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Unnamed Document Mutations M287L and Q266I in the Glycine Receptor ␣1 Subunit Change Sensitivity to Volatile Anesthetics in Oocytes and Neurons, but Not the Minimal Alveolar Concentration in Knockin Mice Cecilia M. Borghese, Ph.D.,* Wei Xiong, Ph.D.,† S. Irene Oh, B.S.,‡ Angel Ho, B.S.,§ S. John Mihic, Ph.D.,ʈ Li Zhang, M.D.,# David M. Lovinger, Ph.D.,** Gregg E. Homanics, Ph.D.,†† Edmond I. Eger 2nd, M.D.,‡‡ R. Adron Harris, Ph.D.§§ ABSTRACT What We Already Know about This Topic • Inhibitory spinal glycine receptor function is enhanced by vol- Background: Volatile anesthetics (VAs) alter the function of atile anesthetics, making this a leading candidate for their key central nervous system proteins but it is not clear which, immobilizing effect if any, of these targets mediates the immobility produced by • Point mutations in the ␣1 subunit of glycine receptors have been identified that increase or decrease receptor potentiation VAs in the face of noxious stimulation. A leading candidate is by volatile anesthetics the glycine receptor, a ligand-gated ion channel important for spinal physiology. VAs variously enhance such function, and blockade of spinal glycine receptors with strychnine af- fects the minimal alveolar concentration (an anesthetic What This Article Tells Us That Is New EC50) in proportion to the degree of enhancement. • Mice harboring specific mutations in their glycine receptors Methods: We produced single amino acid mutations into that increased or decreased potentiation by volatile anesthetic in vitro did not have significantly altered changes in anesthetic the glycine receptor ␣1 subunit that increased (M287L, third potency in vivo transmembrane region) or decreased (Q266I, second trans- • These findings indicate that this glycine receptor does not me- membrane region) sensitivity to isoflurane in recombinant diate anesthetic immobility, and that other targets must be receptors, and introduced such receptors into mice. The re- considered sulting knockin mice presented impaired glycinergic trans- mission, but heterozygous animals survived to adulthood, * Research Associate, ʈ Associate Professor, §§ Professor, The and we determined the effect of isoflurane on glycine-evoked University of Texas at Austin, Waggoner Center for Alcohol and responses of brainstem neurons from the knockin mice, and Addiction Research, Austin, Texas. † Research Fellow, # Medical Officer, ** Laboratory Chief, Laboratory for Integrative Neurosci- the minimal alveolar concentration for isoflurane and other ence, National Institute on Alcohol Abuse and Alcoholism, National VAs in the immature and mature knockin mice. Institutes of Health, Rockville, Maryland. ‡ Staff Research Associate, Results: Studies of glycine-evoked currents in brainstem ‡‡ Professor Emeritus, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, Califor- neurons from knockin mice confirmed the changes seen with nia. § Staff Research Assistant, Diabetes Center, University of Cali- recombinant receptors. No increases in the minimal alveolar fornia San Francisco. †† Professor, Departments of Anesthesiology concentration were found in knockin mice, but the minimal and Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania. alveolar concentration for isoflurane and enflurane (but not Received from the Waggoner Center for Alcohol and Addiction halothane) decreased in 2-week-old Q266I mice. This Research, The University of Texas at Austin, Austin, Texas. Submit- change is opposite to the one expected for a mutation that ted for publication October 10, 2011. Accepted for publication June decreases the sensitivity to volatile anesthetics. 7, 2012. Supported by grant nos. 1PO1GM47818 and AA06399 from the National Institutes of Health, Bethesda, Maryland. Drs. Xiong, Conclusion: Taken together, these results indicate that gly- Zhang, and Lovinger acknowledge support from the Division of cine receptors containing the ␣1 subunit are not likely to be Intramural Clinical and Biomedical Research, National Institute on crucial for the action of isoflurane and other VAs. Alcohol Abuse and Alcoholism, National Institutes of Health, Rock- ville, Maryland. Address correspondence to Dr. Harris: The University of PRESENT consensus suggests that volatile anesthetics Texas at Austin, Waggoner Center for Alcohol and Addiction (VAs) bind to proteins to produce their effects, includ- Research, 1 University Station A4800, Austin, Texas 78712-0159. A 1 [email protected]. Information on purchasing reprints may ing immobility. The key question is, “Which proteins?” The be found at www.anesthesiology.org or on the masthead page at list of candidates is short.1–3 A top candidate is the glycine the beginning of this issue. ANESTHESIOLOGY’s articles