title: Regulation of anterograde transport of adrenergic and angiotensin II receptors by Rab2 and Rab6 GTPases.
abstract: 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.
authors: Department of Pharmacology and Experimental Therapeutics, Louisiana State University, Health Sciences Center, New Orleans, LA 70112, USA.
authors: Chunmin
authors: C
authors: Dong
authors: Guangyu
authors: G
authors: Wu
mesh_terms: D000818:Animals; D002460:Cell Line; D005799:Genes, Dominant; D005973:Glutamine / Q000235:genetics; D006801:Humans; D008239:Lysine / Q000235:genetics; D050505:Mutant Proteins / Q000378:metabolism; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D020693:rab2 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D034741:RNA, Small Interfering; C094135:Rab6 protein; D044140:Receptor, Angiotensin, Type 1; D018341:Receptors, Adrenergic, alpha-2; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D005973:Glutamine; D020691:rab GTP-Binding Proteins; D020693:rab2 GTP-Binding Protein; D008239:Lysine
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