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Mechanisms of cyclic AMP-dependent regulation of vesicular monoamine transport and of extracellular dopamine concentration of dopaminergic neurons in central nervous system.

Research Project

Project/Area Number 07672027
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional basic dentistry
Research InstitutionMeikai University

Principal Investigator

NAKANISHI Nobuo  Meikai University School of Dentistry, Biochemistry, Assist.Prof., 歯学部, 講師 (20118574)

Co-Investigator(Kenkyū-buntansha) KURIHARA Kinji  Meikai University School of Dentistry, Physiology, Research Assistant, 歯学部, 助手 (10170086)
Project Period (FY) 1995 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1997: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1996: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1995: ¥700,000 (Direct Cost: ¥700,000)
Keywordsvesicular monoamine transport / cyclic AMP / protein kinase / protein phosphatase / dopamine / serotonin / monoaminergic neuron / antidepressant
Research Abstract

Vesicular monoamine transport (VMT) plays a vital role in regulation of extracellular neurotransmitter levels. We found that cyclic AMP (cAMP) down-regulated VMT in pheochromocytoma PC12 cells. In this project, we investigated the mechanism of this cAMP action on the VMT,and cAMP effect on extracellular dopamine level in central nervous system. Effect of protein kinase C (PKC) on the VMT was also examined.
1.We demonstrated that cAMP has inhibitory effect on VMT and thereby greatly increases extracellular dopamine level of PC12 cultures (J.Neurochem.64,600-607, l995). Then we established an assay method for VMT activity with PC12 cells in culture by permeabilizing their plasma membranes with digitonin. This method made it possible to test the effects of endogenous neuromodulators and various drugs on the VMT (J.Biochem.118,291-296, l995).
2.Studies with protein kinase inhibitors and protein phosphatase inhibitors, protein phosphorylation process(es) was shown to be involved in the cAMP-dependent inhibition of VMT (Pteridines 6,126-128,1995 ; FEBS Lett.368,411-414,1995).
3.PKC activators inhibited the VMT and this was also mediated by protein phosphorylation (submitted for publication).
4.Administration of dibutyryl cAMP (dBcAMP) by microdialysis apparatus into striatum of freely moving rats increased extracellular DA concentration. From the comparison of this effect of dBcAMP with those of DA uptake inhibitors, reserpine and nomifensine, the increase in extracellular DA by dBcAMP was thought to be resulted from the inhibition of VMT.
5.Preliminary studies with antibody against vesicular monoamine transporter (VMAT) peptide suggested that phosphorylation of the transporter protein might not be involved in the inhibition of VMT by PKA or PKC.This should be further examined with techniques of molecular genetics, e.g., the mutant VMATcDNA which lacks consensus sites for phosphorylation by protein kinases.

Report

(4 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • 1995 Annual Research Report
  • Research Products

    (48 results)

All Other

All Publications (48 results)