are made receptor (GlyR). freely accessible to all readers, for personal use only, 6 months from the cover date of the issue. Evidence for the GlyR as a target for VA includes their Copyright © 2012, the American Society of Anesthesiologists, Inc. Lippincott localization and sensitivity to VAs. The RNAs encoding the 4 Williams & Wilkins. Anesthesiology 2012; 117:765–71 GlyR subunits are mostly in the spinal cord and brainstem, Anesthesiology, V 117 • No 4 765 October 2012 Glycine Receptors and Anesthesia and the spinal cord mediates the immobility effect of VA.5 in 50% of test subjects) of anesthetics in wild-type and Moreover, anesthetic concentrations of VAs substantially en- knockin mice. hance inhibitory currents through the GlyR, both in heter- ologous systems6–8 and neurons.8 More direct evidence Materials and Methods arises from the use of strychnine, a competitive GlyR-specific Knockin mouse production and the electrophysiological antagonist, both at the neuronal and whole animal level. The techniques were described in detail in Borghese et al.21 We application of halothane to decerebrate rats depressed the briefly describe them here, and add pertinent details. The spinal cord sensory neuronal activity to noxious stimuli; experimental work on animals conformed to the guidelines the concurrent application of strychnine partially reversed laid out in the Guide for the Care and Use of Laboratory the halothane-induced depression.9 Sevoflurane reduced Animals, and approval of the corresponding institutional spontaneous action potential firing of ventral horn interneu- Animal Care Committees was obtained. rons in cultured spinal cord tissue slices; application of Electrophysiology in Xenopus Oocytes strychnine decreased the sevoflurane effect.10 Intrathecal ad- Chloroform was purchased from Sigma-Aldrich (Saint ministration of strychnine increased the minimal alveolar Louis, MO), and isoflurane was purchased from Marsam concentration (MAC) of isoflurane.11 The magnitude of Pharmaceuticals (Cherry Hill, NJ). Isoflurane and chloro- GlyR potentiation expressed in oocytes varies according to 12 form solutions were prepared in buffer immediately before the VA used. Intrathecal administration of strychnine to application. rats anesthetized with halothane, isoflurane, or cyclopropane Manually isolated oocytes from Xenopus laevis frogs were increased MAC in proportion to the enhancement of GlyRs 13 injected in the nuclei with complementary DNA encoding observed in vitro . Furthermore, intrathecal glycine reduced ␣ 14 wild-type and mutated human 1 GlyR subunits. After 1–5 the isoflurane MAC in rats. These results are compatible days, recordings were carried out using the whole cell two- with the hypothesis that GlyRs partly mediate the capacity of electrode voltage clamp configuration. All drugs were ap- VAs to produce immobility. plied by bath-perfusion and solutions were prepared the day Construction of chimeric glycine-␥-aminobutyric acid of the experiment. To study the chloroform (1 mM) and type A receptors (GABAA-Rs) allowed the identification of isoflurane (0.3 mM) modulation of glycine currents, the gly- transmembrane amino acids crucial to the VAs’ action, cine concentration equivalent to 5% of the maximal glycine- namely S267 and A288 in the second and third GlyR trans- evoked current (EC5) was determined after applying the gly- 15 membrane domains. Mutation of S267 to cysteine and cine concentration that produced maximal current (3 mM for subsequent labeling with thiol-specific reagents blocked the wild-type, 10 mM for mutant). Glycine was removed with a VA potentiation of GlyRs.16,17 Furthermore, a crystal struc- washout of 5 min between all applications, except after ap- ture of a prokaryotic protein closely related to GlyR was plication of maximal glycine concentrations (15 min). After obtained in the presence of VAs and showed selective bind- two applications of EC5 glycine, each of the modulators was ing of the anesthetics to the regions proposed in the earlier preapplied for 1 min and then coapplied with glycine for 18 studies of GlyR. 30 s. EC5 glycine was applied between coapplication of gly- The identification of a mutation in a receptor that renders cine and modulator. The concentrations of isoflurane and it insensitive or hypersensitive to modulation by VAs would chloroform were chosen as equivalent to 1 x MAC.22 All allow construction of a knockin mouse that could be tested experiments shown include data obtained from oocytes for changes in the sensitivity to VAs. This approach was taken from at least two different frogs, and oocytes that pre- sented a maximal current more than 20 ␮A were not in- successful in showing that specific GABAA-Rs are responsi- ble for
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