Dopa as a neurotransmitter in heart failure and acute kidney injury

• Project/Area Number: 18K06896
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Kanagawa Dental College (2020); Yokohama City University (2018-2019)
• Principal Investigator: Hashimoto Tatsuo 神奈川歯科大学, 大学院歯学研究科, 教授 (20363806)
• Co-Investigator(Kenkyū-buntansha): 古賀 資和 横浜市立大学, 医学部, 助教 (00637233) ; 増川 太輝 横浜市立大学, 医学部, 助教 (10711898) ; 田村 功一 横浜市立大学, 医学研究科, 教授 (40285143)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: ドーパ / 肺高血圧 / 心不全 / GPR143 / 腎結石 / 腎不全

Outline of Final Research Achievements

3,4-Dyhydroxyphenylalanine (DOPA) has been believed to be an inert amino acid precursor of dopamine. We proposed DOPA as a neurotransmitter. Recently, the ocular albinism 1 gene product, OA1/GRP143 (GPR143), was identified as a receptor for DOPA. DOPA modifies contraction mediated through alpha-1 adrenergic receptor (a1AR) via GPR143 in mouse arteries to control daily systemic blood pressure.
In this study we have investigated the participation of GPR143-signaling in pulmonary hypertension and heart failure using GPR143 gene deficient animal. GPR143-signaling were found to have an important role in both pulmonary hypertension and heart failure. DOPA modifies contraction, proliferation, and migration mediated through a1AR via GPR143 in rat arteries to control pulmonary hypertension.

Academic Significance and Societal Importance of the Research Achievements

本研究は、単独での作用がないと考えられてきたドーパミン前駆体、ドーパ自体に病態形成に関与する作用があることを示す初めての研究成果である。
関与する可能性のある疾患は、肺高血圧症と心不全である。いずれも新たな治療ターゲットが求められている疾患であり、新薬の糸口になる可能性がある。

Research Products

• [Journal Article] l-DOPA and Its Receptor GPR143: Implications for Pathogenesis and Therapy in Parkinson’s Disease (2019)
  • Author(s): Goshima Yoshio、Masukawa Daiki、Kasahara Yuka、Hashimoto Tatsuo、Aladeokin Aderemi Caleb
  • Journal Title: Frontiers in Pharmacology Volume: 10 Pages: 1-9
  • DOI: 10.3389/fphar.2019.01119
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 肺高血圧症におけるドーパ性神経伝達機構の解析 (2020)
  • Author(s): 中野雅友樹、橋本達夫、古賀資和、増川太輝、奥真哉、水野祐介、後藤隆久、田村功一、五嶋良郎
  • Organizer: 第93回日本薬理学会年会
• [Presentation] GPR143, an L-DOPA receptor, may help control inflammation in adenine-induced chronic kidney disease (2019)
  • Author(s): Tatsuo Hashimoto, Masayuki Nakano, Shota Suzuki, Takayuki Yamada, Daiki Masukawa, Motokazu Koga, Ryuichi Ito, Kotaro Haruhara, Hiromichi Wakui, Koichi Tamura, Yoshio Goshima
  • Organizer: 第92回日本薬理学会年会
• [Presentation] L-DOPA CHE, an L-DOPA antagonist, protects neurostimulated contractile response in mice heart (2018)
  • Author(s): Tatsuo Hashimoto, Shogo Hamaguchi, Daiki Masukawa, Motokazu Koga, Nakano Masayuki, Hikaru Tanaka, Koichi Tamura, Yoshio Goshima
  • Organizer: 第18回国際薬理学・臨床薬理学会議
  • Int'l Joint Research