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2007 Fiscal Year Final Research Report Summary

modulation mechanism of transient receptor potential A1 by proteinase activated receptor 2

Research Project

Project/Area Number 18613024
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pain science
Research InstitutionHyogo College of Medicine

Principal Investigator

DAI Yi  Hyogo College of Medicine, Faculty of Medicine, Assistant Professor (20330441)

Co-Investigator(Kenkyū-buntansha) NOGUCHI Koichi  Hyogo College of Medicine, Faculty of Medicine, Professor (10212127)
Project Period (FY) 2006 – 2007
KeywordsTRPA1 / PAR-2 / PIP2 / PLC / DRG / inflammation / pain / patch clamp
Research Abstract

Proinflammatory agents trypsin and mast cell tryptase cleave and activate PAR2, which is expressed on sensory nerves to cause neurogenic inflammation. Transient receptor potential channels V1 (TRPV1) and Al (TRPA1) are excitatory ion channel on primary sensory nerves of pain pathway. Here, we show that a functional interaction of PAR2 with TRPV1 or TRPA1 in primary sensory neurons could contribute to the sensation of inflammatory pain.
Frequent colocalization of the TRP channels with PAR2 was found in rat dorsal root ganglion (DRG) neurons.
PAR2 activation could increase both the TRPV1 and TRPA1 currents evoked by its agonists in HEK293 cells transfected with the TRP channels, as well as DRG neurons. However, the cellular mechanism of these potentiation showed Application of phospholipase C (PLC) inhibitors or phosphatidylinositol-4,5-bisphosphate (PIP2) suppressed potentiation of TRPA1. Decrease of plasma membrane PIP2 levels through antibody sequestration or PLC-mediated hydrolysis mimicked the potentiating effects of PAR2 activation at the cellular level. Thus, the increased TRPA1 sensitivity may have been due to activation of PLC, which releases the inhibition of TRPA1 from plasma membrane PIP2. These results identify for the first time to our knowledge a sensitization mechanism of TRPA1 and a novel mechanism through which trypsin or tryptase released in response to tissue inflammation might trigger the sensation of pain by TRPA1 activation.

  • Research Products

    (60 results)

All 2008 2007 2006 Other

All Journal Article (40 results) (of which Peer Reviewed: 19 results) Presentation (20 results)

  • [Journal Article] Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injury2008

    • Author(s)
      Katsura, H., et. al.
    • Journal Title

      Glia (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain2008

    • Author(s)
      Kobayashi, K., et. al.
    • Journal Title

      J.Neurosci. 28

      Pages: 2892-2902

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Phospholipase C and protein kinase A mediate bradykinin sensitization of TRPA1:a molecular mechanism of inflammatory pain2008

    • Author(s)
      Wang, S., et. al.
    • Journal Title

      Brain (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Two types of GABAergic miniature inhibitory postsynaptic currents in mouse substantia gelatinosa neurons2007

    • Author(s)
      Takahashi, A., et. al.
    • Journal Title

      Eur.J.Pharmacol. 553

      Pages: 120-128

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Intensity-dependent activation of extracellular signal-regulated protein kinases 5 in sensory neurons contributes to pain hypersensitivity2007

    • Author(s)
      Mizushima, T., et. al.
    • Journal Title

      J.Pharmacol.Exp.Ther. 321

      Pages: 28-34

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Tissue type plasminogen activator induced in rat dorsal horn astrocytes contributes to mechanical hypersensitivity following dorsal root injury2007

    • Author(s)
      Kozai, T., et. al.
    • Journal Title

      Glia 55

      Pages: 595-603

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Frequency-dependent ERK phosphorylation in spinal neurons by electric stimulation of the sciatic nerve and the role in electrophysiological activity2007

    • Author(s)
      Fukui, T., et. al.
    • Journal Title

      Mol.Pain 3.18

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain2007

    • Author(s)
      Dai, Y., et. al.
    • Journal Title

      J.Clin.Invest. 117

      Pages: 1979-1987

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Activation of extracellular signal-regulated protein kinases 5 in primary afferent neurons contributes to heat and cold hyperalgesia after inflammation2007

    • Author(s)
      Katsura, H., et. al.
    • Journal Title

      J.Neurochem. 102

      Pages: 1614-1624

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Roles of extracellular signal-regulated protein kinases 5 in spinal microglia and primary sensory neurons for neuropathic pain2007

