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Molecular Pharmacology

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Research ArticleArticle

Identification of Protein Kinase C Phosphorylation Sites Involved in Phorbol Ester-Induced Desensitization of the Histamine H1 Receptor

Katsumi Fujimoto, Kazumi Ohta, Kenji Kangawa, Ushio Kikkawa, Satoshi Ogino and Hiroyuki Fukui
Molecular Pharmacology April 1999, 55 (4) 735-742;
Katsumi Fujimoto
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Kazumi Ohta
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Kenji Kangawa
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Ushio Kikkawa
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Satoshi Ogino
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Hiroyuki Fukui
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Abstract

The histamine H1 receptor (H1R)-mediated signaling cascade is inhibited by phorbol ester-induced protein kinase C (PKC) activation. Cloning studies of the H1Rs have shown that several potential PKC phosphorylation sites are located in the third intracellular loop of H1R. To elucidate the molecular mechanism of PKC-mediated desensitization, we identified amino acid residues that are involved in the desensitization of the H1R. Two amino acid residues (Ser396, Ser398) were determined to be PKC phosphorylation sites by in vitro phosphorylation studies using a series of synthetic peptides. Treatment with phorbol ester decreased histamine-induced accumulation of inositol phosphates in Chinese hamster ovary cells expressing the H1R with a rightward shift in the EC50 value, which implies the uncoupling of the receptor from the G protein. Site-directed mutagenesis studies showed that substitution of alanine for Ser398 but not for Ser396 markedly attenuated the effect of phorbol ester, which suggests that the Ser398 residue was primarily involved in PKC-mediated desensitization.

Footnotes

  • Send reprint requests to: Dr. Hiroyuki Fukui, Department of Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokushima, 1–78-1 Shomachi, Tokushima 770-8505, Japan. E-mail:hfukui{at}ph.tokushima-u.ac.jp

  • ↵1 Current affiliation: Dept. of Biochemistry, School of Dentistry, Hiroshima University, Hiroshima, Japan.

  • This work was supported in part by grants from JSPS Research Fellowships and Research Foundation for Clinical Pharmacology, and Grants-in-Aid from the Ministry of Education Science and Culture of Japan.

  • Abbreviations:
    H1R
    histamine H1 receptor
    PLC
    phospholipase C
    IP3
    inositol 1,4,5-trisphosphate
    PMA
    phorbol-12-myristate-13-acetate, PKC, protein kinase C
    cAPK
    cAMP-dependent protein kinase
    CaMK II
    calcium/calmodulin-dependent protein kinase II
    GRK
    G protein-coupled receptor kinase
    CHO
    Chinese hamster ovary
    IP
    inositol phospate(s)
    SDS
    sodium dodecyl sulfate
    PAGE
    polyacrylamide gel electrophoresis
    • Received October 1, 1998.
    • Accepted December 17, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (4)
Molecular Pharmacology
Vol. 55, Issue 4
1 Apr 1999
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Research ArticleArticle

Identification of Protein Kinase C Phosphorylation Sites Involved in Phorbol Ester-Induced Desensitization of the Histamine H1 Receptor

Katsumi Fujimoto, Kazumi Ohta, Kenji Kangawa, Ushio Kikkawa, Satoshi Ogino and Hiroyuki Fukui
Molecular Pharmacology April 1, 1999, 55 (4) 735-742;

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Research ArticleArticle

Identification of Protein Kinase C Phosphorylation Sites Involved in Phorbol Ester-Induced Desensitization of the Histamine H1 Receptor

Katsumi Fujimoto, Kazumi Ohta, Kenji Kangawa, Ushio Kikkawa, Satoshi Ogino and Hiroyuki Fukui
Molecular Pharmacology April 1, 1999, 55 (4) 735-742;
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