Regulation of anterograde transport of adrenergic and angiotensin II receptors by Rab2 and Rab6 GTPases

Cell Signal. 2007 Nov;19(11):2388-99. doi: 10.1016/j.cellsig.2007.07.017. Epub 2007 Aug 1.


Three Rab GTPases, Rab1, Rab2 and Rab6, are involved in protein transport between the endoplasmic reticulum (ER) and the Golgi. Whereas Rab1 regulates the anterograde ER-to-Golgi transport, Rab2 and Rab6 coordinate the retrograde Golgi-to-ER transport. We have previously demonstrated that Rab1 differentially modulates the export trafficking of distinct G protein-coupled receptors (GPCRs). In this report, we determined the role of Rab2 and Rab6 in the cell-surface expression and signaling of alpha(2B)-adrenergic (alpha(2B)-AR), beta(2)-AR and angiotensin II type 1 receptors (AT1R). Expression of the GTP-bound mutant Rab2Q65L significantly attenuated the cell-surface expression of both alpha(2B)-AR and beta(2)-AR, whereas the GTP-bound mutant Rab6Q72L selectively inhibited the transport of beta(2)-AR, but not alpha(2B)-AR. Similar results were obtained by siRNA-mediated selective knockdown of endogenous Rab2 and Rab6. Consistently, Rab2Q65L and Rab2 siRNA inhibited alpha(2B)-AR and beta(2)-AR signaling measured as ERK1/2 activation and cAMP production, respectively, whereas Rab6Q72L and Rab6 siRNA reduced signaling of beta(2)-AR, but not alpha(2B)-AR. Similar to the beta(2)-AR, AT1R expression at the cell surface and AT1R-promoted inositol phosphate accumulation were inhibited by Rab6Q72L. Furthermore, the nucleotide-free mutant Rab6N126I selectively attenuated the cell-surface expression of beta(2)-AR and AT1R, but not alpha(2B)-AR. These data demonstrate that Rab2 and Rab6 differentially influence anterograde transport and signaling of GPCRs. These data also provide the first evidence indicating that Rab6-coordinated retrograde transport selectively modulates intracellular trafficking and signaling of GPCRs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Genes, Dominant
  • Glutamine / genetics
  • Humans
  • Lysine / genetics
  • Mutant Proteins / metabolism
  • Protein Transport
  • RNA, Small Interfering / metabolism
  • Rats
  • Receptor, Angiotensin, Type 1 / metabolism
  • Receptors, Adrenergic, alpha-2 / metabolism
  • Receptors, Adrenergic, beta-2 / metabolism
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction
  • Subcellular Fractions / metabolism
  • rab GTP-Binding Proteins / metabolism*
  • rab2 GTP-Binding Protein / metabolism*


  • Mutant Proteins
  • RNA, Small Interfering
  • Rab6 protein
  • Receptor, Angiotensin, Type 1
  • Receptors, Adrenergic, alpha-2
  • Receptors, Adrenergic, beta-2
  • Receptors, G-Protein-Coupled
  • Glutamine
  • rab GTP-Binding Proteins
  • rab2 GTP-Binding Protein
  • Lysine