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2003 Fiscal Year Final Research Report Summary

Molecular mechanisms of gaseous anesthetics on glutamate receptors : Identification of action site and examination of anesthetic behaviors in knock-out mice

Research Project

Project/Area Number 13557130
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Anesthesiology/Resuscitation studies
Research InstitutionNiigata University

Principal Investigator

YAMAKURA Tomohiro  Niigata University, Graduate School of Medical and Dental Sciences, Associate Professor, 大学院・医歯学総合研究科, 助教授 (80272847)

Co-Investigator(Kenkyū-buntansha) SAKIMURA Kenji  Niigata University, Brain Research Institute, Professor, 脳研究科, 教授 (40162325)
Project Period (FY) 2001 – 2003
KeywordsGaseous anesthetics / Glutamate receptor / NMDA receptor / AMPA receptor / Kainate receptor / Acetylcholine receptor / Knock-out mice
Research Abstract

The effects of gaseous anesthetics on ligand-gated ion channels were investigated. Nitrous oxide (0.58 atmosphere (atm)) and xenon (0.46 atm) exhibited quite similar effects on various receptors. Glycine and GABA_A receptors were potentiated by gaseous anesthetics much less than by isoflurane, while nitrous oxide inhibited GABA_C receptors. Glutamate receptors were inhibited by gaseous anesthetics more markedly than by isoflurane, but less than by ethanol. NMDA receptors were the most sensitive among glutamate receptors, and were inhibited by nitrous oxide by 31%. 5-HT_3 receptors were slightly inhibited by nitrous oxide. The nicotinic acetylcholine (nACh) receptors were inhibited by gaseous and volatile anesthetics, but ethanol potentiated them. The sensitivity was different between α4β2 and α4β2 n ACh receptors ; α4β2 receptors were inhibited by nitrous oxide was non-competitive, and was slightly different depending on membrane potentials for NMDA receptors, but not for nACh receptors. The results of chimeric and point mutant rat nAChRs suggest that a single amino acid residue (β2-V253 or β4-F255) near the middle of the second transmembrane segment determines gaseous anesthetic sensitivity. Mutations of this residue in β subunits and the homologous residue of α4 subunits (α4-V254) showed that this position also determines sensitivities of n AChRs to acetylcholine, isoflurane, pentobarbital, and hexanol. The site-directed mutagenesis of ε2 and ζ1 NMDA receptor subunits showed that the conserved asparagine residue in the second hydrophobic segment M2 of the ζ1 subunit determines gaseous anesthetic sensitivity of NMDA receptors.

  • Research Products

    (50 results)

All Other

All Publications (50 results)

