ADP-ribosylation factors modulate the cell surface transport of G protein-coupled receptors

Chunmin Dong, Xiaoping Zhang, Fuguo Zhou, Huijuan Dou, Matthew T. Duvernay, Ping Zhang, Guangyu Wu

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

ADP-ribosylation factors (ARFs) regulate vesicular traffic through recruiting coat proteins. However, their functions in the anterograde transport of nascent G protein-coupled receptors (GPCRs) from the endoplasmic reticulum to the plasma membrane remain poorly explored. Here we show that treatment with brefeldin A, an inhibitor of guanine nucleotide exchange on ARFs, markedly attenuated the cell surface numbers of α2B-adrenergic receptor (AR), β2-AR, angiotensin II type 1 receptor, and chemokine (CXC motif) receptor 4. Functional inhibition of individual ARF GTPases by transient expression of the GDP-bound, GTP-bound, and guanine nucleotide-deficient mutants showed that the five human ARFs differentially modulated receptor cell surface expression and that the ARF1 mutants produced the most profound inhibitory effect. Furthermore, expression of the ARF1 GTPase-activating protein (GAP) ARFGAP1 significantly blocked receptor transport. Interestingly, the GDP- and GTP-bound ARF1 mutants arrested the receptors in distinct intracellular compartments. Consistent with the reduced receptor cell surface expression, extracellular signal-regulated kinase 1 and 2 activation by receptor agonists was significantly attenuated by the GDP-bound mutant ARF1T31N. Moreover, coimmunoprecipitation showed that α2B-AR associated with ARF1 and glutathione transferase pull-down assay indicated that the α2B-AR C terminus directly interacted with ARF1. These data show that ARF1 GTPase is involved in the regulation of cell surface expression of GPCRs at multiple transport steps.

Original languageEnglish (US)
Pages (from-to)174-183
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume333
Issue number1
DOIs
StatePublished - Apr 2010
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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