1992 年度実績報告書

中枢グルタミン酸受容体の分子構造と生理機能

研究課題

研究課題/領域番号	04267103
研究機関	新潟大学
研究代表者	三品昌美新潟大学, 脳研究所, 教授 (80144351)
研究分担者	勝木元也九州大学, 生体防御医学研究所, 教授 (20051732) 杉山博之九州大学, 理学部, 教授 (20124224) 津本忠治大阪大学, 医学部, 教授 (50028619) 小澤瀞司群馬大学, 医学部, 教授 (40049044) 川合述史自治医科大学, 教授 (00073065)
キーワード	グルタミン酸受容体 / NMDA受容体チャネル / G蛋白共役型グルタミン酸受容体 / 長期増強 / カルシウム / 脱感作 / 標的組換え / mRNA
研究概要	1.cDNAの単離と構造決定によってグルタミン酸受容体チャネルサブユニットには15個を越える分子種が存在することを見いだし、6つのサブファミリーに分類されることを示した。cDNAの発現と機能解析により、αサブファミリーはAMPAに高い親和性を有するグルタミン酸受容体チャネルを、βサブファミリーとγサブファミリーはカイニン酸型グルタミン酸受容体チャネルを、εやζサブファミリーはNMDA受容体チャネルをそれぞれ構製することを明らかにした。さらに、εサブファミリーの分子的多様性がNMDA受容体チャネルの機能的多様性の基盤となっていることを解明した。2.ウシ小脳よりクモ毒をアフィニティ試薬としてグルタミン酸受容体を精製し、小工膜へ再構製することによりAMPAに対するチャネル活性を認めた。3.培養海馬ニューロンのAMPA/カイニン酸受容体チャネルのグルタミン酸に対する脱感作のKineticsを解析した。また、アニラセタムによるグルタミン酸受容体のチャネル活性増強がアゴニスト依存性であることを明らかにした。4.幼若ラット視覚野の切片標本を用い、シナプス伝達の長期増強を引き起こす求心路刺激でシナプス後細胞内カルシウム濃度の著明な上昇が起こること、およびこの増加の大部分はNMDA受容体チャネルからの流入によることを見い出した。5.クローン化したG蛋白共役型グルタミン酸受容体をアフリカツメガエル卵母細胞に発現させ、共役するG蛋白の特異性を明らかにするとともに新しいアゴニストを見い出した。6.グルタミン酸受容体の標的組換えおよび遺伝子置換に必要なターゲッティングベクターを作成し、p53遺伝子をモデルとしてこれらのベクターが実際に有効であることを示した。7.自律神経系および内分泌系における種々のチャネル型およびG蛋白共役型グルタミン酸受容体のmRNAの存在を明らかにした。

研究成果
(36件)

すべてその他

すべて文献書誌 (36件)

