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Elucidation of physiological significance of direct Ca^<2+> channel-phospholipase coupling in cell fate control

Research Project

Project/Area Number 16390076
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionKyoto University

Principal Investigator

MORI Yasuo  Kyoto University, Graduate School of Engineering, Professor, 工学研究科, 教授 (80212265)

Co-Investigator(Kenkyū-buntansha) HARA Yuji  Kyoto University, Graduate School of Engineering, Research Associate, 助手 (60362456)
NISHIDA Motohiro  Kyushu University, Graduate School of Pharmaceutical Sciences, Lecturer, 薬学研究院, 講師 (90342641)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2005: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2004: ¥10,800,000 (Direct Cost: ¥10,800,000)
KeywordsCell fate / Calcium channel / Cellular signal / receptor / calcium signal
Research Abstract

TRP superfamily proteins form plasma membrane cation channels acting as ‘sensors' for diverse cellular stimuli. TRPM2 is a Ca^<2+> permeable channel activated by redox statue changes such as oxidative stress. Although it has been suggested that Ca^<2+> influx via TRPM2 mediate cell death, its physiological significance is still elusive. TRPM2 is expressed in immunocytes such as monocytes and lymphocytes. In monocytic cell line U937, it is known that hydrogen peroxide (H_2O_2) induces chemotactic cytokine interleukin-8 (IL-8) production via Erk/NF-κB pathway and that IL-8 is produced via intracellular Ca^<2+> increases. Here, we reveal that oxidative stress-sensitive TRPM2 Ca^<2+> channels are crucial for H_2O_2-induced IL-8 production in U937. We also report physiological significance of the TRPM2 in vivo with regard to the above biological response by utilizing TRPM2 knockout mice.
We also demonstrate a novel activation mechanism mediated by cysteine S-nitrosylation in TRP channels. TRPC1, C4, C5, V1, V3, and V4 of TRPC and TRPV families, commonly classified as receptor-activated channels and thermosensor channels, show prominent responses to nitric oxide (NO) to elicit Ca^<2+> entry in HEK293 cells. TRPC5 cysteine mutants, examined for NO responsiveness and susceptibility to S-nitrosylation, have revealed Cys553 and Cys558 as modification sites essential for the NO sensitivity. The responsive TRPs harbor conserved cysteines on the same N-terminal side of the pore region. Strikingly, membrane sidedness of reactive disulfide-induced activation via Cys553 modification suggests cytoplasmic accessibility to Cys553. Thus, multidisciplinary approach based upon chemical biology and physiology identifies the structural motif for NO-sensitive activation gate in TRP channels, establishing ‘NO sensors' as a new functional category extending over different TRP subfamilies.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (49 results)

All 2006 2005 2004 Other

All Journal Article (47 results) Book (2 results)

  • [Journal Article] Ca^<2+>/calmodulin dependent myosin light chain kinase is essential for activation of TRPC5 channels expressed in HEK cells.2006

    • Author(s)
      Shimizu S, Yoshida T, Wakamori M, Ishii M, Okada T, Takahashi M, Seto M, Sakurada K, Kiuchi Y, Mori Y
    • Journal Title

      J. Physiol. 570

      Pages: 219-235

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Ca^<2+>/calmodulin dependent myosin light chain kinase is essential for activation of TRPC5 channels expressed in HEK cells.2006

    • Author(s)
      Shimizu S, Yoshida T, Wakamori M, Ishii M, Okada T, Takahashi M, Seto M, Sakurada K, Kiuchi Y, Mori Y
    • Journal Title

      J.Physiol. 570

      Pages: 219-235

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] FPL-64176 modification of Ca_v1.2 L-type calcium channels : dissociation of effects on ionic current and gating current.2005

    • Author(s)
      McDonough SI, Mori Y, Bean BP.
    • Journal Title

      Biophys. J. 81

      Pages: 211-223

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Comprehensive analysis of the ascidian genome reveals novel insights into the molecular evolution of ion channel genes2005

