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Mechanism of pain hypersensitivity of diabetic neuropathy involving functional interaction of TRP channels and AMP kinase

Research Project

Project/Area Number 17K09048
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pain science
Research InstitutionHyogo University of Health Sciences

Principal Investigator

Dai Yi  兵庫医療大学, 薬学部, 教授 (20330441)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords糖尿病性ニューロパチー / Nedd4-2 / AMPK / 糖尿病性疼痛過敏 / TRPA1 / DRG / diabetic neuropathy
Outline of Final Research Achievements

In this study, we demonstrated a functional interaction between AMP activated protein kinase (AMPK) and transient receptor potential (TRP) channels in dorsal root ganglion (DRG) neurons, in which AMPK activation resulted in downregulation of membrane-associated TRPA1 and its channel activity in both short-term and long-term manner. Treatment with two AMPK activators, metformin or AICAR, inhibited TRPA1 activity in DRG neurons by decreasing the amount of membrane-associated TRPA1. Conversely, in diabetic db/db mice, AMPK activity was impaired in DRG neurons, and this was associated with a concomitant increase in membrane-associated TRPA1 and mechanical allodynia. Notably, these molecular and behavioral changes were normalized following treatment with AMPK activators. Our results identify AMPK as a previously unknown regulator of TRPA1 channels. AMPK modulation of TRPA1 could thus serve as an underlying mechanism and potential therapeutic molecular target in painful diabetic neuropathy.

Academic Significance and Societal Importance of the Research Achievements

本研究は、感覚神経に発現している疼痛センサー(TRPA1)は、エネルギー代謝センサー(AMPK)とそのシグナルによって負の制御を受ける新しい生理現象を解明した。本研究成果は、糖尿病や肥満症など体内エネルギー代謝異常による感覚神経機能の変調(疼痛過敏など)の発症機序を示唆した。また、メトホルミン(商品名メトグルコ)など細胞AMPKシグナルをコントロールする薬剤の疼痛緩和効果が証明された。
今後、これに基づく疼痛治療薬の開発や、既存AMPK薬剤の適応拡大に繋がる臨床試験が期待され、糖尿病性ニューロパチーの患者にとって希望をもたらすであろう。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (7 results)

All 2019 2018 2017 Other

All Int'l Joint Research (1 results) Journal Article (2 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (3 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results) Remarks (1 results)

  • [Int'l Joint Research] 北京中医薬大学(中国)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] TRPA1-expressing lamina propria mesenchymal cells regulate colonic motility2019

    • Author(s)
      Yanjing Yang, Shenglan Wang, Kimiko Kobayashi, Yongbiao Hao, Hirosato Kanda, Takashi Kondo, Yoko Kogure, Hiroki Yamanaka, Satoshi Yamamoto, Junxiang Li, Hiroto Miwa, Koichi Noguchi, Yi Dai
    • Journal Title

      JCI insight

      Volume: 印刷中

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Negative Regulation of TRPA1 by AMPK in Primary Sensory Neurons as a Potential Mechanism of Painful Diabetic Neuropathy.2018

    • Author(s)
      Wang S, Kobayashi K, Kogure Y, Yamanaka H, Yamamoto S, Yagi H, Noguchi K, Dai Y
    • Journal Title

      Diabetes

      Volume: 67(1) Issue: 1 Pages: 98-109

    • DOI

      10.2337/db17-0503

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Cellular mechanisms of TRPA1 channel modulation in primary sensory neurons2018

    • Author(s)
      Yi Dai
    • Organizer
      日本疼痛学会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] AMPK-regulated neuronal TRPA1 plasma membrane expression in painful diabetic neuropathy2017

    • Author(s)
      Shenglan Wang, Kimiko Kobayashi, Yoko Kogure, Hiroki Yamanaka, Satoshi Yamamoto, Hideshi Yagi, Koichi Noguchi, Yi Dai.
    • Organizer
      47th annual meeting of neuroscience, USA
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 一次知覚神経におけるAMPキナーゼによるTRPA1膜発現の制御2017

    • Author(s)
      王勝蘭, 小林希実子, 小暮洋子, 山中博樹, 山本悟史, 八木秀司, 野口光一, 戴 毅
    • Organizer
      第39回日本疼痛学会
    • Related Report
      2017 Research-status Report
  • [Remarks] 研究論文が、米国の権威ある医学雑誌「Diabetes」に掲載

    • URL

      https://www.huhs.ac.jp/7282

    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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