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G PROTEIN-DEPENDENT SIGNAL : DESENSITIZATION AND DISEASES

Research Project

Project/Area Number 17590955
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Endocrinology
Research InstitutionThe University of Tokyo

Principal Investigator

MAKITA Noriko  The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (60353455)

Co-Investigator(Kenkyū-buntansha) IIRI Taroh  The University of Tokyo, Faculty of Medicine, Project Lecturer, 医学部附属病院, 特任講師 (90313022)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
KeywordsG protein / GPCR / molecular mechanism / desensitization / disease / G protein disease / レセプター
Research Abstract

1) ELUCIDATION OF DESENSITIZATION OF G PROTEINS BASED ON THE ANALYSIS OF G PROTEIN DISEASES
(1) G protein-coupled receptor (GPCR) signaling and desensitization
Desensitization may explain, at least in part, each cell specific responsiveness to receptor-dependent signaling. We analyzed the potential role of lipid modification on G proteins in signal desensitization.
(2) Potential desensitization mechanism on G proteins
We have shown that overexpression of palmitoyl esterase causes signal inhibition and translocation of Gs.
2) NOVEL MECHANISMS OF RECEPTOR-G PROTEIN SIGNAL AND PATHOPHYSIOLOGY
(1) Gene delivery of molecules working on GPCR desensitization
We have analyzed the effect of transfection of GRK, arrestin, and Gt on GPCR dependent signal and desentization.
(2) Signal Switching
We have discovered a novel Ca-sensing receptor (CaSR) autoantibody in a human disease, acquired hypocalciuric hypercalcemia. CaSR is known to activate multiple G proteins including Gq and Gi, thereby activates a variety of signals and inhibits parathyroid hormone secretion. We have shown our autoantibody works as an allosteric modulator to CaSR and that a Ca-stimulated CaSR primed by this autoatibody adopts a unique conformation that activates Gq but not Gi. We speculate that physiological modulators may exist that enable an agonist to specifically activate only one signaling pathway via a GPCR that activates multiple signaling pathways.
(3) Analysis and Screening of inverse agonists to GPCRs

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (20 results)

All 2007 2006 2005 Other

All Journal Article (19 results) Book (1 results)

  • [Journal Article] Acquired Hypocalciuric Hypercalcemia Autoantibody Induces Allosteric Transition among Multiple Active Conformations2007

    • Author(s)
      Makita N, Iiri T et al.
    • Journal Title

      Proc. Natl. Acad. Sci. U.S.A 104

      Pages: 5443-5448

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Acquired Hypocalciuric Hypercalcemia Autoantibody Induces Allosteric Transition among Multiple Active Conformations2007

    • Author(s)
      Makita N, Iiri T, et al.
    • Journal Title

      Proc.Natl.Acad.Sci.U.S.A. 104

      Pages: 5443-5448

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Acquired Hypocalciuric Hypercalcemia Autoantibody Induces Allosteric Transition among Multiple Active Confomations2007

    • Author(s)
      Makita N, Iiri T, et al.
    • Journal Title

      Proc. Natl. Acad. Sei. U.S.A 104

      Pages: 5443-5448

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Angiotensin receptor 1a2006

    • Author(s)
      Makita N, Fujita T, Iiri T
    • Journal Title

      AfCS Nature (Online)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] An Instructive Case Suggesting Cyclical Primary Hyperparathyroidism2006

    • Author(s)
      Makita N, Iiri T et al.
    • Journal Title

      Endocrine J. 53

      Pages: 311-316

    • NAID

      10018177866

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] G protein signaling and hypertension2006

    • Author(s)
      Makita N, Iiri T
    • Journal Title

      Nippon Rinsho 64(suppl 5)

      Pages: 193-196

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] G protein genes2006

    • Author(s)
      Manaka K, Makita N, Iiri T
    • Journal Title

      Nippon Rinsho 64(suppl 5)

      Pages: 407-410

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Angiotensin receptor 1a2006

    • Author(s)
      Makita N, Fujita T, Iiri T
    • Journal Title

      AfCS Nature (doi:10.1038/mp.a000275.01)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] An Instructive Case Suggesting Cyclical Primary Hyperparathyroidism2006

    • Author(s)
      Makita N, Iiri T, et al.
    • Journal Title

      Endocrine J. 53

      Pages: 311-316

    • NAID

      10018177866

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Angiotensin receptor la2006

    • Author(s)
      Makita N, Fujita T, Iiri T
    • Journal Title

      AfCS Nature Online

    • Related Report
      2006 Annual Research Report
  • [Journal Article] G蛋白質異常による疾患群2006

    • Author(s)
      槙田紀子, 飯利太朗
    • Journal Title

      ホルモンと臨床 54・増2

      Pages: 176-178

    • Related Report
      2006 Annual Research Report
  • [Journal Article] 高血圧とG蛋白質共役受容体2006

    • Author(s)
      飯利太朗, 槙田紀子
    • Journal Title

      日本医事新報 4266

      Pages: 1-7

    • Related Report
      2006 Annual Research Report
  • [Journal Article] G蛋白質シグナルの異常としての高血圧2006

    • Author(s)
      槙田紀子, 飯利太朗
    • Journal Title

      日本臨床 64・増5

      Pages: 193-196

    • Related Report
      2006 Annual Research Report
  • [Journal Article] An Instructive Case Suggesting Cyclical Primary Hyperparathyroidism2006

    • Author(s)
      Makita N et al.
    • Journal Title

      Endocrine J. 53(In press)

    • NAID

      10018177866

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Roles of CTPL/Sfxn3 and Sfxn Family Members in Pancreatic Islet2005

    • Author(s)
      Yoshikumi Y, Iiri T et al.
    • Journal Title

      J. Cell Biochem 95

      Pages: 1157-1168

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Roles of CTPL/Sfxn3 and Sfxn Family Members in Pancreatic Islet2005

    • Author(s)
      Yoshikumi Y, Iiri T, et al.
    • Journal Title

      J.Cell Biochem. 95

      Pages: 1157-1168

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Hormone Receptor Diseases2005

    • Author(s)
      Makita N, Iiri T
    • Journal Title

      Lectures on Endocrinology and Metabolism

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Roles of CTPL/Sfxn3 and Sfxn Family Members in Pancreatic Islet2005

    • Author(s)
      Yoshikumi Y et al.
    • Journal Title

      J.Cell Biochem. 95

      Pages: 1157-1168

    • Related Report
      2005 Annual Research Report
  • [Journal Article] AT1a in Molecule Page - Signaling Gateway.

    • Author(s)
      Makita N, Iiri T
    • Journal Title

      AfCS in Nature http://www.signaling-gateway.org/molecule/query?afcsid=A000275 (掲載確定)

    • Related Report
      2005 Annual Research Report
  • [Book] 「講義録 内分泌・代謝学」ホルモン受容体異常症2005

    • Author(s)
      槙田紀子, 飯利太朗
    • Total Pages
      514
    • Publisher
      メジカルビュー社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary

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Published: 2005-04-01   Modified: 2016-04-21  

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