    • Author(s)
      Okamura Y, Murata Y, Nakajo K, Iwasaki I, Ohtsuka Y, Tanaka-Kunishima M, Takahashi N, Hara Y, Yoshida T, Nishida M, Okado H, Watari H, Meinertzhagen IA, Nishino A, Satoh N, Takahashi K, Satou Y, Okada Y, Mori Y
    • Journal Title

      Physiological Genomics 222

      Pages: 269-282

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] The non-selective cation permeating channel TRPC3 is a tetrahedron with a cap in the large cytoplasmic end2005

    • Author(s)
      Mio K, Ogura T, Hara Y, Mori Y, Sato C
    • Journal Title

      Biochem. Biophys. Res. Comm. 333

      Pages: 768-777

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The role of canonical transient receptor potential 7 (TRPC7) in B-cell receptor-activated channels.2005

    • Author(s)
      Lievremont J-P, Numaga T, Vazquez G, Lemonnier L, Hara Y, Mori E, Trebak M, Trebak M, Moss SE, Bird GS, Mori Y, Putney Jr JW
    • Journal Title

      J. Biol. Chem. 280

      Pages: 35346-35351

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] FPL-64176 modification of Cav1.2 L-type calcium channels : dissociation of effects on ionic current and gating current.2005

    • Author(s)
      McDonough SI, Mori Y, Bean BP.
    • Journal Title

      Biophys.J. 81

      Pages: 211-223

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The non-selective cation permeating channel TRPC3 is a tetrahedron with a cap in the large cytoplasmic end2005

    • Author(s)
      Mio K, Ogura T, Hara Y, Mori Y, Sato C
    • Journal Title

      Biochem.Biophys.Res.Comm.

      Pages: 333768-333777

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The role of canoincal transient receptor potential 7 (TRPC7) in B-cell receptor-activated channels.2005

    • Author(s)
      Lievremont J-P, Numaga T, Vazquez G, Lemonnier L, Hara Y, Mori E, Trebak M, Moss SE, Bird GS, Mori Y, Putney Jr JW
    • Journal Title

      J.Biol.Chem. 280

      Pages: 35346-35351

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] FPL-64176 modification of Ca_v1.2 L-type calcium channels : dissociation of effects on ionic current and gating current.2005

    • Author(s)
      McDonough SI, Mori Y, Bean BP
    • Journal Title

      Biophys.J. 81

      Pages: 211-223

    • Related Report
      2005 Annual Research Report
  • [Journal Article] The non-selective cation permeating channel TRPC3 is a tetrahedron with a cap in the large cytoplasmic end2005

    • Author(s)
      Mio K, Ogura T, Hara Y, Mori Y, Sato C
    • Journal Title

      Biochem.Biophys.Res.Comm. 333

      Pages: 768-777

    • Related Report
      2005 Annual Research Report
  • [Journal Article] The role of canonical transient receptor potential 7 (TRPC7) in B-cell receptor-activated channels.2005

    • Author(s)
      Lievremont J-P, Numaga T, Vazquez G, Lemonnier L, Hara Y, Mori E, Trebak M, Trebak M, Moss SE, Bird GS, Mori Y, Putney Jr JW
    • Journal Title

      J.Biol.Chem. 280

      Pages: 35346-35351

    • Related Report
      2005 Annual Research Report
  • [Journal Article] FPL-64176 modification of Ca_ν1.2 L-type calcium channels : dissociation of effects on ionic current and gating current.2005

    • Author(s)
      McDonough SI, Mori Y, Bean BP.
    • Journal Title

      Biophys.J. 81

      Pages: 211-223

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Novel real time sensors to quantitatively assess in vivo inositol 1,4,5-trisphosphate production in intact cells.2004

    • Author(s)
      Sugimoto K, Nishida M, Otsuka M, Ohkubo K, Mori Y, Morii T.
    • Journal Title