    • Author(s)
      Obata, K., et. al.
    • Journal Title

      J.Neurochem. 102

      Pages: 1569-1584

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Activation of fibroblast growth factor receptor by axotomy,through downstream p38 in dorsal root ganglion,contributes to neuropathic pain2007

    • Author(s)
      Yamanaka, H., et. al.
    • Journal Title

      Neuroscience 150

      Pages: 202-211

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Suppression of the p75 neurotrophin receptor in uninjured sensory neurons reduces neuropathic pain after nerve injury2006

    • Author(s)
      Obata, K., et. al.
    • Journal Title

      J.Neurosci. 26

      Pages: 11974-11986

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] The effect of site and type of nerve injury on the expression of brain-derived neurotrophic factor in the dorsal root ganglion and on neuropathic pain behavior2006

    • Author(s)
      Obata, K., et. al.
    • Journal Title

      Neuroscience 137

      Pages: 961-970

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Antisense knock down of TRPA1,but not TRPM8,alleviates cold hyperalgesia after spinal nerve ligation in rats2006

    • Author(s)
      Katsura, H., et. al.
    • Journal Title

      Exp.Neurol. 200

      Pages: 112-123

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] The role of ERK signaling and the P2X receptor on mechanical pain evoked by movement of inflamed knee joint2006

    • Author(s)
      Seino, D., et. al.
    • Journal Title

      Pain 123

      Pages: 193-203

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Noxious cold stimulation induces MAPK activation in TRPA1-and TRPM8-containing small sensory neurons2006

    • Author(s)
      Mizushima, T., et. al.
    • Journal Title

      Neuroscience 140

      Pages: 1337-1348

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Neurons and glial cells differentially express P2Y receptor mRNAs in the rat dorsal root ganglion and spinal cord2006

    • Author(s)
      Kobayashi, K., et. al.
    • Journal Title

      J.Comp.Neurol. 498

      Pages: 443-454

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Agonist of PAR2 increases painful behavior produced by a,b-methylene ATP2006

    • Author(s)
      Zhu, W., et. al.
    • Journal Title

      Neuroreport 17

      Pages: 1257-1261

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury2006

    • Author(s)
      Katsura, H., et. al.
    • Journal Title

      J.Neurosci. 26

      Pages: 8680-8690

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Suppression of the p75 neurotrophin receptor in uninjured sensory neuros reduces neuropathic pain after nerve injury

    • Author(s)
      Obata, K. et. al
    • Journal Title

      J. Neurosci 26

      Pages: 11974-11986

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] The effect of site and type of nerve injury on the expression ofr brain-derived neurotrophic factor in the dorsal root ganglion and on neuropathic pain

    • Author(s)
      Obata, K. et. al
    • Journal Title

      Neuroscience 137

      Pages: 961-970

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Antisense knock down of TRPA1, but not TRPM8, alleviates cold hyperalgesia after spinal nerve ligation in rats.

    • Author(s)
      Katsura, H. et. al
    • Journal Title

      Exp. Neurol 200

      Pages: 112-123

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] The role of ERK signaling and the P2X receptor in mechanical pain evoked by movement of inflamed knee joint.

    • Author(s)
      Seino, D., et. al.
    • Journal Title

      Pain 123

      Pages: 193-203

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Noxious cold stimulation induces mitogen-activated protein kinase activation in transient receptor potential(TRP) channels TRPA1-and TRPM8-containing small sensory neurons

    • Author(s)
      Mizushima, T. et. al
    • Journal Title

      Neuroscience 140

      Pages: 1337-1348

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Neurons and glial cells defferentially express P2Y receptor mRNAs in the dorsal root ganglion and spinal cord

    • Author(s)
      Kobayshi, K. et. al
    • Journal Title

      J. Comp. Neurol 498

      Pages: 443-454

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Agonist of PAR2 increases painful behavior produced by alpha, beta-methylene adenosine 5'-triphosphate

    • Author(s)
      Zhu, W. J. et. al
    • Journal Title

      Neuroreport 17

      Pages: 1257-1261

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury

    • Author(s)
      Katsura, H. et. al
    • Journal Title

      J. Neurosci 26

      Pages: 8680-8690

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Two types of GABAergic miniture inhibitory postsynaptic currents in mouse substantia gelatinosa neruons