  • [Publications] Nobuo Nakanishi: "Cyclic AMP-dependent modulation of vesicular monoamine transport in pheochromocytoma cells" Journal of Neurochemistry. 64. 600-607 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi: "Vesicular monoamine uptake by digitonin-permeabilized PC12 cells:inhibitory effect of neuromodulators and drugs on the amine transport" Journal of Biochemistry. 118. 291-296 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi: "Effect of H-7,a protein kinase inhibitor,on cyclic AMP-dependent inhibition of monoamine transport in PC12 cells" Pteridines. 6. 126-128 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hiroyuki Hasegawa: "Rapid turnover of tryptophan hydroxylase in serotonin producing cells:demonstration of ATP-dependent proteolytic degradation" FEBSLett.368. 151-154 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi: "Effects of protein kinase inhibitors and protein phosphatase inhibitors on cyclic AMP-dependent down-regulation of vesicular monoamine transport in pheochromocytoma PC12 cells" FEBSLetters. 368. 414-414 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi: "Inhibition of vesicular monoamine transport by treatment of PC12 cells with phorbol ester,PMA" Soc.Neurosci.Abst.21. 1382-1382 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 中西 信夫: "褐色細胞腫細胞PC12の細胞外のビオプテリンに対するdibutyryl cyclic AMPとタンパク質合成阻害の影響" 明海大学歯学雑誌. 24. 188 195 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 中西 信夫: "褐色細胞腫細胞PC12のdopamineとbiopterinに対するnomifensineの影響" 明海大学歯学雑誌. 24. 196 203 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 中西 信夫: "PC12細胞のin vivoにおけるdopaとdopamine産生の調節:芳香族アミノ酸とカテコールの影響" 明海大学歯学雑誌. 24. 204 212 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 大城 一乃: "自由行動下ラット脳の細胞外液中dopamine濃度に対するモノアミン輸送阻害剤の影響" 明海大学歯学雑誌. 24. 311 320 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi: "Regulation of intra and extracellular biopterin levels of PC12 cells in culture by cyclic AMP:stimulation of biosynthesis and inhibition of transport" Pteridines. 7. 35 37 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hiroyuki Hasegawa: "Stimulation of tryptophan hydroxylase production in a serotonin-producing cell line(RBL2H3)by intracellular calcium mobilizing reagents" FEBSLett.392. 289 292 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hiroyuki Hasegawa: "Rapid turnover of tryptophan hysroxylase:the turnover rate is unaffected after elevation of the enzyme amount induced by treatment of the cells with calcium ionophores and protease inhibitors" Pteridines. 7. 94 97 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kazumasa Yomamoto: "Tetrahydrobiopterin uptake by RBL2H3 cells:a comparison with sepiapterin uptake" Pteridines. 7. 154 156 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi: "Muscarine inhibits cyclic AMP-dependent modulation of monoamine transport in PC12 cells" Soc.Neurosci.Abst.22. 1785 1785 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Yoshiyuki Hattori: "GTP cyclohydrolase I mRNA induction and tetrahydrobiopterin synthesis in human endothelial cells" Biochim.Biophys.Acta. 1358. 61 66 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kazumasa Yamamoto: "In:Chemistry and Biology of Pteridines and Folates 1997.(Pfleiderer,W.& Lokos,H.,eds.)Blackwell Wiss.-Verl.,Berlin,Vienna" Uptake of tetrahydrobiopterin by cells in monolayer cultures of RBL2H3 and PC12 cell lines, 759-763 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi: "In:Chemistry and Biology of Pteridines and Folates 1997.(Pfleiderer,W.& Lokos,H.,eds.)Blackwell Wiss.-Verl.,Berlin,Vienna" Cellular uptake of tetrahydrobiopterin by PC12 cells and its release:inhibition of the outward flow by reserpine, 777-780 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi et al.: "Cyclic AMP-dependent modulation of vesicular monoamine transport in pheochromocytoma cells" Journal of Neurochemistry. 64. 600-607 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi et al.: "Vesicular monoamine uptake by digitonin-permeabilized PC12 cells : inhibitory effect of neuromodulators and drugs on the amine transport" Journal of Biochemistry. 118. 291-296 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi et al.: "Effect of H-7, a protein kinase inhibitor, on cyclic AMP-dependent inhibition of monoamine transport in PC12 cells" Pteridines. 6. 126-128 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hiroyuki Hasegawa et al.: "Rapid turnover of tryptophan hydroxylase in serotonin producing cells : demonstration of ATP-dependent proteolytic degradation" FEBS Letters. 368. 151-154 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi et a1.: "Effects of protein kinase inhibitors and protein phosphatase inhibitors on cyclic AMP-dependent down-regulation of vesicular monoamine transport in pheochromocytoma PC12 cells" FEBS Letters. 368. 411-414 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi et al.: "Inhibition of vesicular monoamine transport by treatment of PC12 cells with phorbol ester, PMA" Soc.Neurosci.Abst.21. 1382 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi et al.: "Effect of dibutyryl cyclic AMP and protein synthesis inhibition on intra-and extracellular biopterin in pheochromocytoma PC12 cells in culture" J.Meikai Univ.Sch.Dent.24. 188-195 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi et al.: "Effect of nomifensine on dopamine and biopterin contents in PC12 pheochromocytoma culture" J.Meikai Univ.Sch.Dent.24. 