The physiological ligand and activation mechanisms of an orphan metabotropic receptor Prrt3

• Project/Area Number: 16K18999
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General physiology
• 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)
• Research Collaborator: KUBO Yoshihiro 生理学研究所, 教授 ; TATEYAMA Michihiro 生理学研究所, 准教授 ; YAMAMOTO Tomomi 生理学研究所, 技術職員 ; FUKATA Yuko 生理学研究所, 准教授 ; UESUGI Motonari 京都大学, 教授
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: Ligand / GPCR / Receptor / 生理学

Outline of Final Research Achievements

Prrt3 is an orphan family C metabotropic receptor. There is no publication concerning Prrt3 and the physiological roles and functioning mechanisms of Prrt3 are totally unknown. In the present study, we aim to clarify the physiological ligand and activation mechanisms of Prrt3. We performed molecular biological, electrophysiological and [Ca2+]i imaging experiments using Xenopus oocytes and HEK293 cells, and we observed the following results: (1) Gi/o, but not Gq, is coupled with Prrt3; (2) Prrt3 is not activated by the cleavage of its N-terminal extracellular domain; (3) some muscarinic receptor agonists, but not ACh, slightly activates the Prrt3; (4) we happened to identify a novel activator of GIRK channel, ivermectin.

Research Products

• [Journal Article] Ivermectin and its target molecules: shared and unique modulation mechanisms of ion channels and receptors by ivermectin. (2018)
  • Author(s): Chen IS, Kubo Y.
  • Journal Title: J Physiol Volume: 印刷中 Issue: 10 Pages: 1833-1845
  • DOI: 10.1113/jp275236
  • Peer Reviewed
• [Journal Article] Ivermectin activates GIRK channels in a PIP2 -dependent, Gβγ-independent manner and an amino acid residue at the slide helix governs the activation. (2017)
  • Author(s): Chen, I.S., Tateyama, M., Fukata, Y., Uesugi, M., & Kubo, Y.
  • Journal Title: Journal of Physiology Volume: 595 Issue: 17 Pages: 5895-5912
  • DOI: 10.1113/jp274871
  • Peer Reviewed
• [Presentation] Effects and activation mechanisms of ivermectin on G-protein-gated inwardly rectifying potassium channels (2018)
  • Author(s): I-Shan Chen, Michihiro Tateyama, Yuko Fukata, Motonari Uesugi, Yoshihiro Kubo
  • Organizer: The 62nd Annual Meeting of the Biophysical Society
  • Int'l Joint Research
• [Presentation] Novel regulation mechanisms of the GIRK channel activity by small molecules (2018)
  • Author(s): I-Shan Chen, Yoshihiro Kubo
  • Organizer: 第95回日本生理学会大会
• [Presentation] Behavioral analyses of forebrain specific knock-out mice of an orphan metabotropic receptor Prrt3 and screening of small molecule library toward identification of its ligand (2017)
  • Author(s): I-Shan Chen
  • Organizer: The 40th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: Makuhari Messe, chiba, chiba
  • Year and Date: 2017-07-20
• [Presentation] Effects and activation mechanisms of antiparasitic agents on GIRK channels (2017)
  • Author(s): I-Shan Chen, Yoshihiro Kubo
  • Organizer: 第94回日本生理学会大会
• [Presentation] Behavioral analyses of forebrain specific knock-out mice of an orphan metabotropic receptor Prrt3 and screening of small molecule library toward identification of its ligand (2017)
  • Author(s): I-Shan Chen, Tomomi Yamamoto, Li Zhou, Rie Natsume, Kohtaro Konno, Motonari Uesugi, Masahiko Watanabe, Keizo Takao, Tsuyoshi Miyakawa, Kenji Sakimura, Yoshihiro Kubo
  • Organizer: 第40回日本神経科学大会
• [Presentation] Activation mechanisms of G-protein-gated inwardly rectifying K+ channel by ivermectin (2017)
  • Author(s): I-Shan Chen, Michihiro Tateyama, Yuko Fukata, Motonari Uesugi, Yoshihiro Kubo
  • Organizer: 第64回中部日本生理学会
• [Remarks] 研究報告：抗寄生虫剤イベルメクチンによるGIRKチャネルの活性化機構の解明
  • URL: http://www.nips.ac.jp/nips_research/2017/08/girk.html