    • Author(s)
      Takahashi, A., et. al.
    • Journal Title

      Eur. J. Pharmacol 553

      Pages: 120-128

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Axotomy increases plasma membrane Ca<2+>pump isoform4 in primary afferent neurons

    • Author(s)
      Ogura, H. et. al
    • Journal Title

      Neuroreport 18

      Pages: 17-22

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Alternation of the cell adhesion molecule L1 expression in a specific subset of primary afferent neurons contributes to neuropathic pain

    • Author(s)
      Yamanaka, H. et. al
    • Journal Title

      Eur. J. Neurosci 25

      Pages: 1097-1111

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Tissue type plasminogen activator induced in rat dorsal horn astrocytes contributes to mechanical hypersensitivity following dorsal root injury

    • Author(s)
      Kozai, T. et. al
    • Journal Title

      Glia 55

      Pages: 595-603

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Intensity-dependent activation of extracellular signal-regulated protein kinases(ERK) 5 in sencory neurons contributes to pain hypersensitivity

    • Author(s)
      Mizushima, T. et. al
    • Journal Title

      J. Pharmacol. Exp. Ther 321

      Pages: 28-34

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Roles of extracellular signal-regulated protein kinases(ERK) 5 in spinal microglia and primary sensory neurons for neuropathic pain

    • Author(s)
      Obata, K. et. al
    • Journal Title

      J. Neurochem 102

      Pages: 1569-1584

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Activation of extracellular signal-regulated protein Kinases(ERK) 5 in primary afferent neurons contributes to heat and cold hyperalgesia after inflammation

    • Author(s)
      Kastura, H., et. al.
    • Journal Title

      J. Neurochem 102

      Pages: 1614-1624

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Frequency-dependent ERK phosphorylation in spinal neurons by electric stimulation of the sciatic nerve and the role in electrophysiological activity

    • Author(s)
      Fukui, T., et. al.
    • Journal Title

      Mol. Pain 3

      Pages: 18

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Activation of fibroblast growth factor receptor by axotomy, through downstream p38 in dorsal root ganglion, contributes to the neuropathic pain

    • Author(s)
      Yamanaka, H. et. al
    • Journal Title

      Neuroscience 150

      Pages: 202-211

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Sensitization of TRPA1 by PAR-2 through PLC-PIP2-dependent mechanisms contributes to infalmmatory pain

    • Author(s)
      Dai, Y., et. al.
    • Journal Title

      J. Clin. Invest 117

      Pages: 1979-1987

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Phospholipase C and protein kinase A mediate bradykinin senstitization of TRPA1 : a molecular mechanism of inflammatory pain

    • Author(s)
      Wang S, et. al.
    • Journal Title

      Brain 131(Pt5)

      Pages: 1241-1251

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain

    • Author(s)
      Kobayshi, K. et. al
    • Journal Title

      J. Neurosci 12, 28

      Pages: 2892-2902

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Transforming growth factor-activated kinase 1 induced in spinal astrocyted contributed to mechanical hypersensitivity after nerve injury

    • Author(s)
      Katsura, H. et. al
    • Journal Title

      Glia 56

      Pages: 723-733

    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Sensitization of TRPA1 by PAR-2 through PLC/PIP2-dependent mechanisms contributes to inflammatory pain2007

    • Author(s)
      Dai, Y., et. al.
    • Organizer
      37th Annual Meeting Society for Neuroscience
    • Place of Presentation
      San Diego
    • Year and Date
      20071103-07
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Potentiation of TRPA1 activity by bradykinin through both PLC-and PKA-dependent mechanisms2007

    • Author(s)
      Wang, S., et. al.
    • Organizer
      37th Annual Meeting Society for Neuroscience
    • Place of Presentation
      San Diego
    • Year and Date
      20071103-07
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Sensitization of TR PA1 by PAR-2 through PLC/P I P2-dependent mechanisms contributes to inflammatory pain2007

    • Author(s)
      Dai, Y., et. al.
    • Organizer
      37th Annual Meeting Society for Neuroscience
    • Place of Presentation
      San Diego, U.S.A.
    • Year and Date
      20071103-07
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Potentiation of TR PA1 activity by bradykinin through both PLC- and PKA-dependent mechanisms2007

    • Author(s)
      Wang, S. et.al.
    • Organizer
      37th Annual Meeting Society for Neuroscience
    • Place of Presentation
      San Diego, U.S.A.
    • Year and Date
      20071103-07
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Protease-activated receptor2によるTRPA1活性の増強2007

