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Development of TRPC6 channel specific inhibitor as a new prototypic anti-hypertensive drug.

Research Project

Project/Area Number 14570079
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionKyushu University

Principal Investigator

INOUE Ryuji  Department of Pharmacology, Graduate School of Medical Sciences, Associate Professor, 大学院・医学研究院, 助教授 (30232573)

Co-Investigator(Kenkyū-buntansha) SHIMOHIGASHI Yasuyuki  Department of Structural Biochemistry, Graduate School of Sciences, Professor, 大学院・理学研究院, 教授 (00211293)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2003: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2002: ¥2,300,000 (Direct Cost: ¥2,300,000)
KeywordsTRP protein / receptor-operated Ca channel / vascular sympathetic nerve / α1-adrenerigic receptor / blood pressure / specific inhbitor / natural toxin screening / new antihypertensives / α_1アドレナリン受容体
Research Abstract

Recent investigations including ours have suggested that a mammalian homologue of transient receptor potential (TRP) protein, TRPC6, is, the most abundantly expressed TRP protein in vascular smooth muscle tissues and plays a pivotal role in vascular tone regulation as a receptor-operated Ca^<2+> entry channel activated during the vascular sympathetic nerve excitation. Based on these findings, we have launched on the development of a new prototypic antihypertensive drug targeting TRPC6 by means of natural toxin screening which specifically inhibits its channel activities. In the first step of this project, we screened commercially available toxins extracted from both terrestrial and marine organisms which reportedly inhibit several voltage-dependent and fast ligand-gated channels, but none of them were found to be effective. In the next step, we collected crude toxin extracts from several snakes and tried to purify them to a single fraction containing TRPC6 channel-specific inhibitory a … More ctivities, by repeating the purification processes of the crude toxins with Sephadex chromatography and Ion exchange chromatography. As the result, two small subfractions which show potent and dose-dependent inhibitory actions on TRPC3 and TRPC7 (two closely related homologues of TRPC6) but not on TRPC6, have been isolated. The estimated molecular weight of toxins contained in the two subfractions is 65,000 and <1000KDa, respectively. Exploration of the site of actions of these subfractions by use of chimaeric TRP channels have revealed that the transmembrane region is involved in this inhibition. TRPC3, 6 and 7 channels constitute a subfamily amongst which more than 80% amino acid identity is found, but exhibit differential sensitivities to Ca^<2+>, flufenamate and mechanical stress imposed on the cell membrane. These findings strongly suggest that subtle differences in amino acid sequence, especially near the ion conductive pore region, would greatly change the sensitivity of these channels to various physiological modulators as well as pharmacological agents. In the subsequent period of research, we will put forward the purification process of the effective subfractions to yield single inhibitory peptides with computer-aided structural analysis, and simultaneously the identification of the sites of their actions, whereby the indispensable database for the development of specific TRP channel inhibitors is obtained, which would eventually lead to the discovery of a new generation of antihypertensive drug. Less

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (33 results)

All Other

All Publications (33 results)

