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Nonhalogenated Alkanes Cyclopropane and Butane Affect Neurotransmitter-Gated Ion Channel and G-Protein–Coupled Receptors

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Nonhalogenated Alkanes Cyclopropane and Butane Affect Neurotransmitter-Gated Ion Channel and G-Protein–Coupled Receptors Anesthesiology 2002; 97:1512–20 © 2002 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Nonhalogenated Alkanes Cyclopropane and Butane Affect Neurotransmitter-gated Ion Channel and G-protein–coupled Receptors Differential Actions on GABAA and Glycine Receptors Koji Hara, M.D., Ph.D.,* Edmond I. Eger II, M.D.,† Michael J. Laster, D.V.M.,‡ R. Adron Harris, Ph.D.§ Background: Anesthetic mechanisms of nonhalogenated al- that these channels are plausible targets for anesthet- kanes cyclopropane and butane are not understood. This study 1–3 ics. A wide variety of structurally diverse general an- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/97/6/1512/336165/0000542-200212000-00025.pdf by guest on 27 September 2021 was designed to look at which neurotransmitter receptors are possible targets for these anesthetics. esthetics, including inhaled and intravenous anesthetics, Methods: Effects of cyclopropane and butane on eight recom- enhance GABAA receptor function. In addition to the binant receptors expressed in Xenopus oocytes were examined neurotransmitter-gated ion channels, some anesthetics electrophysiologically. To address molecular mechanisms of are also known to affect G-protein–coupled receptors, interaction with glycine and ␥-aminobutyric acid type A 4 such as muscarinic1 (M1) receptors and G-protein–cou- (GABAA) receptors, cyclopropane was further tested on 5 ␣ ␣ ␤ pled inwardly rectifying potassium (GIRK) channels. 1(S267C) glycine receptor and 2(S270X) 1 GABAA receptors that were mutated to amino acids with larger side chains. These molecules may account for some clinical aspects Results: Cyclopropane (1, 2, and 5 minimum alveolar concen- of anesthesia by anesthetics and ethanol, including anal- tration [MAC]) potentiated glycine responses by 39, 62, and gesia, amnesia, and sedation.6–8 161%, respectively, and butane (1 MAC) potentiated by 64% with an increase in apparent affinity for glycine, but yielded A recent report showed that two alkane anesthetics, barely detectable potentiation of GABAA receptors. The efficacy cyclopropane and butane, failed to increase agonist af- of cyclopropane for glycine receptors was less than isoflurane finity for the GABAA and Torpedo nACh receptors and and halothane. The potentiation by cyclopropane was elimi- that they suppressed the functions of nACh and NMDA nated for the ␣ (S267C) glycine receptor. Mutant GABA recep- 1 A receptors.9 This suggests a spectrum of action that is tors in which the corresponding amino acid was substituted with larger amino acids did not produce significant potentia- different from halogenated alkane anesthetics, but ef- tion. Cyclopropane and butane inhibited nicotinic acetylcho- fects of cyclopropane and butane on other receptors line and N-methyl-D-aspartate receptors, potentiated G-protein– have not been examined. In this study, we examine coupled inwardly rectifying potassium channels, and did not other targets that could contribute to anesthesia (immo- change 5-hydroxytryptamine3A or muscarinic1 receptor func- tion. Only cyclopropane markedly inhibited ␣-amino-3-hy- bility) produced by nonhalogenated alkanes. droxy-5-methyl-4-isoxazole propionic acid receptors. We tested the effects of nonhalogenated alkane anes- Conclusions: Glycine, nicotinic acetylcholine, and N-methyl- thetics on recombinant neurotransmitter-gated ion chan- D-aspartate receptors are sensitive to nonhalogenated alkanes, ␣ ␤ ␥ ␣ ␤ ␣ nels ( 1 2 2S and 2 1 GABAA, 1 glycine, NR1/NR2A and the authors propose that glycine and N-methyl-D-aspartate ␣ receptors are good candidates for anesthetic immobility. The NMDA, GluR1/GluR2 -amino-3-hydroxy-5-methyl-4-iso- ␣ ␤ authors also suggest that the distinct effects on glycine and xazole propionic acid [AMPA], 4 2 neuronal nACh, GABAA receptors are not due to the small volumes of these 5HT3A), and G-protein–coupled receptors (M1) and ion anesthetics. channels (GIRK1/2) expressed in Xenopus oocytes. The subunit compositions of the recombinant receptors NEUROTRANSMITTER-GATED ion channels, such as were chosen on the basis of the predominance of sub- ␥ -aminobutyric acid type A (GABAA), glycine, neuronal unit distribution in the central nervous system (CNS). nicotinic acetylcholine (nACh), 5-hydroxytryptamine3 In this study, we found that cyclopropane and butane (5-HT3), and/or N-methyl-D-aspartate (NMDA) receptors, at clinical concentrations moderately enhance the glycine are known to be sensitive to most anesthetics, indicating receptors, whereas GABAA receptors are insensitive. To elucidate the mechanism underlying the differential effects