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

• Project/Area Number: 17K09048
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pain science
• Research Institution: Hyogo 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: ¥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。

Research Products

• [Int'l Joint Research] 北京中医薬大学(中国)
• [Journal Article] TRPA1-expressing lamina propria mesenchymal cells regulate colonic motility (2019)
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Presentation] Cellular mechanisms of TRPA1 channel modulation in primary sensory neurons (2018)
  • Author(s): Yi Dai
  • Organizer: 日本疼痛学会
  • Invited
• [Presentation] AMPK-regulated neuronal TRPA1 plasma membrane expression in painful diabetic neuropathy (2017)
  • 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
  • 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
• [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