      Chem. Biol. 11

      Pages: 475-485

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Ca^<2+> store-independent augmentation of [Ca^<2+>]i responses to G-protein coupled receptor activation in recombinantly TRPC5-expressed rat pheochromocytoma (PC12) cells.2004

    • Author(s)
      Ohta T, Morishita M, Mori Y, Ito S.
    • Journal Title

      Neurosci. Lett. 358

      Pages: 161-164

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Mutations in EFHC1 cause juvenile myoclonic epilepsy.2004

    • Author(s)
      Suzuki T, et al.Mori Y, Yamakawa K.
    • Journal Title

      Nat. Genet. 36

      Pages: 842-846

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Involvement of TRPM7 in cell growth as spontaneously activated Ca^<2+> entry pathway in human retinoblastoma cells.2004

    • Author(s)
      Hanano T, Hara Y, Shi J, Itonaga Y, Mori E, Ito Y, Mori Y, Inoue R.
    • Journal Title

      J Pharmacol. Sci. 95

      Pages: 403-419

    • NAID

      10014165738

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Polyglutamine repeats of spinocerebellar ataxia 6 impair the cell death-preventing effect of Cav2.1 Ca^<2+> channel.2004

    • Author(s)
      Yanagisawa N, Aoki Y, Black III JL, Lennon VA, Mori Y, Imoto K, Inuzuka T, Matsuyama Z.
    • Journal Title

      Neurobiol. Disease 17

      Pages: 198-204

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Activation of RASGRP3 by phosphorylation of Thr133 is required for BCR-mediated Ras activation.2004

    • Author(s)
      Aiba Y, Oh-hora M, Kiyonaka S, Kimura Y, Hijikata A, Mori Y, Kurosaki T.
    • Journal Title

      Proc. Natl. Acad. Sci. USA. 101

      Pages: 16612-16617

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Identification of R(-)-isomer of efonidipine as a selective blocker of T-type Ca^<2+> channels.2004

    • Author(s)
      Furukawa T, Miura R, Honda M, Kamiya N, Mori Y, Takeshita S, Isshiki T, Nukada T.
    • Journal Title

      J. Pharmacol. 143

      Pages: 1050-1057

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Multiple regulation by calcium of murine homologues of transient receptor potential proteins TRPC6 and TRPC7 expressed in HEK293 cell.2004

    • Author(s)
      Shi J, Mori E, Mori Y, Mori M, Li J, Ito Y, Inoue R.
    • Journal Title

      J. Physiol. 561

      Pages: 415-432

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Novel real time sensors to quantitatively assess in vivo inositol 1,4,5-trisphosphate production in intact cells.2004

    • Author(s)
      Sugimoto K, Nishida M, Otsuka M, Ohkubo K, Mori Y, Morii T.
    • Journal Title

      Chem.Biol. 11

      Pages: 475-485

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Ca^<2+> store-independent augmentation of [Ca^<2+>]_i responses to G-protein coupled receptor activation in recombinantly TRPC5-expressed rat pheochromocytoma (PC12) cells.2004

    • Author(s)
      Ohta T, Morishita M, Mori Y, Ito S.
    • Journal Title

      Neurosci.Lett. 358

      Pages: 161-164

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Mutations in EFHC1 cause juvenile myoclonic epilepsy.2004

    • Author(s)
      Suzuki T, et al.Mori Y, Yamakawa K.
    • Journal Title

      Nat.Genet. 36

      Pages: 842-846

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Involvement of TRPM7 in cell growth as spontaneously activated Ca^<2+> entry pathway in human retinoblastoma cells.2004

    • Author(s)
      Hanano T, Hara Y, Shi J, Itonaga Y, Mori E, Ito Y, Mori Y, Inoue R.
    • Journal Title

