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マルチモーダルセンサーTRPA1の機能調節機構

Research Project

Project/Area Number 19045027
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionHyogo College of Medicine

Principal Investigator

野口 光一  Hyogo College of Medicine, 医学部, 教授 (10212127)

Co-Investigator(Kenkyū-buntansha) 戴 毅  兵庫医療大学, 薬学部, 准教授 (20330441)
Project Period (FY) 2007 – 2008
Project Status Completed (Fiscal Year 2008)
Budget Amount *help
¥6,300,000 (Direct Cost: ¥6,300,000)
Fiscal Year 2008: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2007: ¥3,100,000 (Direct Cost: ¥3,100,000)
Keywords疼痛 / 後根神経節 / TRPA1 / シグナル伝達 / パッチクランプ
Research Abstract

本研究の目的は、炎症性メディエーターであるBradykinin, NGF, ATP, Tryptaseなどによる、TRPA1のチャネル活性を調節する細胞内メカニズムを解明し、TRPA1のモーダルシフトのメカニズムを解明することである。今年度は、bradykininによるTRPA1の調節機構について詳細に検討した。
ラットDRGニューロンにおいて、Bradykinin受容体をもつ細胞の大半はTRPA1陽性であることを示した。強制発現系HEK細胞とDRGニューロンにおいて、Bradykinin投与はAITC-induced TRPA1電流を増大させた。PLCおよびPKAのinhibitorはこの増大効果をブロックした。またPLCやPKAのactivatorを投与すると、Bradykininと同様の増大効果が観察された。ラット初代培養DRGニューロンにおいて、Bradykinin投与による細胞内cAMPの上昇をEIA法で確認した。occlusion実験により、PLCとPKAのシグナルは別々の経路でTRPA1チャンネルの機能を調節することが明らかになった。Bradykininの事前投与はAITCで引き起こされた疼痛行動を有意に増強した。この増強効果は1時間継続した。細胞で観察されたBradykininとTRPA1の相互関係が生体レベルにおいても証明された。
本研究により、BradykininによるTRPA1チャンネルの機能調節の分子メカニズムが解明された。また、従来はBradykinin受容体の下流でPLCの系が主に働くと認識されてきたが、本研究よりBradykininによるcAMP-PKAシグナルを介した、感覚神経細胞機能の調節機構が明らかとなった。このような炎症性疼痛過敏発症における新規メカニズムは、炎症性疼痛治療の新薬開発のシーズとなることが期待される。以上の結果は、神経学の英文誌Brain 2008に発表した。

Report

(2 results)
  • 2008 Annual Research Report
  • 2007 Annual Research Report
  • Research Products

    (32 results)

All 2008 2007

All Journal Article (20 results) (of which Peer Reviewed: 20 results) Presentation (11 results) Book (1 results)

  • [Journal Article] Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury2008

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

      J. Neurosci 28

      Pages: 12775-12787

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Comparative study of the distribution of the alpha-subunits of voltage-gated sodium channels in normal and axotomized rat dorsal root ganglion neurons2008

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

      J. Comp. Neurol 510

      Pages: 188-206

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [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 56

      Pages: 723-733

    • Related Report
      2008 Annual Research Report
    • 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

    • Related Report
      2008 Annual Research Report
    • 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 131

      Pages: 1241-1251

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Toll-like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury2008

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

      J. Neurochem 105

      Pages: 2249-2259

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Activation of extracellular signal-regulated protein kinase in sensory neurons after noxious gastric distention and its involvement in acute visceral pain in rats2008

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

      Gastroenterology 134

      Pages: 1094-1103

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Differential activation of p38 and extracellular signal-regulated kinase in spinal cord in a model of bee venom-induced inflammation and hyperalgesia2008

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

      Mol. Pain

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 神経障害性疼痛における一次知覚ニューロンの役割2008

    • Author(s)
      小畑浩一, 他
    • Journal Title

      ペインクリニック 29

      Pages: 170-178

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 神経因性疼痛の分子メカニズム2008

    • Author(s)
      小畑浩一, 他
    • Journal Title

      Brain and Nerve 60

      Pages: 483-492

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [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)

    • Related Report
      2007 Annual Research Report
    • 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

    • Related Report
      2007 Annual Research Report
    • 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)

    • Related Report
      2007 Annual Research Report
    • 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

    • Related Report
      2007 Annual Research Report
    • 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

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Frequency-dependent ERK phosphorylation in spinal neurons by electric stimutation of the sciatic nerve and the role in electrophysiological activity2007

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

      Mol. Pain 318

    • Related Report
      2007 Annual Research Report
    • 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

    • Related Report
      2007 Annual Research Report
    • 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

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Roles of extracellular signal-regulated protein kinases 5 in spinal microplia and primary sensory neurons for neuropathic pain2007

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

      J. Neurochem. 102

      Pages: 1569-1584

    • Related Report
      2007 Annual Research Report
    • 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

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Presentation] TRP channels and nociception2008

    • Author(s)
      Noguchi, K.
    • Organizer
      12th World Congress on Pain
    • Place of Presentation
      Glasgow
    • Year and Date
      2008-08-22
    • Related Report
      2008 Annual Research Report
  • [Presentation] MAP kinase regulation of pain : peripheral, central and glial mechanisms2008

    • Author(s)
      Noguchi, K.
    • Organizer
      12th World Congress on Pain
    • Place of Presentation
      Glasgow
    • Year and Date
      2008-08-18
    • Related Report
      2008 Annual Research Report
  • [Presentation] Neuropathic pain mechanisms : TRP family and signal transduction molecules2008

    • Author(s)
      Noguchi, K.
    • Organizer
      NeuPSIG satellite to the Glasgow 2008 World Congress on Pain
    • Place of Presentation
      London
    • Year and Date
      2008-08-13
    • Related Report
      2008 Annual Research Report
  • [Presentation] Contribution of changes in signal transduction molecules in DRG and spinal cord to neuropathic pain2008

    • Author(s)
      Noguchi, K.
    • Organizer
      The 3rd Asian Pain Symposium
    • Place of Presentation
      Fukuoka
    • Year and Date
      2008-07-18
    • Related Report
      2008 Annual Research Report
  • [Presentation] 疼痛伝達の分子メカニズムの解明2007

    • Author(s)
      野口光一
    • Organizer
      第313回大阪大学神経科学懇話会
    • Place of Presentation
      大阪
    • Year and Date
      2007-12-22
    • Related Report
      2007 Annual Research Report
  • [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
    • Related Report
      2007 Annual Research Report
  • [Presentation] 侵害刺激センサーTRPA1とその調節機構2007

    • Author(s)
      野口光一
    • Organizer
      特定領域研究「細胞感覚」夏のシンポジウム
    • Place of Presentation
      東京
    • Year and Date
      2007-08-11
    • Related Report
      2007 Annual Research Report
  • [Presentation] 分子と痛み(1):シグナルと痛み-MAPKを中心として2007

    • Author(s)
      野口光一
    • Organizer
      第2回痛み研究者の集い
    • Place of Presentation
      京都
    • Related Report
      2007 Annual Research Report
  • [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
    • Related Report
      2007 Annual Research Report
  • [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
    • Related Report
      2007 Annual Research Report
  • [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
    • Related Report
      2007 Annual Research Report
  • [Book] 痛みのメカニズム, 運動器の痛み診療ハンドブック(山下敏彦 編)2007

    • Author(s)
      小畑浩一
    • Total Pages
      354
    • Publisher
      南江堂
    • Related Report
      2007 Annual Research Report

URL: 

Published: 2007-04-01   Modified: 2018-03-28  

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