1992 年度実績報告書

心筋興奮・伝導の細胞内調節機構

研究課題

研究課題/領域番号	04248103
研究機関	名古屋大学
研究代表者	小澤高将名古屋大学, 医学部, 教授 (80022771)
研究分担者	堅田利明東京工業大学, 生命理工学部, 教授 (10088859) 今井昭一新潟大学, 医学部, 教授 (60013869) 飯島俊彦秋田大学, 医学部, 教授 (30004724) 中谷晴昭千葉大学, 医学部, 教授 (60113594) 遠藤政夫山形大学, 医学部, 教授 (40004668)
キーワード	心筋 / 不整派 / c-fos遺伝子 / Cキナーゼ / フォスファチジルイノシトール / カリウムチャネル / フリーラジカル / ミトコンドリアDNA
研究概要	心筋の興奮と伝導は、ホルモンなどによって種々に修飾される一方、細胞内のCa濃度や代謝によって調節されている。その破綻は心筋興奮・伝導の異常としての不整派に繋がる。本研究では、これらの細胞内調節の分子機構の解明をめざした。堅田らは細胞膜を介する情報伝達系において、受容体、G蛋白、効果器系分子間の相互作用を制御する蛋白性補助因子の分離精製に成功した。貝淵は、心筋興奮におけるプロテインキナーゼC系の関与を解明するために、c-fos遺伝子の発現制御機構を、Cキナーゼ系やAキナーゼ系とras p21やraf遺伝子産物との相互関係において明らかにした。中谷らは、単離心筋細胞の細胞内潅流しながら、パッチ電極法により膜電流を、イオン選択性微小電極により細胞内pHを記録した。α受容体刺激時のCキナーゼ活性化による変化と、心筋細胞のAキナーゼ系あるいはtyrosine kinase系を刺激した時の変化の相違を明らかにした。遠藤らは、α受容体刺激による心筋電気現象のイオン機序と両者の間に介在する分子機構を解明するために、α受容体サブタイプの機能調節をフォスファチジルイノシトール代謝回転との因果関係の点から明らかにした。飯島らはβ受容体刺激時の強心効果に関連したKチャネルの役割を明らかにした。今井らはcyclic GMP/G-kinaseによる燐酸化の基質と考えられる蛋白を精製し、Ca-ATPase活性化における意義を検討した。中谷らは、フリーラジカルと不整派発生の関連に注目し、細胞内代謝産物として脂肪酸中間代謝産物の心筋の電流系に対する影響を検討した。小澤らは、ミトコンドリアDNAの変異による心筋細胞エネルギー障害と不整派の相関を解明するため、ミトコンドリア遺伝子の酸化的DNA障害について解析し、これと、点変異ならびに欠失などの変異の蓄積との関連を明らかにした。

研究成果

(34件)

すべてその他

すべて文献書誌 (34件)