      J Pharmacol.Sci. 95

      Pages: 403-419

    • NAID

      10014165738

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary 2004 Annual Research Report
  • [Journal Article] Polyglutamine repeats of spinocerebellar ataxia 6 impair the cell death-preventing effect of Cav2.1 Ca^<2+> channel.2004

    • Author(s)
      Yanagisawa N, Aoki Y, Black III JL, Lennon VA, Mori Y, Imoto K, Inuzuka T, Matsuyama Z.
    • Journal Title

      Neurobiol.Disease 17

      Pages: 198-204

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary 2004 Annual Research Report
  • [Journal Article] Activation of RASGRP3 by phosphorylation of Thr133 is required for BCR-mediated Ras activation.2004

    • Author(s)
      Aiba Y, Oh-hora M, Kiyonaka S, Kimura Y, Hijikata A, Mori Y, Kurosaki T.
    • Journal Title

      Proc.Natl.Acad.Sci.USA. 101

      Pages: 16612-16617

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary 2004 Annual Research Report
  • [Journal Article] Ca^<2+> channel mutations and associated diseases. In "Ca channel pharmacology book"2004

    • Author(s)
      Mori Y, Itsukaichi Y, Nishida M, Oka H.
    • Journal Title

      Ca channel pharmacology book 27

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Identification of R(-)-isomer of efonidipine as a selective blocker of T-type Ca^<2+> channels.2004

    • Author(s)
      Furukawa T, Miura R, Honda M, Kamiya N, Mori Y, Takeshita S, Isshiki T, Nukada T.
    • Journal Title

      J.Pharmacol. 143

      Pages: 1050-1057

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Multiple regulation by calcium of murine homologues of transient receptor potential proteins TRPC6 and TRPC7 expressed in HEK293 cell.2004

    • Author(s)
      Shi J, Mori E, Mori Y, Mori M, Li J, Ito Y, Inoue R.
    • Journal Title

      J.Physiol. 561

      Pages: 415-432

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Novel real time sensors to quantitatively assess in vive inositol 1,4,5-trisphosphate production in intact cells.2004

    • Author(s)
      Sugimoto K, Nishida M, Otsuka M, Ohkubo K, Mori Y, Morii T.
    • Journal Title

      Chem.Biol. 11

      Pages: 475-485

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Ca^<2+> store-independent augmentation of [Ca^<2+>]i responses to G-protein coupled receptor activation in recombinantly TRPC5-expressed rat pheochromocytoma (PC12) cells.2004

    • Author(s)
      Ohta T, Morishita M, Mori Y, Ito S
    • Journal Title

      Neurosci.Lett. 358

      Pages: 161-164

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Mutations in EFHC1 cause juvenile myoclonic epilepsy.2004

    • Author(s)
      Suzuki T, et al., Mori Y, Yamakawa K.
    • Journal Title

      Nat.Genet. 36

      Pages: 842-846

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Identification of R(-)-isomer of efonidipine as a selective blocker of T-type Ca^<2+> channels2004

    • Author(s)
      Furukawa T, Miura R, Honda M, Kamiya N, Mori Y, Takeshita S, Isshiki T, Nukada T.
    • Journal Title

      J.Pharmacol. 143

      Pages: 1050-1057

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Multiple regulation by calcium of murine homologues of transient receptor potential proteins TRPC6 and TRPC7 expressed HEK293 cell.2004

    • Author(s)
      Shi J, Mori E, Mori Y, Mori M, Li J, Ito Y, Inoue R.
    • Journal Title

      J.Physiol. 561

      Pages: 415-432

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Phoneutria nigriventer ω-Phonetoxin IIA : A new tool for anti-calcium channel autoantibody assays in Lambert-Eaton myasthenic syndrome

    • Author(s)
      Martin-Moutot N, Haro LD, Santos RG, Mori Y, Seagar M
    • Journal Title

      Neurobiol. Dis. (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Intracellular-produced hydroxyl radical mediates H_2O_2-induced TRPM2 channel activation and cell death in rat β-cell line RIN-5F.