[文献書誌] Sakimura,K.,et al.: "Primary sructure and expression of the γ2 subunit of the glutamate reutamate receptor channel selective for kainate." Neuron. 8. 267-274 (1992)
[文献書誌] Morita,T.,et al.: "Cloning and functional expression of cDNA encoding the mouse β2 subunit of the kainate-selective glutamate receptor channel." Mol.Brain Res.14. 143-146 (1992)
[文献書誌] Yamazaki,M.,et al.: "Molecular cloning of a cDNA encoding a novel member of the mousr glutamate receptor channel family." Biochem.Biophys.Res.Commun.183. 886-892 (1992)
[文献書誌] Yamazaki,M.,et al.: "Cloning,expression and modulation of a mouse NMDA receptor subunit." FEBS Lett.300. 39-45 (1992)
[文献書誌] Meguro,H.,et al.: "Functional characterization of a heteromeric NMDA receptor channel expressed from cloned cDNAs." Nature. 357. 70-74 (1992)
[文献書誌] Kutsuwada,T.,et al.: "Molecular diversity of the NMDA receptor channel." Nature. 358. 36-41 (1992)
[文献書誌] Mori,H.,et al.: "Identification by mutagenesis of a Mg^<2+> block site of the NMDA receptor channel." Nature. 358. 673-675 (1992)
[文献書誌] Uchino,S.,et al.: "Mutations in a putative agonist binding region of the AMPA-selective glutamate receptor channel." FEBS Lett.308. 253-257 (1992)
[文献書誌] Morita,T.,et al.: "Synaptocanalin I,a protein associated with brain ω-conotoxin-sensitive calcium channesl." Biomed.Res.13. 357-364 (1992)
[文献書誌] Ikeda,K.,et al.: "Cloning and expression of the ε4 subunit of the NMDA receptor channel." FEBS Lett.313. 34-38 (1992)
[文献書誌] Watanabe,M.,et al.: "Developmental changes in distribution of the NMDA receptor channel subunit mRNAs in the brain." NeuroReport. 3. 1138-1140 (1992)
[文献書誌] Shimazaki,K.,et al.: "Purification of AMPA type glutamate receptor by a spider toxin." Mol.Brain Res.13. 331-337 (1992)
[文献書誌] Tsubokawa,H.,et al.: "Abnormal Ca^<2+> homeostasis before cell death revealed by whole cell recording of ischemic CA1 hippocampal neurons." Neurosci.49. 807-817 (1992)
[文献書誌] Kirino,T.,et al.: "Disturbance of membrane function proceding ischemic delayed neuronal death in the gerbil hippocampus." F.Cereb.Blood Flow Metab.12. 408-417 (1992)
[文献書誌] Ishida,A.,et al.: "Ischemia-induced changes in Pip_2 levels of gerbil hippocampus." Neurosci.Res.15. 305-309 (1992)
[文献書誌] Tsuzuki,K.,et al.: "Agonist- and subunit-dependent potentiation of glutamate receptors by a nootropic drug aniracetam." Mol.Brain Res.16. 105-110 (1992)
[文献書誌] Ozawa,S.: "Glutamate receptor channels in hippocampal neurons." Japanese Journal of Physiology.(1993)
[文献書誌] Tamura,H.et al.: "Activity-dependent potentiation and depression of visual cortical responses to potic nerve stimulation in kittens." Journal of Neurophysiology. 68. 1603-1612 (1992)
[文献書誌] Funauchi,M.et al.: "Long-term depression is induced in Ca2+/ calmodulin kinase-inhibited neurons in visual cortex." NeuroRoport. 3. 173-176 (1992)
[文献書誌] Tsumoto,T.: "Long-term potentiation and long-term depression in the neocortex." Progress in Neurobiology. 39. 209-228 (1992)
[文献書誌] Hata,Y.et al.: "Development of local horizontal interactions in cat visual cortex studied by cross-correlation analysis." Journal of Neurophysiology. 69. 40-56 (1993)
[文献書誌] Minakami.R.,et al.: "Postnatal development of mRNA specific for a metabotropic glutamate receptor in the rat brain." Neurosci.Res.15. 58-63 (1992)
[文献書誌] Ito,I.,et al.: "3,5-Dihydroxyphenylglycine:A potent agonist of metabotropic glutamate receptors." NeuroReport. 3. 1013-1016 (1992)
[文献書誌] Shimano,H.et al: "Plasma Lipoprotein metabolism in transgenic mice overexpressing apolipo- protein E:Accelerated clearance of lipoproteins containing apolipoprotein B." J.Clin.Invest.90. 2084-2091 (1992)
[文献書誌] Sasaoka,T.et al: "Analysis of the human tyrosine hydroxylase promoter-chloramphenicol acetyltransferase chimeric gene expression in transgenic mice." Mol.Brain Res.16. 274-286 (1992)
[文献書誌] Abeliovich,A.et al: "On somatic recombination in the central nervous system of transgenic mice." Science. 257. 404-408 (1992)
[文献書誌] Takagi,K.et al: "A rapid and efficient protocol of the inverted PCR using two primer pairs." Biotechniques. 13. 176-178 (1992)
[文献書誌] Izawa,M.et al: "Inhibition of chemical carcinogenesis in vivo by azatyrosine." Cancer Res.52. 1628-1630 (1992)
[文献書誌] Kobayashi,K.et al: "Genetic alteration of catecholamine specificity in transgenic mice" Proc Natl Acad Sci USA. 89. 1631-1635 (1992)
[文献書誌] Araki,T.,et al.: "Localization of GABA -receptor γ_2 subunit mRNA contain-ing neurons in the ra^^At central nervous system." Neuroscience. 47. 45-61 (1992)
[文献書誌] Sato,M.,et al.: "Different postnatal development of cells expressing mRNA encoding neurotensin receptor." Neuroscience. 48. 137-149 (1992)
[文献書誌] Araki,T.,et al.: "The GABA a receptor γ_1 subunit is expressed by distinct neuronal populations." Mol.Brain Res.15. 121-132 (1992)
[文献書誌] Sato,K.,et al.: "Regional distribution of cells expressing glycine receptor α_2 subunit mRNA in the rat brain." Brain Res.590. 95-108 (1992)
[文献書誌] Araki,T.,et al.: "GABA receptor subunit messenger RNAs show differential expre^^Assion during cortical development in the rat brain." Neuroscience. 51. 583-591 (1992)
[文献書誌] Minakami,R.,et al.: "Postnatal development of mRNA specific for a metabotro-pic glutamate receptor in the rat brain." Neurosci.Res.15. 58-63 (1992)
[文献書誌] N.Kawai,et al.eds.: "Neuroreceptors,Ion Channels and the Brain" Elsevier, 234 (1992)