[文献書誌] M.Endou: "Electrophysiologic mechanisms responsible for inotropic responses to ketamine in guinea pig and rat myocardium." Anesthesiology. 76. 409-18 (1992)
[文献書誌] H.Nakaya: "Electrophysiologic and anticholinergic effects of pirmenol enantiomers in guinea-pig myocardium." Naunyn Schmiedebergs Arch Pharmacol. 346. 555-62 (1992)
[文献書誌] H.Nakaya: "Voltage-dependent modification of Vmax recovery from use-dependent block by permenol in guinea pig papillary muscles:comparison with other class I drugs." J Cardiovasc Pharmacol. 19. 140-7 (1992)
[文献書誌] H.Nakaya: "Mechanism of the membrane depolarization induced by oxidative stress in guinea-pig ventricular cells." J Mol Cell Cardiol. 24. 523-34 (1992)
[文献書誌] S.Shida: "Effects of Cl-channel blockers on beta-adrenoceptor-mediated decreases in resting potential and intracellular Cl-activity in guinea-pig heart." Eur J Pharmacol. 212. 267-70 (1992)
[文献書誌] N.Tohse: "Alpha 1-adrenoceptor stimulation enhances the delayed rectifier K+ current of guinea pig ventricular cells through the activation of protein kinase C." Circ Res. 71. 1441-6 (1992)
[文献書誌] M.Hayakawa: "Age-associated oxygen damage and mutations in mitochondrial DNA in human hearts." Biochem Biophys Res Commun. 189. 979-85 (1992)
[文献書誌] T.Ito: "Mitochondrial DNA mutations in cardiomyopathy." Jpn Circ J. 56. 1045-53 (1992)
[文献書誌] K.Torii: "Ageng-associated deletions of human diaphragmatic mitochondrial DNA." Am J Respir Cell Mol Biol. 6. 543-9 (1992)
[文献書誌] M.Katayama: "Deleted mitochondrial DNA in the skeletal muscle of aged individuals." Biochem int. 25. 47-56 (1992)
[文献書誌] T.Ozawa: "Mitochondrial DNA mutations and disturbances of energy metabolism in myocardium." Jpn Circ J. 55. 1158-64 (1991)
[文献書誌] S.Sugiyama: "Quantitative analysis of age-associated accumulation of mitochondrial DNA with deletion in human hearts." Biochem Biophys Res Commun. 180. 894-9 (1991)
[文献書誌] M.Adachi: "Induction of smg p21/rap1Ap21/krev-1p21 gene expression during phorbol ester-induced differentiation of a human megakaryocytic leukemia cell line." Oncogene. 7. 323-9 (1992)
[文献書誌] S.Ando: "Post-translational processing of rac p21s is important both for their interaction with the GDP/GTP exchange proteins and for their activation of NADPH oxidase." J Biol Chem. 267. 25709-13 (1992)
[文献書誌] H.Fujioka: "Transforming and c-fos promoter/enhancer-stimulating activities of a stimulatory GDP/GTP exchange protein for small GTP-binding proteins." J Biol Chem. 267. 926-30 (1992)
[文献書誌] K.Hiraoka: "Both stimulatory and inhibitory GDP/GTP exchange proteins,smg GDS and rho GDI,are active on multiple small GTP-binding proteins." Biochem Biophys Res Commun. 182. 921-30 (1992)
[文献書誌] K.Hirata: "Involvement of rho p21 in the GTP-enhanced calcium ion sensitivity of smooth muscle contraction." J Biol Chem. 267. 8719-22 (1992)
[文献書誌] H.Horiuchi: "The posttranslational processing of ras p21 is critical for its stimulation of yeast adenylate cyclase." Mol Cell Biol. 12. 4515-20 (1992)
[文献書誌] A.Kikuchi: "Molecular cloning of the human cDNA for a stimulatory GDP/GTP exchange protein for C-Ki-ras p21 and smg p21." Oncogene. 7. 289-93 (1992)
[文献書誌] Y.Miura: "Phosphorylation of smg p21B/rap1Bp21 by cyclic GMP-dependent protein kinase." Febs Lett. 297. 171-4 (1992)
[文献書誌] T.Mizuno: "Regulation of the superoxide-generating NADPH oxidase by a small GTP-binding protein and its stimulatory and inhibitory GDP/GTP exchange proteins." J Biol Chem. 267. 10215-8 (1992)
[文献書誌] M.Muramatsu: "Protein kinase C mutants in the auto-inhibitory region exhibit two distinct properties." Febs Lett. 311. 75-9 (1992)
[文献書誌] T.Sakoda: "smg/rap1/Krev-1p21s inhibit the signal pathway to the c-fos promoter/enhancer from c-Ki-ras p21 but not from c-raf-1 kinase in NIH3T3 cells." Oncogene. 7. 1705-11 (1992)
[文献書誌] H.Shirataki: "A possible target protein for smg-25A/rab3A small GTP-binding protein." J Biol Chem. 267. 10946-9 (1992)
[文献書誌] Y.Takai: "Small GTP-binding proteins." Int Rev Cytol. 133. 187-230 (1992)
[文献書誌] K.Chiba: "The primary structure of the alpha subunit of a starfish guanosine-nucleotide-binding regulatory protein in volved in 1-methyladenine-induced oocyte maturation." Eur J Biochem. 207. 833-8 (1992)
[文献書誌] T.Iiri: "Modification of the function of pertussis toxin substrate GTP-binding protein by cholera toxin-catalyzed ADP-ribosylation." J Biol Chem. 267. 1020-6 (1992)
[文献書誌] H.Ito: "On the mechanism of G protein beta gamma subunit activation of the muscarinic K+ channel in guinea pig atrial cell membrane. Comparison with the ATP-sensitive K+ channel." J Gen Physiol. 99. 961-83 (1992)
[文献書誌] Y.kanaho: "A protein kinase C inhibitor,staurosporine,Activates phospholipase Dvi a pertussis toxin-sensitive GTP-binding protein in rabbit peritoneal nertrophils." J Biol Chem. 267. 23554-9 (1992)
[文献書誌] K.Kontani: "Molecular heterogeneity of the beta gamma-subunits of GTP-binding proteins in bovine brain membranes." Arch Biochem Biophys. 294. 527-33 (1992)
[文献書誌] H.Tadenuma: "Properties of 1-methyladenine receptors in starfish oocyte membranes:involvement of pertussis toxin-sensitive GTP-binding protein in the receptor-mediated signal transduction." Biochem Biophys Res Commun. 186. 114-21 (1992)
[文献書誌] Y.Takei: "A GTP-bindin protein in rat liver nuclei serving as the specific substrate of pertussis toxin-catalyzed ADP-ribosylation." J Biol Chem. 267. 5085-9 (1992)
[文献書誌] H.Yamamoto: "Direct activation of purified Go-type GTP binding protein by tricyclic antidepressants." Neurosci Lett. 139. 194-6 (1992)
[文献書誌] W.Sato: "Deletion of mitochondrial DNA in patient with conduction block" Am Heart J. 125. 550-552 (1993)

