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Research ArticleArticle

Role of Receptor and Protein Kinase C Activation in the Internalization of the Gastrin-Releasing Peptide Receptor

Barbara Y. Williams, Stéphane B. Dion and Agnes Schonbrunn
Molecular Pharmacology November 1998, 54 (5) 889-898; DOI: https://doi.org/10.1124/mol.54.5.889
Barbara Y. Williams
Department of Integrative Biology and Pharmacology, University of Texas Medical School, Houston, Texas 77225
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Stéphane B. Dion
Department of Integrative Biology and Pharmacology, University of Texas Medical School, Houston, Texas 77225
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Agnes Schonbrunn
Department of Integrative Biology and Pharmacology, University of Texas Medical School, Houston, Texas 77225
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Abstract

The mechanisms regulating receptor internalization are not well understood and vary among different G protein-coupled receptors. The bombesin (Bn)/gastrin-releasing peptide receptor GRP-R, which is coupled to phospholipase C via the Gq family of transducing proteins, is internalized rapidly after Bn binding. Agonist stimulation leads to rapid receptor phosphorylation, as does activation of protein kinase C (PKC) by phorbol-12-myristate-13-acetate (PMA). However, agonist- and PMA-induced phosphorylation occur at different receptor sites. Here, we examined the role of PKC in GRP-R internalization after agonist and antagonist binding. We synthesized [d-Tyr6]Bn(6–13)propylamide ([d-Tyr6]Bn(6–13)PA) and found that it potently inhibited Bn-stimulated insulin release and [125I-Tyr4]Bn binding (K i = 4.72 nm) in the HIT-T15 pancreatic cell line. The radiolabeled antagonist peptide, [125I-d-Tyr6]Bn(6–13)PA, bound with high affinity (K D = 0.29 nm at 4°) to a single class of receptor sites, and competition binding studies exhibited the analog specificity expected for the GRP-R subtype. Although the agonist [125I-Tyr4]Bn was internalized rapidly at 37° and subsequently degraded, [125I-d-Tyr6]Bn(6–13)PA was not internalized and was released into the medium mainly as intact peptide. The lysosomal inhibitor chloroquine (200 μm) increased the intracellular accumulation of [125I-Tyr4]Bn but had no effect on the subcellular distribution of [125I-d-Tyr6]Bn(6–13)PA. Consistent with these observations, the treatment of cells with 100 nm Bn at 37° reduced cell surface receptors within minutes, whereas [d-Tyr6]Bn(6–13)PA had no effect. The addition of PMA did not induce the internalization of antagonist-occupied receptors, but pharmacological inhibition of PKC decreased the rate of agonist-induced receptor internalization. These results therefore demonstrate that although PKC contributes to agonist-induced internalization of the GRP-R, it does not elicit receptor internalization of the antagonist-occupied receptor.

Footnotes

    • Received March 30, 1998.
    • Accepted July 30, 1998.
  • Send reprint requests to: Agnes Schonbrunn, Ph.D., Department of Integrative Biology and Pharmacology, University of Texas Medical School, P.O. Box 20708, Houston, TX 77225. E-mail:aschonb{at}farmr1.med.uth.tmc.edu

  • ↵1 Current affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030.

  • ↵2 Current affiliation: McGill University, Lady Davis Institute, Montreal, Quebec, Canada H3T 1E2.

  • This investigation was supported by the Texas Advanced Technology Program (Grant 1823). B.Y.W. is the recipient of a Pharmaceutical Manufacturers Association Foundation Advanced Predoctoral Fellowship. S.B.D. was supported by a postdoctoral fellowship from the Fonds de la Recherche on Sante du Quebec.

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Molecular Pharmacology: 54 (5)
Molecular Pharmacology
Vol. 54, Issue 5
1 Nov 1998
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Research ArticleArticle

Role of Receptor and Protein Kinase C Activation in the Internalization of the Gastrin-Releasing Peptide Receptor

Barbara Y. Williams, Stéphane B. Dion and Agnes Schonbrunn
Molecular Pharmacology November 1, 1998, 54 (5) 889-898; DOI: https://doi.org/10.1124/mol.54.5.889

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Research ArticleArticle

Role of Receptor and Protein Kinase C Activation in the Internalization of the Gastrin-Releasing Peptide Receptor

Barbara Y. Williams, Stéphane B. Dion and Agnes Schonbrunn
Molecular Pharmacology November 1, 1998, 54 (5) 889-898; DOI: https://doi.org/10.1124/mol.54.5.889
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