196-203 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi et al.: "Regulation of dopa and dopamine production of PC12 cells in vivo : effect of aromatic amino acid and catecholes" J.Meikai Univ.Sch.Dent.24. 204-212 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ichino Oshiro et a1.: "Effect of dialysis perfusion of monoamine transport inhibitors on the extracellular dopamine level in the striatum of freely moving rats" J.Meikai Univ.Sch.Dent.24. 311-320 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi et al.: "Regulation of intra and extracellular biopterin levels of PC12 cells in culture by cyclic AMP : stimulation of biosynthesis and inhibition of transport" Pteridines. 7. 35-37 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hiroyuki Hasegawa et al.: "Stimulation of tryptophan hydroxylasc production in a serotonin-producing cell line (RBL2H3) by intracellular calcium mobilizing reagents" FEBS Letters. 392. 289-292 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hiroyuki Hasegawa et al.: "Rapid turnover of tryptophan hysroxylase : the turnover rate is unaffected after elevation of the enzyme amount induced by treatment of the cells with calcium ionophores and protease inhibitors" Pteridines. 7. 94-97 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kazumasa Yamamoto et al.: "Tetrahydrobiopterin uptake by RBL2H3 cells : a comparison with sepiapterin uptake" Pteridenes. 7. 154-156 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi et al.: "Muscarine inhibits cyclic AMP-dependent modulation of monoamine transport in PC12 cells" Soc.Neurosci.Abst.22. 1785 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Yoshiyuki Hattori et al.: "GTP cyclohydrolase 1 mRNA induction and tetrahydrobiopterin synthesis in human endothelial cells" Biochimica et Biophysica Acta. 1358. 61-66 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kazumasa Yamamoto et al.: Blackwell Wiss.-Verl., Berlin, Vienna. Uptake of tetrahydrobiopterin by cells in monolayr cultures of RBL2H3 and PC12 cell, In : Chemistry and Biology of Pteridines and Folates 1997 (Pfleiderer, W.& Lokos, H., eds.), 759-763 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nobuo Nakanishi et al.: Blackwell Wiss.-Verl., Berlin, Vienna. Cellular uptake of tetrahydrobiopterin by PC12 cells and its release : inhibition of the outward flow by reserpine, In : Chemistry and Biology of Pteridines and Folates 1997 (Pfleiderer, W.& Lokos, H., eds.), 777-780 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Yoshiyuki Hattori: "GTP cyclohydrolase I mRNA induction and tetrahydrobiopterin synthesis in human endothelial cells" Biochim.Biophys.Acta. 1358. 61-66 (1995)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nobuo Nakanishi: "In : Chemistry and Biology of Pteridines and Folates 1997.(Pfleiderer,W.& Lokos,H.,eds.)Blackwell wiss.-Verl.,Berlin,Vienna" Cellular uptake of tetrahydrobiopterin by PC12 cells and its release : inhibition of the outward flow by reserpine, 777-780 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kazumasa Yamamoto: "In : Chemistry and Biology of Pteridines and Folates 1997.(Pfleiderer,W.& Lokos,H.,eds.)Blackwell wiss.-Verl.,Berlin,Vienna" Uptake of tetrahydrobiopterin by cells in monolayer cultures of RBL2H3 and PC12 cell lines, 759-763 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nobuo Nakanishi: "Inhibition of versicular monoamine transport by treatment of PC12 cells with phorbol ester,PMA" Soc.Neurosci.Abst.21. 1382-1382 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Nobuo Nakanishi: "Regulation of intra and extracellular biopterin levels of PC12 cells in culture by cyclic AMP:stimulation of biosynthesis and inhibition of transport" Pteridines. 7. 35-37 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hiroyuki Hasegawa: "Simulation of tryptophan hydroxylase production in a serotonin-producing cell line (RBL2H3) by intracellular calcium mobilizing reagents" FEBS Lett.392. 289-292 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Nobuo Nakanishi: "Muscarine inhibits cyclic AMP-dependent modulation of monoamine transport in PC12 cells" Soc.Neurosci.Abst.22. 1785-1785 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Nobuo Nakanishi: "Cyclic AMP-dependent modulation of vesicular monoamine transport in pheochromocytoma cells" Journal of Neurochemistry. 64. 600-607 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Nobuo Nakanishi: "Vesicular monoamine uptake by digitonin-permeabilized PC12 cells: inhibitory effect of neuromodulators and drugs on the amine transport" Journal of Neurochemistry. 118. 291-296 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Nobuo Nakanishi: "Effect of H-7, a protein kinase inhibitor, on cyclic AMP-dependent inhibition of monoamine transport in PC12 cells" Pteridines. 6. 126-128 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Nobuo Nakanishi: "Effects of protein kinase inhibitors and protein phosphatase inhibitors on cyclic AMP-dependent down-regulation of vesicular monoamine transport in pheochromocytoma PC12" FEBS Letters. 368. 414-414 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 大城一乃: "自由行動下ラット脳の細胞外液中dopamine濃度に対するモノアミン輸送阻害剤の影響" 明海大学歯学雑誌. 24. 311-320 (1995)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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