  • [Publications] Inoue, R., Okada T et al.: "TRPC6 is the essential component of vascular α1-adrenoceptor activated Ca^<2+> permeable cation channel."Circulation Research. 88. 325-332 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Morita H, Shi J, Ito Y, Inoue, R: "T-channel-like pharmacological properties of high voltage-activated, nifedipine-insensitive Ca^<2+> currents in the rat terminal mesenteric artery."British Journal of Pharmacology. 137. 467-476 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shi, J., Li, J., Ito, Y., Inoue, R.: "Glycolytic ATP production regulates muscarinic cation currents in guinea-pig ileum."Journal of Smooth Muscle Research. 39(1). 21-29 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inoue, R., Mori, Y.: "New target molecules in the drug control of blood pressure and circulation."Current Drug Targets : cardiovascular-haematological disorders. 3(1). 59-72 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inoue, R., Hanano, T., Shi, J., Mori, Y., Ito, Y.: "TRP proteins as a non-voltage-gated Ca^<2+> entry channel involved in diverse pathophysiological functions."J.Pharmacol. Sci.. 91(4). 271-276 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 西田基宏, 原雄二, 井上隆司, 森泰生: "TRPチャネルを中心としたシグナル複合体形成と細胞の増殖・死の制御"日薬理誌(Folia Pharmacol.Jpn.). 121. 223-232 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inoue, R: "Molecular linkage of TRP proteins to smooth muscle receptor-operated Ca^<2+> -permeable cation channels."Neurophysiology. 36(3/4). 203-208 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 森泰生, 稲垣千代子, 久野みゆき, 井上隆司, 岡田泰伸, 今泉祐治: "細胞増殖・分化・死を制御するイオンメカニズムと創薬"日薬理誌(Folia Pharmacol.Jpn.). 122. 201-214 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inoue R, Morita H, Ito Y.: "Newly emerging Ca^<2+> entry channel molecules that regulate the vascular tone."Expert Opinion on Therapeutic Targets. (In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hanano H, Hara Y, Shi J, Morita H, Umebayashi C, Mori E, Sumimoto H, Ito Y, Mori Y, Inoue, R: "Ionic mechanisms underlying the regulation of cell proliferation, differentiation and death."Folia Pharmacol.Jpn.. 122(In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inoue, R: "Transient receptor potential protein as a newly emerging non-voltage-gated Ca^<2+> entry channel superfamily."Current Pharmacological Design. (In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inoue_R, Okada T, Onoue H, Hara Y, Shimizu S, Naitoh S., Ito Y, Mori Y: "TRP6 is the essential component of vascular α_1-adrenoceptor activated Ca^<2+>-permeable cation channel."Circulation Research. 88. 325-332 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Morita, H., Shi, J., Ito, Y., Inoue, R.: "pharmacological properties of high voltage-activated, nifedipine-insensitive Ca^<2+> currents in the rat terminal mesenteric artery."British Journal of Pharmacology. 137. 467-476 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shi, J., Li, J., Ito, Y., Inoue, R.: "production regulates muscaninic cation currents in guinea-pig ileum."Journal of Smooth Muscle Research. 39(1). 21-29 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inoue, R., Mori, Y.: "New target molecules in the drug control of blood pressure and circulation."Current Drug Targets : cardiovascular-haematological disorders. 3(1). 59-72 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inoue, R., Hanano, T., Shi, J., Mori, Y., Ito, Y.: "TRP proteins as a non-voltage-gated Ca^<2+> entry channel involved in diverse pathophysiological functions."J. Pharmacol. Sci.. 91(4). 271-276 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nishida, M, Hara Y, Inoue, R., Mori Y.: "TRP channels : formation of signal complex and regulation of cellular functions."Folia Pharmacol. Jpn.. 121. 223-232 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inoue, R.: "Molecular linkage of TRP proteins to smooth muscle receptor-operated Ca^<2+> -permeable cation channels."Neurophysiology. 36(3/4). 203-208 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mori Y, Inagaki C, Kuno M, Inoue R, Okada Y, Imaizumi Y.: "Ionic mechanisms underlying the regulation of cell proliferation, differentiation and death."Folia Pharmacol. Jpn.. 122. 201-214 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inoue R, Morita H, Ito Y.: "Newly emerging Ca^<2+> entry channel molecules that regulate the vascular tone."Expert Opinion on Therapeutic Targets.. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hanano T, Hara Y, Shi J, Monita H, Umebayashi C, Mori E, Sumimoto H, Ito Y, Mori Y, Inoue R.: "Involvement of TRPM7 in cell growth as a spontaneously activated Ca^<2+> entry pathway in human retinoblasmotma cells."J. Pharmacol. Sci.. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inoue R: "Transient receptor potential protein as a newly emerging non-voltage-gated Ca^<2+> entry channel superfamily"Current Pharmacol. Design. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inoue, R., Mori, Y.: "New target molecules in the drug control of blood pressure and circulation."Current Drug Targets : cardiovascular-haematological disorders. 3(1). 59-72 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shi, J., Li, J., Ito, Y., Inoue, R.: "Glycol tic ATP production regulates muscatine cation currents in guinea-pig ileum."Journal of Smooth Muscle Research. 39(1). 21-29 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 西田基宏, 原雄二, 井上隆司, 森泰生: "TRPチャネルを中心としたシグナル複合体形成と細胞の増殖・死の制御"日薬理誌(Folia Pharmacol.Jpn.). 121. 223-232 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Inoue, R., Hanano, T., Shi, J., Mori, Y., Ito, Y.: "TRP proteins as a non-voltage-gated Ca^<2+> entry channel involved in diverse pathophysiological functinos."J.Pharmacol.Sci.. 91(4). 271-276 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 森泰生, 稲垣千代子, 久野みゆき, 井上隆司, 岡田泰伸, 今泉祐治: "細胞増殖・分化・死を制御するイオンメカニズムと創薬"日薬理誌(Folia Pharmacol.Jpn.). 122. 201-214 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Inoue, R: "Molecular linkage of TRP proteins to smooth muscle receptor-operated Ca^<2+> -permeable cation channels."Neurophysiology. 36(3/4). 203-208 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 井上隆司, 伊東祐之, 森泰生: "標的蛋白質からみた創薬:急速に拡大するTRP蛋白質ファミリーと新しい創薬の可能性"日本臨床. 66・1. 18-24 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hiromitsu Morita, Juan Shi, Yushi Ito, Ryuji Inoue: "T-channel-like pharmacological properties of high voltage-activated, nifedipine-insensitive Ca2+ currents in the rat terminal mesenteiric artery"British Journal of Pharmacology. 137. 467-476 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ryuji Inoue, Yasuo Mori: "New target molecules in the drug control of blood pressure and circulation"Current Drug Targets. 3. 59-72 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ryuji Inoue, Toyohisa Hanano, Juan Shi, Yasuo Mori, Yushi Ito: "TRP protein as a novel non-voltage-gated Ca^<2+> entry channel involved in pathophysiological functions"Journal of Pharmacological Sciences. 91・4(In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 西田基宏, 原雄二, 井上隆司, 森泰生: "TRPチャネルを中心としたシグナル複合体形成と細胞の増殖・死の制御"日本薬理学会誌(Folia Pharmacologica Japonica). 121(In press). (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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