    • Author(s)
      戴 毅
    • Organizer
      第30回日本神経科学大会
    • Place of Presentation
      横浜
    • Year and Date
      20070910-12
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] BradykininによるTRPA1活性の増強2007

    • Author(s)
      王 勝蘭
    • Organizer
      第30回日本神経科学大会
    • Place of Presentation
      横浜
    • Year and Date
      20070910-12
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] ニューロパチックペインモデルのDRG及び脊髄における分子変化2007

    • Author(s)
      野口 光一
    • Organizer
      第30回日本神経科学大会
    • Place of Presentation
      横浜
    • Year and Date
      20070910-12
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Molecular changes in DRG and spinal cord in the model of neuropathic pain2007

    • Author(s)
      Noguchi, K.
    • Organizer
      30th Annual Meeting of the Japan Neuroscience Society
    • Place of Presentation
      Yokohama
    • Year and Date
      20070910-12
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Sensitization of TR PA1 by PAR-2 through PLC/PIP2-dependent mechanisms2007

    • Author(s)
      Dai, Y., et. al.
    • Organizer
      30th Annual Meeting of the Japan Neuroscience Society
    • Place of Presentation
      Yokohama
    • Year and Date
      20070910-12
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Potentiation of TR PA1 activity by bradykinin2007

    • Author(s)
      Wang, S. et.al.
    • Organizer
      30th Annual Meeting of the Japan Neuroscience Society
    • Place of Presentation
      Yokohama
    • Year and Date
      20070910-12
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Roles of ERK5 in spinal microglia and primary sensory neurons for neuropathic pain2007

    • Author(s)
      Noguchi, K
    • Organizer
      7th IBRO World Congress of Neuroscience
    • Place of Presentation
      Melbourne
    • Year and Date
      20070712-17
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Roles of ERK5 in spinal microglia and primary sensory neurons for neuropathic pain2007

    • Author(s)
      Noguchi, K.
    • Organizer
      7th IBRO World Congress of Neuroscience
    • Place of Presentation
      Melbourne, Australia
    • Year and Date
      20070712-17
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] 桂皮の薬理作用におけるTRPA1受容体の関与2007

    • Author(s)
      戴 毅
    • Organizer
      第58回日本東洋医学会学術総会
    • Place of Presentation
      広島
    • Year and Date
      20070615-17
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Roles of extracellular signal-regulated protein kinase (ERK)5 in spinal microglia and primary sensory neurons for neuropathic pain2007

    • Author(s)
      Noguchi, K
    • Organizer
      Second International Congress on Neuropathic Pain
    • Place of Presentation
      Berlin
    • Year and Date
      20070607-10
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Roles of extracellular signal-regulated protein kinase(ERK) 5 in spinal microglia and primary sensory neurons for neuropathic pain2007

    • Author(s)
      Noguchi, K.
    • Organizer
      Second International Congress on Neuropathic Pain
    • Place of Presentation
      Berlin, Germany
    • Year and Date
      20070607-10
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] TRP channel family and cutaneous sensation2007

    • Author(s)
      野口 光一
    • Organizer
      第17回国際痒みシンポジウム
    • Place of Presentation
      大阪
    • Year and Date
      2007-09-15
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] TRP channel family and cutaneous sensation2007

    • Author(s)
      Noguchi, K.
    • Organizer
      17th International Symposium of Itch
    • Place of Presentation
      Osaka
    • Year and Date
      2007-09-15
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Protease-activated receptor2によるTRPA1活性の増強2007

    • Author(s)
      戴 毅
    • Organizer
      第29回日本疼痛学会
    • Place of Presentation
      横浜
    • Year and Date
      2007-07-07
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] BradykininによるTRPA1活性の増強2007

    • Author(s)
      王 勝蘭
    • Organizer
      第29回日本疼痛学会
    • Place of Presentation
      横浜
    • Year and Date
      2007-07-07
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Activation of Proteinase-activated receptor 2 potentiates TRPA1 channel activity2006

    • Author(s)
      Dai, Y., et. al.
    • Organizer
      36th Annual Meeting Society for Neuroscience
    • Place of Presentation
      Atlanta
    • Year and Date
      20061014-18
    • Description
      「研究成果報告書概要(和文)」より

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Published: 2010-02-04  

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