  • [Publications] Eger II EI, et al.: "Relevant concentrations of inhaled anesthetics for in vitro studies of anesthetic mechanisms"Anesthesiology. 94(5). 915-921 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 山倉智宏: "Effects of general anesthetics on G-ptotein-coupled inwardly rectifying potassium channels"麻酔と蘇生Anesthesia and Resuscitation. 37(3・4). 89-90 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hara K, et al.: "Mutational analysis of ethanol interactions with G-protein-coupled inwardly rectifying potassium channels"Alcohol. 24(1). 5-8 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hashimoto K, et al.: "Roles of glutamate receptor δ2 subunit (GluRδ2) and metabotropic glutamate receptor subtype 1 (mGluR1) in climbing fiber synapse elimination during postnatal cerebellar development"J Neurosci. 21(24). 9701-9712 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ikeno K, et al.: "The Lurcher mutation reveals Ca^<2+> permeability and PKC modification of the GluRd channels"Neurosci Res. 41(2). 193-200 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kitayama K, et al.: "Purkinje cell-specific and inducible gene recombination system generated from C57BL/6 mouse ES cells"Biochem Biophys Res Commun. 281(5). 1134-1140 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mascia MP, et al.: "Does acetaldehyde mediate ethanol action in the central nervous system?"Alcohol Clin Exp Res. 25(11). 1570-1575 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Minami T, et al.: "Characterization of the glutamatergic system for induction and maintenance of allodynia"Brain Res. 895(1-2). 178-185 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Qi S, et al.: "Sublethal cerebral ischemia inhibits caspase-3 activation induced by subsequent prolonged ischemia in the C57Black/Crj6 strain mouse"Neurosci Lett. 315(3). 133-136 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takeuchi T, et al.: "Roles of the glutamate receptor ε2 and δ2 subunits in the potentiation and prepulse inhibition of the acoustic startle reflex"Eur J Neurosci. 14(1). 153-160 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamada K, et al.: "NMDA receptor subunits GluRε1, GluRε3 and GluRζ1 are enriched at the mossy fibre-granule cell synapse in the adult mouse cerebellum"Eur J Neurosci. 13(11). 2025-2036 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamakura T, et al.: "Anesthetics and ion channels : molecular models and sites of action"Annu Rev Pharmacol Toxicol. 41. 23-51 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamakura T, et al.: "Differential effects of general anesthetics on G-protein-coupled inwardly rectifying and other potassium channels"Anesthesiology. 95(1). 144-153 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamazaki M, et al.: "Differential palmitoylation of two mouse glutamate receptor interacting protein 1 forms with different N-terminal sequences"Neurosci Lett. 304(1-2). 81-84 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Zhang Y, et al.: "Luciferase as a model for the site of inhaled anesthetic action"Anesth Analg. 93(5). 1246-1252 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ichikawa R, et al.: "Distal extension of climbing fiber territory and multiple innervation caused by aberrant wiring to adjacent spiny branchlets in cerebellar Purkinje cells lacking glutamate receptor δ2"J Neurosci. 22(19). 8487-8503 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shimizu M, et al.: "Propofol enhances GABA_A receptor-mediated presynaptic inhibition in human spinal cord"Neuroreport. 13(3). 357-360 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Zhan RZ, et al.: "Ischemic preconditioning is capable of inducing mitochondrial tolerance in the rat brain"Anesthesiology. 97(4). 896-901 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Petrenko AB, et al.: "The role of N-methyl-D-aspartate (NMDA) receptors in pain : A review"Anesth Analg. 97(4). 1108-1116 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Petrenko AB, et al.: "Unaltered pain-related behavior in mice lacking NMDA receptor GluRε1 subunit"Neurosci Res. 46(2). 199-204 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tobita T, et al.: "Diagnosis of spinal disease with ultrafine flexible fiberscopes in patients with chronic pain"Spine. 28(17). 2006-2012 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tobita T, et al.: "The effects of isoflurane on conditioned inhibition by dorsal column stimulation"Anesth Analg. 97(2). 436-441 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kitano T, et al.: "Characterization of N-methyl-D-aspartate receptor subunits involved in acute ammonia toxicity"Neurochem Int. 44(2). 83-90 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamakura T: "Editorial : Volatile anesthetic antagonism by long-chain free fatty acids"J Anesth. (in press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 山倉智宏: "麻酔薬の作用機序-イオンチャネル分子への作用と麻酔作用の連関性-"新潟医学会雑誌. (in press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 山倉智宏: "全身麻酔薬とグルタミン酸受容体-分子作用と麻酔作用-"Pharmacoanesthesiology. (in press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Petrenko AB, et al.: "Recent Advances in Anaesthesia and Intensive Care"Greenwich Medical Media Limited. 177-207 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Eger II EI, et al.: "Relevant concentrations of inhaled anesthetics for in vitro studies of anesthetic mechanisms"Anesthesiology. 94(5). 915-921 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hara K, et al.: "Mutational analysis of ethanol interactions with G-protein-coupled inwardly rectifying potassium channels"Alcohol. 24(1). 5-8 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hashimoto K, et al.: "Roles of glutamate receptor δ2 subunit (GluRδ2) and metabotropic glutamate receptor subtype 1 (mGluR1) in climbing fiber synapse elimination during postnatal cerebellar"J Neurosci. 21(24). 9701-9712 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ikeno K, et al.: "The Lurcher mutation reveals Ca^<2+> permeability and PKC modification of the GluRd channels"Neurosci Res. 41(2). 193-200 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kitayama K, et al.: "Purkinje cell-specific and inducible gene recombination system generated from C57BL/6 mouse ES cells"Biochem Biophys Res Commun. 281(5). 1134-1140 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mascia MP, et al.: "Does acetaldehyde mediate ethanol action in the central nervous system?"Alcohol Clin Exp Res. 25(11). 1570-1575 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Minami T, et al.: "Characterization of the glutamatergic system for induction and maintenance of allodynia"Brain Res. 895(1-2). 178-185 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Qi S, et al.: "Sublethal cerebral ischemia inhibits caspase-3 activation induced by subsequent prolonged ischemia in the C57Black/Crj6 strain mouse"Neurosci Lett. 315(3). 133-136 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takeuchi T, et al.: "Roles of the glutamate receptor ε2 and δ2 subunits in the potentiation and prepulse inhibition of the acoustic startle reflex"Eur J Neurosci. 14(1). 153-160 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamada K, et al.: "NMDA receptor subunits GluRε1, GluRε3 and GluRζ1 are enriched at the mossy fibre-granule cell synapse in the adult mouse cerebellum"Eur J Neurosci. 13(11). 2025-2036 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamakura T, et al.: "Anesthetics and ion channels : molecular models and sites of action"Annu Rev Pharmacol Toxicol. 41. 23-51 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamakura T, et al.: "Differential effects of general anesthetics on G-protein-coupled inwardly rectifying and other potassium channels"Anesthesiology. 95(1). 144-153 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamazaki M, et al.: "Differential palmitoylation of two mouse glutamate receptor interacting protein 1 forms with different N-terminal sequences"Neurosci Lett. 304(1-2). 81-84 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Zhang Y, et al.: "Luciferase as a model for the site of inhaled anesthetic action"Anesth Analg. 93(5). 1246-1252 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ichikawa R, et al.: "Distal extension of climbing fiber territory and multiple innervation caused by aberrant wiring to adjacent spiny branchlets in cerebellar Purkinje cells lacking glutamate receptor"J Neurosci. 22(19). 8487-8503 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shimizu M, et al.: "Propofol enhances GABA_A receptor-mediated presynaptic inhibition in human spinal cord"Neuroreport. 13(3). 357-360 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Zhan RZ, et al.: "Ischemic preconditioning is capable of inducing mitochondrial tolerance in the rat brain"Anesthesiology. 97(4). 896-901 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Petrenko AB, et al.: "The role of N-methyl-D-aspartate (NMDA) receptors in pain : A review"Anesth Analg. 97(4). 1108-1116 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Petrenko AB, et al.: "Unaltered pain-related behavior in mice lacking NMDA receptor GluRε1 subunit"Neurosci Res. 46(2). 199-204 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tobita T, et al.: "Diagnosis of spinal disease with ultrafine flexible fiberscopes in patients with chronic pain"Spine. 28(17). 2006-2012 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tobita T, et al.: "The effects of isoflurane on conditioned inhibition by dorsal column stimulation"Anesth Analg. 97(2). 436-441 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kitano T, et al.: "Characterization of N-methyl-D-aspartate receptor subunits involved in acute ammonia toxicity"Neurochem Int. 44(2). 83-90 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamakura T: "Editorial : Volatile anesthetic antagonism by long-chain free fatty acids"J Anesth. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2005-04-19  

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