    • Author(s)
      Ishii M, Shimizu S, Hara Y, Hagiwara T, Miyazaki A, Mori Y, Kiuchi Y
    • Journal Title

      Cell Calcium (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A functional AMPA receptor-calcium channel complex in the postsynaptic membrane.

    • Author(s)
      Kang, MG, Chen CC, Wakamori M, Hara Y, Mori Y, Campbell KP
    • Journal Title

      Proc. Natl. Acad. Sci. USA (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A critical role of TRPM2 in neuronal cell death by hydrogen peroxide

    • Author(s)
      Kaneko S, Kawakami S, Hara Y, Itoh E, Minami T, Takada Y, Kume T, Katsuki H, Mori Y, Akaike A
    • Journal Title

      J Pharmacol. Sci. (in press)

    • NAID

      10018237407

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Phoneutria nigriventer □-Phonetoxin IIA : A new tool for anti-calcium channel autoantibody assays in Lambert-Eaton myasthenic syndrome

    • Author(s)
      Martin-Moutot N, Haro LD, Santos RG, Mori Y, Seagar M
    • Journal Title

      Neurobiol.Dis. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Intracellular-produced hydroxyl radical mediates H_2O_2-induced TRPM2 channel activation and cell death in rat □-cell line RIN-5F.

    • Author(s)
      Ishii M, Shimizu S, Hara Y, Hagiwara T, Miyazaki A, Mori Y, Kiuchi Y
    • Journal Title

      Cell Calcium (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A functional AMPA receptor-calcium channel complex in the postsynaptic membrane.

    • Author(s)
      Kang, MG, Chen CC, Wakamori M, Hara Y, Mori Y, Campbell KP
    • Journal Title

      Proc.Natl.Acad.Sci.USA (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A critical role of TRPM2 in neuronal cell death by hydrogen peroxide

    • Author(s)
      Kaneko S, Kawakami S, Hara Y, Itoh E, Minami T, Takada Y, Kume T, Katsuki H, Mori Y, Akaike A
    • Journal Title

      J Pharmacol.Sci. (in press)

    • NAID

      10018237407

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Phoneutria nigriventer ω-Phonetoxin IIA : A new tool for anti-calcium channel autoantibody assays in Lambert-Eaton myasthenic syndrome

    • Author(s)
      Martin-Moutot N, Haro LD, Santos RG, Mori Y, Seagar M
    • Journal Title

      Neurobiol.Dis. (in press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Intracellular-produced hydroxyl radical mediates H_2O_2-induced TRPM2 channel activation and cell death in rat β-cell line RIN-5F.

    • Author(s)
      Ishii M, Shimizu S, Hara Y, Hagiwara T, Miyazaki A, Mori Y, Kiuchi Y
    • Journal Title

      Cell Calcium (in press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] A functional AMPA receptor-calcium channel complex in the postsynaptic membrane.

    • Author(s)
      Kang, MG, Chen CC, Wakamori M, Hara Y, Mori Y, Campbell KP
    • Journal Title

      Proc.Natl.Acad.Sci.USA (in press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] A critical role of TRPM2 in neuronal cell death by hydrogen peroxide

    • Author(s)
      Kaneko S, Kawakami S, Hara Y, Itoh E, Minami T, Takada Y, Kume T, Katsuki H, Mori Y, Akaike A
    • Journal Title

      J Pharmacol.Sci. (in press)

    • NAID

      10018237407

    • Related Report
      2005 Annual Research Report
  • [Book] Ca channel pharmacology book2004

    • Author(s)
      Mori Y, Itsukaichi Y, Nishida M, Oka H.
    • Total Pages
      27
    • Publisher
      Ca^<2+> channel mutations and associated diseases. In "Ca channel pharmacology book"
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] Ca channel pharmacology book2004

    • Author(s)
      Mori Y, Itsukaichi Y, Nishida M, Oka H.
    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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