1992 年度 実績報告書

心筋興奮・伝導の細胞内調節機構

研究代表者

小澤 高将 名古屋大学, 医学部, 教授 (80022771)

研究成果

[文献書誌] M.Endou: "Electrophysiologic mechanisms responsible for inotropic responses to ketamine in guinea pig and rat myocardium." Anesthesiology. 76. 409-18 (1992)

[文献書誌] H.Nakaya: "Electrophysiologic and anticholinergic effects of pirmenol enantiomers in guinea-pig myocardium." Naunyn Schmiedebergs Arch Pharmacol. 346. 555-62 (1992)

[文献書誌] H.Nakaya: "Voltage-dependent modification of Vmax recovery from use-dependent block by permenol in guinea pig papillary muscles:comparison with other class I drugs." J Cardiovasc Pharmacol. 19. 140-7 (1992)

[文献書誌] H.Nakaya: "Mechanism of the membrane depolarization induced by oxidative stress in guinea-pig ventricular cells." J Mol Cell Cardiol. 24. 523-34 (1992)

[文献書誌] S.Shida: "Effects of Cl-channel blockers on beta-adrenoceptor-mediated decreases in resting potential and intracellular Cl-activity in guinea-pig heart." Eur J Pharmacol. 212. 267-70 (1992)

[文献書誌] N.Tohse: "Alpha 1-adrenoceptor stimulation enhances the delayed rectifier K+ current of guinea pig ventricular cells through the activation of protein kinase C." Circ Res. 71. 1441-6 (1992)

[文献書誌] M.Hayakawa: "Age-associated oxygen damage and mutations in mitochondrial DNA in human hearts." Biochem Biophys Res Commun. 189. 979-85 (1992)

[文献書誌] T.Ito: "Mitochondrial DNA mutations in cardiomyopathy." Jpn Circ J. 56. 1045-53 (1992)

[文献書誌] K.Torii: "Ageng-associated deletions of human diaphragmatic mitochondrial DNA." Am J Respir Cell Mol Biol. 6. 543-9 (1992)

[文献書誌] M.Katayama: "Deleted mitochondrial DNA in the skeletal muscle of aged individuals." Biochem int. 25. 47-56 (1992)

[文献書誌] T.Ozawa: "Mitochondrial DNA mutations and disturbances of energy metabolism in myocardium." Jpn Circ J. 55. 1158-64 (1991)

[文献書誌] S.Sugiyama: "Quantitative analysis of age-associated accumulation of mitochondrial DNA with deletion in human hearts." Biochem Biophys Res Commun. 180. 894-9 (1991)

[文献書誌] M.Adachi: "Induction of smg p21/rap1Ap21/krev-1p21 gene expression during phorbol ester-induced differentiation of a human megakaryocytic leukemia cell line." Oncogene. 7. 323-9 (1992)

[文献書誌] S.Ando: "Post-translational processing of rac p21s is important both for their interaction with the GDP/GTP exchange proteins and for their activation of NADPH oxidase." J Biol Chem. 267. 25709-13 (1992)