1992 年度 実績報告書

中枢グルタミン酸受容体の分子構造と生理機能

研究代表者

三品 昌美 新潟大学, 脳研究所, 教授 (80144351)

研究成果

[文献書誌] Sakimura,K.,et al.: "Primary sructure and expression of the γ2 subunit of the glutamate reutamate receptor channel selective for kainate." Neuron. 8. 267-274 (1992)

[文献書誌] Morita,T.,et al.: "Cloning and functional expression of cDNA encoding the mouse β2 subunit of the kainate-selective glutamate receptor channel." Mol.Brain Res.14. 143-146 (1992)

[文献書誌] Yamazaki,M.,et al.: "Molecular cloning of a cDNA encoding a novel member of the mousr glutamate receptor channel family." Biochem.Biophys.Res.Commun.183. 886-892 (1992)

[文献書誌] Yamazaki,M.,et al.: "Cloning,expression and modulation of a mouse NMDA receptor subunit." FEBS Lett.300. 39-45 (1992)

[文献書誌] Meguro,H.,et al.: "Functional characterization of a heteromeric NMDA receptor channel expressed from cloned cDNAs." Nature. 357. 70-74 (1992)

[文献書誌] Kutsuwada,T.,et al.: "Molecular diversity of the NMDA receptor channel." Nature. 358. 36-41 (1992)

[文献書誌] Mori,H.,et al.: "Identification by mutagenesis of a Mg^<2+> block site of the NMDA receptor channel." Nature. 358. 673-675 (1992)

[文献書誌] Uchino,S.,et al.: "Mutations in a putative agonist binding region of the AMPA-selective glutamate receptor channel." FEBS Lett.308. 253-257 (1992)

[文献書誌] Morita,T.,et al.: "Synaptocanalin I,a protein associated with brain ω-conotoxin-sensitive calcium channesl." Biomed.Res.13. 357-364 (1992)

[文献書誌] Ikeda,K.,et al.: "Cloning and expression of the ε4 subunit of the NMDA receptor channel." FEBS Lett.313. 34-38 (1992)

[文献書誌] Watanabe,M.,et al.: "Developmental changes in distribution of the NMDA receptor channel subunit mRNAs in the brain." NeuroReport. 3. 1138-1140 (1992)

[文献書誌] Shimazaki,K.,et al.: "Purification of AMPA type glutamate receptor by a spider toxin." Mol.Brain Res.13. 331-337 (1992)

[文献書誌] Tsubokawa,H.,et al.: "Abnormal Ca^<2+> homeostasis before cell death revealed by whole cell recording of ischemic CA1 hippocampal neurons." Neurosci.49. 807-817 (1992)

[文献書誌] Kirino,T.,et al.: "Disturbance of membrane function proceding ischemic delayed neuronal death in the gerbil hippocampus." F.Cereb.Blood Flow Metab.12. 408-417 (1992)

