by similar response latencies in the hotplate test. Thus, no gross abnormalities were evident in the ß3(N265M) mice.
2. Anesthetic responses are reduced in electrophysiological recordings from ß3(N265M) brain preparations
Decreased sensitivities to anesthetic agents were observed in electrophysiological recordings from ß3(N265M) mouse brain preparations. Etomidate (20 µM) was significantly less effective in enhancing GABAA receptor-mediated currents in CA1 pyramidal cells in acute brain slices derived from the mutant (120±37%, n=6) compared with wild-type mice (352±95%, n=12; P<0.05, t test), confirming a phenotypic difference between functional GABAA receptors at the cellular level. Significant reductions in the depression of network responses to clinically relevant concentrations of etomidate (0.2 µM) and the volatile anesthetic enflurane (0.4 mM) were seen in cultured neocortical brain slices from ß3(N265M) mice compared with wild-type mice (31±8%, n=9 vs. 65±5%, n=9 for etomidate; 19±11%, n=9 vs. 65±5%, n=7 for enflurane; P<0.01; t test). This demonstrates that the point mutation significantly influences neuronal network responses to both an i.v. and a volatile anesthetic at concentrations that can be considered clinically relevant.
3. ß3(N265M) mice are strongly resistant to i.v. anesthetics
The most prominent finding in the ß3(N265M) mice was a strongly reduced sensitivity to the i.v. anesthetics etomidate and propofol. Two different end points of the anesthetic state were assessed in these mice: 1) loss of the righting reflex, as a measure of the hypnotic response, and 2) loss of the hind limb withdrawal reflex, as a measure of the immobilizing response to a noxious stimulus. Both etomidate and propofol induced a strongly diminished duration of the loss of righting reflex in ß3(N265M) mice compared with wild-type mice (Fig. 1
A, B). For instance, at doses of 10 mg/kg etomidate and 30 mg/kg propofol, a 70% and 71% reduction, respectively, in the duration of this end point was observed in the mutants compared with wild-type. Regarding the immobilizing response, an almost complete abolition of this end point was observed in the mutants in response to both drugs (Fig. 1D, E
), with almost none of the ß3(N265M) mice losing this reflex even at doses of etomidate (15 mg/kg) and propofol (40 mg/kg) that are lethal for wild-type mice. Other responses to noxious stimuli, such as the forelimb withdrawal reflex and the cutaneous reflex, were fully retained in mutant mice while suppressed in wild-type mice. These striking changes in etomidate and propofol sensitivity appear to be specifically attributable to the mutation, since ß3(N265M) mice exhibit normal responsiveness when administered the neurosteroidal anesthetic mix alphaxolone/alphadolone (Fig. 1C, F
), in agreement with previous results in which this point mutation does not affect neurosteroid action in vitro.
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4. ß3(N265M) mice have decreased sensitivity to volatile anesthetics
ß3(N265M) mice also displayed decreased sensitivity to the immobilizing effects of the volatile anesthetics enflurane and halothane, as evidenced by a significantly greater EC50 value for the loss of the hind limb withdrawal reflex response in the mutants vs. wild-type for both anesthetics (EC50 values for mutant mice were 16% and 21% greater than wild-type for enflurane and halothane, respectively; P<0.01 for both drugs). However, no difference in the loss of righting reflex between ß3(N265M) mice or wild-type mice was observed with either enflurane or halothane.
CONCLUSIONS AND SIGNIFICANCE
We show in this study that the introduction of the point mutation N265M into the ß3 subunit of the GABAA receptor leads to a dramatic reduction in sensitivity to the i.v. anesthetics etomidate and propofol, as measured by the complete abolition of the suppression of noxious-evoked withdrawal responses, and a significant reduction (up to 70%) in the duration of the loss of righting reflex in the mutants. These differences in sensitivity to etomidate and propofol were specific, as the mutation had no effect on responses to the neurosteroidal anesthetic mix alphaxolone/alphadolone. Thus, the asparagine-265 residue located within the second transmembrane region of the GABAA receptor ß3 subunit has a profound influence on two major behavioral responses evoked by the i.v. anesthetics etomidate and propofol, indicating that a single target site largely mediates the in vivo actions of these clinically relevant general anesthetics. This means that other potential targets, such as voltage-dependent potassium channels, sodium channels or L-type calcium channels at which propofol has actions in vitro, are likely to play a minor, if any, role at all in mediating propofol’s hypnotic and immobilizing actions.
An open question in this field is whether most general anesthetics act via a common molecular target. Our findings provide evidence to support the hypothesis that the mechanisms governing general anesthesia are likely to be agent specific, since the volatile anesthetics enflurane and halothane appear to act for the most part via different targets than etomidate and propofol. We observed no difference in ß3(N265M) mice with regard to the obtunding response to enflurane and halothane; however, the mutant mice required a slightly higher concentration of both drugs to produce immobility in response to a noxious stimulus. This increase in the EC50 values for enflurane and halothane with regard to the immobilizing response implies that ß3-containing GABAA receptors do indeed play a role in mediating this particular end point. However, other targets such as ß1- or ß2-containing GABAA receptors, two-pore domain background potassium channels, neuronal nicotinic acetylcholine receptors, or glutamate receptors, at which volatile anesthetics have been shown to have actions in vitro, are likely to play a major role in mediating enflurane’s and halothane’s actions.
By generating the knock-in mouse line ß3(N265M), we demonstrate that residue N265, located in the second transmembrane domain of the ß3 subunit, has a key role in mediating the hypnotic and immobilizing responses to etomidate and propofol in vivo. Whether this residue is involved in forming a binding site for these anesthetics, or rather results in the alteration of the receptor conformation so that these agents can no longer transduce their effects, remains speculative. The generation of additional knock-in mice will enable other amino acids critically involved in anesthetic actions in vivo to be identified, leading ultimately to a mechanistic understanding of how general anesthetics achieve their drug effects. Meanwhile, further analysis of the ß3(N265M) mice is expected to reveal whether other end points of general anesthesia such as anterograde amnesic action, or undesired drug effects such as cardiovascular or respiratory depression, are also mediated by ß3-containing GABAA receptors. Such studies may lead to the rational design of novel general anesthetic agents that can discriminate between receptor subtypes, and hence have more selective clinical profiles.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-0611fje; to cite this article, use FASEB J. (December 3, 2002) 10.1096/fj.02-0611fje 
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