[文献書誌] H.Fujioka: "Transforming and c-fos promoter/enhancer-stimulating activities of a stimulatory GDP/GTP exchange protein for small GTP-binding proteins." J Biol Chem. 267. 926-30 (1992)

[文献書誌] K.Hiraoka: "Both stimulatory and inhibitory GDP/GTP exchange proteins,smg GDS and rho GDI,are active on multiple small GTP-binding proteins." Biochem Biophys Res Commun. 182. 921-30 (1992)

[文献書誌] K.Hirata: "Involvement of rho p21 in the GTP-enhanced calcium ion sensitivity of smooth muscle contraction." J Biol Chem. 267. 8719-22 (1992)

[文献書誌] H.Horiuchi: "The posttranslational processing of ras p21 is critical for its stimulation of yeast adenylate cyclase." Mol Cell Biol. 12. 4515-20 (1992)

[文献書誌] A.Kikuchi: "Molecular cloning of the human cDNA for a stimulatory GDP/GTP exchange protein for C-Ki-ras p21 and smg p21." Oncogene. 7. 289-93 (1992)

[文献書誌] Y.Miura: "Phosphorylation of smg p21B/rap1Bp21 by cyclic GMP-dependent protein kinase." Febs Lett. 297. 171-4 (1992)

[文献書誌] T.Mizuno: "Regulation of the superoxide-generating NADPH oxidase by a small GTP-binding protein and its stimulatory and inhibitory GDP/GTP exchange proteins." J Biol Chem. 267. 10215-8 (1992)

[文献書誌] M.Muramatsu: "Protein kinase C mutants in the auto-inhibitory region exhibit two distinct properties." Febs Lett. 311. 75-9 (1992)

[文献書誌] T.Sakoda: "smg/rap1/Krev-1p21s inhibit the signal pathway to the c-fos promoter/enhancer from c-Ki-ras p21 but not from c-raf-1 kinase in NIH3T3 cells." Oncogene. 7. 1705-11 (1992)

[文献書誌] H.Shirataki: "A possible target protein for smg-25A/rab3A small GTP-binding protein." J Biol Chem. 267. 10946-9 (1992)

[文献書誌] Y.Takai: "Small GTP-binding proteins." Int Rev Cytol. 133. 187-230 (1992)

[文献書誌] K.Chiba: "The primary structure of the alpha subunit of a starfish guanosine-nucleotide-binding regulatory protein in volved in 1-methyladenine-induced oocyte maturation." Eur J Biochem. 207. 833-8 (1992)

[文献書誌] T.Iiri: "Modification of the function of pertussis toxin substrate GTP-binding protein by cholera toxin-catalyzed ADP-ribosylation." J Biol Chem. 267. 1020-6 (1992)

[文献書誌] H.Ito: "On the mechanism of G protein beta gamma subunit activation of the muscarinic K+ channel in guinea pig atrial cell membrane. Comparison with the ATP-sensitive K+ channel." J Gen Physiol. 99. 961-83 (1992)

[文献書誌] Y.kanaho: "A protein kinase C inhibitor,staurosporine,Activates phospholipase Dvi a pertussis toxin-sensitive GTP-binding protein in rabbit peritoneal nertrophils." J Biol Chem. 267. 23554-9 (1992)

[文献書誌] K.Kontani: "Molecular heterogeneity of the beta gamma-subunits of GTP-binding proteins in bovine brain membranes." Arch Biochem Biophys. 294. 527-33 (1992)

[文献書誌] H.Tadenuma: "Properties of 1-methyladenine receptors in starfish oocyte membranes:involvement of pertussis toxin-sensitive GTP-binding protein in the receptor-mediated signal transduction." Biochem Biophys Res Commun. 186. 114-21 (1992)

[文献書誌] Y.Takei: "A GTP-bindin protein in rat liver nuclei serving as the specific substrate of pertussis toxin-catalyzed ADP-ribosylation." J Biol Chem. 267. 5085-9 (1992)

[文献書誌] H.Yamamoto: "Direct activation of purified Go-type GTP binding protein by tricyclic antidepressants." Neurosci Lett. 139. 194-6 (1992)

[文献書誌] W.Sato: "Deletion of mitochondrial DNA in patient with conduction block" Am Heart J. 125. 550-552 (1993)

1992 年度実績報告書

小澤高将名古屋大学, 医学部, 教授 (80022771)