[文献書誌] Ishida,A.,et al.: "Ischemia-induced changes in Pip_2 levels of gerbil hippocampus." Neurosci.Res.15. 305-309 (1992)

[文献書誌] Tsuzuki,K.,et al.: "Agonist- and subunit-dependent potentiation of glutamate receptors by a nootropic drug aniracetam." Mol.Brain Res.16. 105-110 (1992)

[文献書誌] Ozawa,S.: "Glutamate receptor channels in hippocampal neurons." Japanese Journal of Physiology.(1993)

[文献書誌] Tamura,H.et al.: "Activity-dependent potentiation and depression of visual cortical responses to potic nerve stimulation in kittens." Journal of Neurophysiology. 68. 1603-1612 (1992)

[文献書誌] Funauchi,M.et al.: "Long-term depression is induced in Ca2+/ calmodulin kinase-inhibited neurons in visual cortex." NeuroRoport. 3. 173-176 (1992)

[文献書誌] Tsumoto,T.: "Long-term potentiation and long-term depression in the neocortex." Progress in Neurobiology. 39. 209-228 (1992)

[文献書誌] Hata,Y.et al.: "Development of local horizontal interactions in cat visual cortex studied by cross-correlation analysis." Journal of Neurophysiology. 69. 40-56 (1993)

[文献書誌] Minakami.R.,et al.: "Postnatal development of mRNA specific for a metabotropic glutamate receptor in the rat brain." Neurosci.Res.15. 58-63 (1992)

[文献書誌] Ito,I.,et al.: "3,5-Dihydroxyphenylglycine:A potent agonist of metabotropic glutamate receptors." NeuroReport. 3. 1013-1016 (1992)

[文献書誌] Shimano,H.et al: "Plasma Lipoprotein metabolism in transgenic mice overexpressing apolipo- protein E:Accelerated clearance of lipoproteins containing apolipoprotein B." J.Clin.Invest.90. 2084-2091 (1992)

[文献書誌] Sasaoka,T.et al: "Analysis of the human tyrosine hydroxylase promoter-chloramphenicol acetyltransferase chimeric gene expression in transgenic mice." Mol.Brain Res.16. 274-286 (1992)

[文献書誌] Abeliovich,A.et al: "On somatic recombination in the central nervous system of transgenic mice." Science. 257. 404-408 (1992)

[文献書誌] Takagi,K.et al: "A rapid and efficient protocol of the inverted PCR using two primer pairs." Biotechniques. 13. 176-178 (1992)

[文献書誌] Izawa,M.et al: "Inhibition of chemical carcinogenesis in vivo by azatyrosine." Cancer Res.52. 1628-1630 (1992)

[文献書誌] Kobayashi,K.et al: "Genetic alteration of catecholamine specificity in transgenic mice" Proc Natl Acad Sci USA. 89. 1631-1635 (1992)

[文献書誌] Araki,T.,et al.: "Localization of GABA -receptor γ_2 subunit mRNA contain-ing neurons in the ra^^At central nervous system." Neuroscience. 47. 45-61 (1992)

[文献書誌] Sato,M.,et al.: "Different postnatal development of cells expressing mRNA encoding neurotensin receptor." Neuroscience. 48. 137-149 (1992)

[文献書誌] Araki,T.,et al.: "The GABA a receptor γ_1 subunit is expressed by distinct neuronal populations." Mol.Brain Res.15. 121-132 (1992)

[文献書誌] Sato,K.,et al.: "Regional distribution of cells expressing glycine receptor α_2 subunit mRNA in the rat brain." Brain Res.590. 95-108 (1992)

[文献書誌] Araki,T.,et al.: "GABA receptor subunit messenger RNAs show differential expre^^Assion during cortical development in the rat brain." Neuroscience. 51. 583-591 (1992)

[文献書誌] Minakami,R.,et al.: "Postnatal development of mRNA specific for a metabotro-pic glutamate receptor in the rat brain." Neurosci.Res.15. 58-63 (1992)

[文献書誌] N.Kawai,et al.eds.: "Neuroreceptors,Ion Channels and the Brain" Elsevier, 234 (1992)

1992 年度実績報告書

三品昌美新潟大学, 脳研究所, 教授 (80144351)