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Molecular mechanism of trafficking regulation of G protein-coupled receptor

Research Project

Project/Area Number 25460326
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General pharmacology
Research InstitutionShiga University of Medical Science (2014-2015)
Hokkaido University (2013)

Principal Investigator

Terada Koji  滋賀医科大学, 医学部, 准教授 (70342722)

Co-Investigator(Renkei-kenkyūsha) MIWA Soichi  北海道大学, 大学院医学研究科, 教授 (40157706)
Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsエンドセリン / ユビキチン / エンドサイトーシス / リサイクリング / エンドセリン受容体 / ユビキチン化 / Gタンパク質共役受容体
Outline of Final Research Achievements

Two types of G protein-coupled receptors for endothelin-1 (ET-1), ET type A receptor (ETAR) and ETBR, resemble each other, but upon ET-1 stimulation, they follow different intracellular trafficking pathways. In this study, we showed that ETBR but not ETAR was ubiquitinated upon ET-1 stimulation, and that ETBR was internalized and degraded in lysosome more rapidly than ETAR. The mutant ETBR (designated “5KR mutant”) in which 5 lysine residues in C-tail were substituted to arginine was not ubiquitinated, and its rates of internalization and degradation after ET-1 stimulation became slower. Confocal microscopic study showed that following ET-1 stimulation, ETAR and 5KR mutant of ETBR were co-localized mainly with Rab11, a marker of recycling endosome, whereas ETBR was with Rab7, a marker of late endosome/lysosome. These results demonstrate that agonist-induced ubiquitination in C-tail of ETBR switches intracellular trafficking from recycling to plasma membrane to targeting to lysosome.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • 2013 Research-status Report
  • Research Products

    (10 results)

All 2016 2014 2013 Other

All Journal Article (7 results) (of which Peer Reviewed: 7 results,  Open Access: 3 results,  Acknowledgement Compliant: 1 results) Presentation (3 results)

  • [Journal Article] Endothelin-1 suppresses insulin-stimulated Akt phosphorylation and glucose uptake via GPCR kinase 2 in skeletal muscle cells2016

    • Author(s)
      Horinouchi T, Hoshi A, Harada T, Higa T, Karki S, Terada T, Higashi T, Mai Y, Nepal P, Mazaki Y, Miwa S
    • Journal Title

      Br J Pharmacol

      Volume: 173 Issue: 6 Pages: 1018-1032

    • DOI

      10.1111/bph.13406

    • NAID

      120005981358

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Agonist-promoted ubiquitination differentially regulates receptor trafficking of endothelin type A and type B receptors.2014

    • Author(s)
      Terada K., Horinouchi T., Fujioka Y., Higashi T., Nepal P., Horiguchi M., Sarita K., Hatate C., Hoshi A., Harada T., Mai Y., Ohba Y. and Miwa S.
    • Journal Title

      J. Biol. Chem.

      Volume: 289 Issue: 51 Pages: 35283-35295

    • DOI

      10.1074/jbc.m113.544171

    • NAID

      120005549588

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] A simple and rapid method for standard preparation of gas phase extract of cigarette smoke.2014

    • Author(s)
      Higashi T., Mai Y., Noya Y., Horinouchi T., Terada K., Hoshi A., Nepal P., Harada T., Horiguchi M., Hatate C., Kuge Y. and Miwa S.
    • Journal Title

      PLos ONE

      Volume: 9 Issue: 9 Pages: e107856-e107856

    • DOI

      10.1371/journal.pone.0107856

    • NAID

      120005496512

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Endothelin-1 activates extracellular signal-regulated kinases 1/2 via transactivation of platelet-derived growth factor receptor in rat L6 myoblasts.2014

    • Author(s)
      Harada T, Horinouchi T, Higa T, Hoshi A, Higashi T, Terada K, Mai Y, Nepal P, Horiguchi M, Hatate C, Miwa S.
    • Journal Title

      Life Sci.

      Volume: 104 Issue: 1-2 Pages: 24-31

    • DOI

      10.1016/j.lfs.2014.04.002

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Journal Article] Filamin-interacting proteins, Cfm1 and Cfm2, are essential for the formation of cartilaginous skeletal elements.2014

    • Author(s)
      Mizuhashi K, Kanamoto T, Moriishi T, Muranishi Y, Miyazaki T, Terada K, Omori Y, Ito M, Komori T, Furukawa T.
    • Journal Title

      Human molecular genetics

      Volume: - Issue: 11 Pages: 2953-2967

    • DOI

      10.1093/hmg/ddu007

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Endothelin receptor signaling: new insight into its regulatory mechanisms2013

    • Author(s)
      Harada T., Horinouchi T., Higa T., Hoshi A., Higashi T., Terada K., Mai Y., Nepal P., Horiguchi M., Hatate C. and Miwa S.
    • Journal Title

      J Pharmacol Sci.

      Volume: 123 Pages: 85-101

    • NAID

      130003382599

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Identification of stable cytotoxic factors in the gas phase extract of cigarette smoke and pharmacological characterization of their cytotoxicity.2013

    • Author(s)
      Noya Y, Seki K, Asano H, Mai Y, Horinouchi T, Higashi T, Terada K, Hatate C, Hoshi A, Nepal P, Horiguchi M, Kuge Y, Miwa S.
    • Journal Title

      Toxicology

      Volume: 314 Issue: 1 Pages: 1-10

    • DOI

      10.1016/j.tox.2013.08.015

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Presentation] エンドセリンB型受容体の細胞内動態におけるユビキチン化の役割2014

    • Author(s)
      寺田晃士、堀之内孝広、東恒仁、堀口美香、Prabha Nepal、Sarita Karki、旗手千鶴、原田拓弥、眞井洋輔、星暁壮、三輪聡一
    • Organizer
      第65回日本薬理学会北部会
    • Place of Presentation
      コラッセふくしま(福島県)
    • Year and Date
      2014-09-26 – 2014-09-27
    • Related Report
      2014 Research-status Report
  • [Presentation] エンドセリンB型受容体のトラフィッキングにおける受容体ユビキチン化の役割2014

    • Author(s)
      寺田晃士、堀之内孝広、東恒仁、Nepal Prabha、堀口美香、旗手千鶴、星暁壮、眞井洋輔、原田拓弥、三輪聡一
    • Organizer
      第87回日本薬理学会年会
    • Place of Presentation
      仙台(仙台国際センター)
    • Related Report
      2013 Research-status Report
  • [Presentation] エンドセリンB型受容体のET-1刺激誘発的な細胞内移行とシグナルの制御におけるユビキチン修飾の役割

    • Author(s)
      寺田晃士、堀之内孝広、東恒仁、Nepal Prabha、堀口美香、旗手千鶴、星暁壮、三輪聡一
    • Organizer
      第64回日本薬理学会北部会
    • Place of Presentation
      旭川(大雪クリスタルホール)
    • Related Report
      2013 Research-status Report

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Published: 2014-07-25   Modified: 2019-07-29  

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