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INVESTIGATION OF DESENSITIZATION/RESENSITIZATION MECHANISMS FOR Gq PROTEIN-COUPLED RECEPTORS

Research Project

Project/Area Number 14572078
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionMEIJI PHARMACEUTICAL UNIVERSITY

Principal Investigator

HISHINUMA Shigeru  MEIJI PHARMACEUTICAL UNIVERSITY, FACULTY OF PHARMACY, lecturer, 薬学部, 講師 (70211505)

Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
KeywordsASTROCYTOMA CELL / HISTAMINE HI RECEPTOR / DESENSITIZATION / RESENSITIZXTlON / RECEPTOR INTERNALIZATION / BINDING AFFINITY / CALMODULIN / CaM KINASE II / CALCINEURIN / CadキナーゼII
Research Abstract

Many G protein-coupled receptors (GPCRs) undergo functional and distributional changes upon stimulation with agonist, i.e., desensitization/internalization of receptors. Phosphorylation of agonist-occupied GPCRs by G protein-coupled receptor kinases (GRKs) is a key event for induction of receptor desensitization and the subsequent arrestin-mediated internalization. However, desensitization/internalization mechanisms of Ca^<2+> receptors coupled to the Gq family of G proteins, such as histamine H_1 receptors (H_1Rs), has been much less studied, in particular, with respect to feedback modulation of the desensitization/internalization process via the Ca^<2+> We investigated Ca~<2+> (CaM)-mediated regulation of H_1Rs in human U373 MG astrocytoma cells, and found that the onset of agonist-induced, clathrin-mediated internalization of H_1Rs was delayed by activation of Ca^<2+>/CaM, possibly due to inhibition of GRK-mediated internalization process. While the H_1Rs remained on the cell surface membrane owing to the Ca^<2+>/CaM-mediated inhibition of receptor internalization, the agonist affinity for the cell surface H_1Rs was regulated by Ca^<2+>/CaM via actiyation of CaM kinase II (for desensitization) and protein phosphatase 2B (for resenisitization). The subsequent decrease in the intracellular Ca^<2+> concentration even in the presence of agonist may allow H_1Rs to be internalized. In contrast, a receptor-non-mediated and sustained increase in the intracellular Ca^<2+> by a Ca^<2+> ionophore, ionomycin, failed to inhibit histamine-mediated internalization of H_1Rs. Thus, it is suggested that the receptor-mediated activation of Ca^<2+>/CaM plays a crucial role in determining both function and distribution of Gq protein-coupled receptors by regulating activity of CaM kinase II, PP2B and GRKs.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (9 results)

All Other

All Publications (9 results)

  • [Publications] Yuko Sato: "Effects of a Ca^<2+> ionophore, ionomycin, on histamine-induced internalization of Gq protein-coupled histamine H_1 receptors in human U373 MG astrocytoma cells."Journal of Pharmacological Sciences. 91(Suppl.I). 248 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shigeru Hishinuma: "Desensitization and internalization of Gq protein-coupled histamine H_1 receptors."Journal of Pharmacological Sciences. 94(Suppl.I). 22 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yuko Sato: "Regulation of the affinity of histamine for histamine H_1 receptors by the ionomycin-induced increase in intracellular Ca^<2+>concentration in human U373 MG astrocytoma cells."Journal of Pharmacological Sciences. 94(Suppl.I). 282 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sato, Y.: "Effects of a Ca^<2+> ionomycin, on histamine-induced internalization of Gq protein-coupled histamine H_1 receptors in human U373 MG astrocytoma cells."J. Pharmacol. Sci.. 91 (Suppl. I). 248 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hishinuma, S.: "Desensitization and internalization of Gq protein-coupled histamine H_1 receptors."J. Pharmacol. Sci.. 94 (Suppl. I). 22 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sato, Y.: "Regulation of the affinity of histamine for histamine H_1 receptors by the jonomycin-induced increase in intracellular Ca^<2+> concentration in human U373 MG astrocytoma cells."J. Pharmacol. Sci.. 94 (Suppl. I). 282 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shigeru Hishinuma: "Desensitization and internalization of Gq Protein-coupled Histamine H_1 receptors"Journal of Pharmacological Sciences. 94(Suppl.I). 22 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yuko Sato: "Regulation of the affinity of histamine for histamine H_1 receptors By the ionomycin-induced increase in intracellular Ca^<2+> concentration in human U373 MG astrocytoma cells"Journal of Pharmacological Sciences. 94(Suppl.I). 282 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shigeru Hishinuma: "Effects of a Ca^<2+> ionophore, ionomycin, on histamine-induced internalization of Gq protein-coupled histamine H_1 receptors in human U373 MG astrocytoma cells"Journal of Pharmacological Sciences. 91(Suppl.I). 248 (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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