Behavioral analyses and ligand screening toward the identification of the physiological roles of an orphan metabotropic receptor Prrt3

• Project/Area Number: 18K15020
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48020:Physiology-related
• Research Institution: National Institute for Physiological Sciences
• Principal Investigator: Chen I-Shan 生理学研究所, 分子細胞生理研究領域, 特任助教 (40757770)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 新規受容体 / Orphan GPCR / GPCR / 生理学

Outline of Final Research Achievements

Prrt3 is an orphan metabotropic receptor of family C GPCR and the physiological functions of Prrt3 are unknown. We have observed that Prrt3 is highly expressed in mouse brain. In the present study, we aim to identify the role of Prrt3. We created homozygous Prrt3 knockout (KO) mice and performed behavioral analyses. By Barnes probe test to analyze the spatial memory, we observed that the scores of Prrt3 KO mice in terms of (1) Latency (2) Error (3) Distance to the target hole were worse than that of wild-type mice. In the course of screening of a small-molecule library towards the identification of Prrt3 ligands, we failed to figure out its physiological ligands. Further experiments are necessary to solve the puzzle.

Academic Significance and Societal Importance of the Research Achievements

我々のこれまでの研究から、マウスの脳におけるPrrt3の発現パターンやPrrt3遺伝子破壊マウスの空間記憶の異常等を観察した。これらの実験結果により、Prrt3は脳機能において重要な役割を果たしていることが強く示唆された。本研究の研究成果は、Prrt3の生理機能の理解を深めるとともに、脳の機能障害を引き起こす新規の分子機構の理解にも繋がると想定される。また、Prrt3はそれに関する病気の新規治療薬標的分子として働くことも期待できる。

Research Products

• [Journal Article] Non-sedating antihistamines block G-protein-gated inwardly rectifying K+ channels. (2019)
  • Author(s): Chen IS, Liu C, Tateyama M, Karbat I, Uesugi M, Reuveny E, Kubo Y
  • Journal Title: Br J Pharmacol Volume: 176 Issue: 17 Pages: 3161-3179
  • DOI: 10.1111/bph.14717
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Inhibitory mechanisms of G-protein-gated inwardly rectifying K+ channel by antihistamines (2020)
  • Author(s): I-Shan Chen, Chang Liu, Michihiro Tateyama, Izhar Barbat, Motonari Uesugi, Eitan Reuveny, Yoshihiro Kubo
  • Organizer: The 64th Annual Meeting of the Biophysical Society
  • Int'l Joint Research
• [Presentation] Physiological roles of Prrt3, an orphan metabotropic receptor: Comprehensive behavioral test battery analysis using homozygous full gene knock-out mice derived from flox mice (2020)
  • Author(s): Tomomi Yamamoto, Satoko Hattori, Li Zhou, Rie Natsume, Kohtarou Konno, I-Shan Chen, Masahiko Watanabe, Kenji Sakimura, Tsuyoshi Miyakawa, Yoshihiro Kubo
  • Organizer: 第97回日本生理学会大会
• [Presentation] Regulation mechanisms of G-protein-gated inwardly rectifying K+ channel by small molecules (2019)
  • Author(s): I-Shan Chen, Chang Liu and Yoshihiro Kubo
  • Organizer: The 9th Federation of Asian and Oceanian Physiological Societies Congress: FAOPS2019
  • Int'l Joint Research
• [Remarks] 非鎮静性抗ヒスタミン薬によるGIRKチャネルの活性阻害機構の解明
  • URL: http://www.nips.ac.jp/nips_research/2019/07/girk_1.html