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Molecular Pharmacology

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Research ArticleArticle

Histamine H2 Receptor Trafficking: Role of Arrestin, Dynamin, and Clathrin in Histamine H2 Receptor Internalization

Natalia Fernandez, Federico Monczor, Alberto Baldi, Carlos Davio and Carina Shayo
Molecular Pharmacology October 2008, 74 (4) 1109-1118; DOI: https://doi.org/10.1124/mol.108.045336
Natalia Fernandez
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Federico Monczor
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Alberto Baldi
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Carlos Davio
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Carina Shayo
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Abstract

Agonist-induced internalization of G protein-coupled receptors (GPCRs) has been implicated in receptor desensitization, resensitization, and down-regulation. In the present study, we sought to establish whether the histamine H2 receptor (H2r) agonist amthamine, besides promoting receptor desensitization, induced H2r internalization. We further studied the mechanisms involved and its potential role in receptor resensitization. In COS7 transfected cells, amthamine induced H2r time-dependent internalization, showing 70% of receptor endocytosis after 60-min exposure to amthamine. Agonist removal led to the rapid recovery of resensitized receptors to the cell surface. Similar results were obtained in the presence of cycloheximide, an inhibitor of protein synthesis. Treatment with okadaic acid, an inhibitor of the protein phosphatase 2A (PP2A) family of phosphatases, reduced the recovery of both H2r membrane sites and cAMP response. Arrestin 3 but not arrestin 2 overexpression reduced both H2r membrane sites and H2r-evoked cAMP response. Receptor cotransfection with dominant-negative mutants for arrestin, dynamin, Eps15 (a component of the clathrin-mediated endocytosis machinery), or RNA interference against arrestin 3 abolished both H2r internalization and resensitization. Similar results were obtained in U937 cells endogenously expressing H2r. Our findings suggest that amthamine-induced H2r internalization is crucial for H2r resensitization, processes independent of H2r de novo synthesis but dependent on PP2A-mediated dephosphorylation. Although we do not provide direct evidence for H2r interaction with β-arrestin, dynamin, and/or clathrin, our results support their involvement in H2r endocytosis. The rapid receptor recycling to the cell surface and the specific involvement of arrestin 3 in receptor internalization further suggest that the H2r belongs to class A GPCRs.

Footnotes

  • This study was supported by grants from the Universidad de Buenos Aires (UBACyT B050) and the Agencia Nacional de Promoción Científica y Tecnológica (PICT 12164 and PICT 38318) and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) (PIP 6110). This work was made possible by CONICET fellowships.

  • ABBREVIATIONS: GPCR, G protein-coupled receptor; GRK, G protein-coupled receptor kinase; H2r, histamine H2 receptor; IBMX, isobutylmethylxanthine; amthamine, 2-amino-4-methylthiazole-5-ethanamine; RNAi, RNA interference; EGFP, enhanced green fluorescent protein; AP-2, activator protein 2.

    • Received January 14, 2008.
    • Accepted July 10, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 74 (4)
Molecular Pharmacology
Vol. 74, Issue 4
1 Oct 2008
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Research ArticleArticle

Histamine H2 Receptor Trafficking: Role of Arrestin, Dynamin, and Clathrin in Histamine H2 Receptor Internalization

Natalia Fernandez, Federico Monczor, Alberto Baldi, Carlos Davio and Carina Shayo
Molecular Pharmacology October 1, 2008, 74 (4) 1109-1118; DOI: https://doi.org/10.1124/mol.108.045336

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Research ArticleArticle

Histamine H2 Receptor Trafficking: Role of Arrestin, Dynamin, and Clathrin in Histamine H2 Receptor Internalization

Natalia Fernandez, Federico Monczor, Alberto Baldi, Carlos Davio and Carina Shayo
Molecular Pharmacology October 1, 2008, 74 (4) 1109-1118; DOI: https://doi.org/10.1124/mol.108.045336
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