on two inhibitory receptors, we hypothesized that a * Research Fellow, § Professor, Waggoner Center for Alcohol and Addiction difference in the volume of binding cavity for the anes- Research. † Professor, ‡ Assistant Researcher, Department of Anesthesia and Perioperative Care, University of California, San Francisco, California. thetics is the determinant of anesthetic modulation. We Received from the Waggoner Center for Alcohol and Addiction Research and extended mutational study for glycine and GABAA recep- the Institute for Cellular and Molecular Biology, University of Texas at Austin, tors as to a position where anesthetics and ethanol have Austin, Texas. Submitted for publication March 18, 2002. Accepted for publica- tion July 23, 2002. Supported by grant No. GM47818 from the National Institutes been proven to interact with both receptors and knew of Health, Bethesda, Maryland. Dr. Eger is a paid consultant to Baxter Healthcare that the difference in the volume cannot account for the Corporation, Liberty Corner, New Jersey. difference in sensitivity between the glycine and the Address reprint requests to Dr. Harris: Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, 2500 Speedway MBB 1.124, GABAA receptors. We also discuss which signaling Austin, Texas 78712-1095. Address electronic mail to: [email protected]. systems might be mediators of immobility by these Individual article reprints may be purchased through the Journal Web site, www.anesthesiology.org. anesthetics. Anesthesiology, V 97, No 6, Dec 2002 1512 ANESTHETIC MECHANISM OF NONHALOGENATED ALKANES 1513 Materials and Methods Electrophysiological Recording Oocytes expressing GABAA, glycine, AMPA, or M1 re- These studies were approved by the Animal Care and ceptors were placed in a rectangular chamber (~100-␮l Use Committee of the University of Texas (Austin, volume) and perfused (2 ml/min) with MBS. Oocytes Texas). expressing NMDA receptors were perfused with Ba2ϩ Ringer’s solution (115 mM NaCl, 2.5 mM KCl, 1.8 mM cDNA and cRNA Preparations BaCl2, and 10 mM HEPES adjusted to pH7.4) to minimize The cDNAs encoding the following receptor subunits the effects of secondarily activated Ca2ϩ-dependent ClϪ ␣ were used for nuclear injections: human wild-type 1 or currents, and oocytes expressing nACh receptors were ␣ 10 2ϩ 1(S267C) glycine (subcloned in pCIS2 vector) ; wild- perfused with Ba Ringer’s solution containing 1 ␮M type human ␣ (subcloned in pBK-CMV N/B-200 vector); 1 atropine sulfate. For the 5-HT3A receptors, oocytes were Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/97/6/1512/336165/0000542-200212000-00025.pdf by guest on 27 September 2021 ␣ ␤ ␥ ␣ 2ϩ 2, 1, 2S, and 2 mutants (S270X) (subcloned in pCIS2 perfused with low-Ca Ringer’s solution (115 mM NaCl, ␤ 11 vector) and 2 (subcloned in pCDM8 vector) GABAA ; 2.5 mM KCl, 0.18 mM CaCl2, and 10 mM HEPES adjusted human NR1 and NR2A NMDA (subcloned in pcDNA to pH7.4) to decrease inhibitory effect of calcium ion. 12 Amp vector) ; and human 5-HT3A (subcloned in pBK- The animal poles of oocytes were impaled with two 13 CMV N/B-200 vector). The cDNAs of rat GluR1 and glass electrodes (0.5–10 ⍀) filled with 3 M KCl, and the GluR2 AMPA receptor subunits (subcloned in pBlue- oocytes were voltage clamped at Ϫ70 mV by using a Ϫ 14 ␣ ␤ script SK vector) ; the cDNAs of rat 4 and 2 nACh Warner Instruments model OC-752B oocyte clamp receptor subunits (subcloned in pSP64 and pSP65 vec- (Hamden, CT). Glycine, GABA, kainic acid (for AMPA tors, respectively)15; the cDNAs of rat GIRK116 and receptors), or ACh (for M receptor) dissolved in MBS Ϫ 1 mouse GIRK217 (subcloned in pBluescript II KS vec- was applied to the oocytes for 20 or 30 s to reach a tor); and the cDNA of rat M1 receptor (subcloned in maximal response. Likewise, L-glutamate plus 10 ␮M pGEM vector)18 were used for cRNA synthesis. In vivo glycine (for NMDA receptors) or ACh (for nACh recep- transcripts were prepared using the mCAP Capping Kit tor) dissolved in Ba2ϩ Ringer’s solution was applied to (Stratagene, La Jolla, CA). the oocytes for 20 s, and 5-HT in low-Ca2ϩ Ringer’s solution was applied for 30 s. To study the effects on Expression of the Receptors in Oocytes both wild-type and mutant GABAA or glycine receptors, Isolation of Xenopus laevis oocytes was conducted as the experiments were performed at EC5 of agonist (con- described previously.19 Isolated oocytes were placed in centrations that produced 5% of the maximal currents modified Barth’s saline (MBS) containing 88 mM NaCl, produced by 1 mM of glycine or GABA). To study the 1mM KCl, 2.4 mM NaHCO3, 0.82 mM MgSO4, 0.91 mM effects on the NMDA, AMPA, nACh, M1, or 5-HT3A re- CaCl2, 0.33 mM Ca(NO3)2, and 10 mM N-2-hydroxyeth- ceptors, the experiments were performed at the half- ylpiperazine-N'-2-ethanesulfonic acid (HEPES) adjusted maximal effective concentration (EC50) of agonists. to pH 7.5.
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