TY - JOUR
T1 - Regulation of anterograde transport of adrenergic and angiotensin II receptors by Rab2 and Rab6 GTPases
AU - Dong, Chunmin
AU - Wu, Guangyu
N1 - Funding Information:
This work was supported by the National Institutes of Health Grant GM076167 (to G.W.) and the American Heart Association, Southeast Affiliate Postdoctoral Fellowship (to C.D.). We thank Dr. Catalin M. Filipeanu for measuring cAMP accumulation and Fuguo Zhou for superb technical assistance. We are grateful to Drs. Stephen M. Lanier, John D. Hildebrandt and Kenneth E. Bernstein for plasmids.
PY - 2007/11
Y1 - 2007/11
N2 - 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 α2B-adrenergic (α2B-AR), β2-AR and angiotensin II type 1 receptors (AT1R). Expression of the GTP-bound mutant Rab2Q65L significantly attenuated the cell-surface expression of both α2B-AR and β2-AR, whereas the GTP-bound mutant Rab6Q72L selectively inhibited the transport of β2-AR, but not α2B-AR. Similar results were obtained by siRNA-mediated selective knockdown of endogenous Rab2 and Rab6. Consistently, Rab2Q65L and Rab2 siRNA inhibited α2B-AR and β2-AR signaling measured as ERK1/2 activation and cAMP production, respectively, whereas Rab6Q72L and Rab6 siRNA reduced signaling of β2-AR, but not α2B-AR. Similar to the β2-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 β2-AR and AT1R, but not α2B-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.
AB - 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 α2B-adrenergic (α2B-AR), β2-AR and angiotensin II type 1 receptors (AT1R). Expression of the GTP-bound mutant Rab2Q65L significantly attenuated the cell-surface expression of both α2B-AR and β2-AR, whereas the GTP-bound mutant Rab6Q72L selectively inhibited the transport of β2-AR, but not α2B-AR. Similar results were obtained by siRNA-mediated selective knockdown of endogenous Rab2 and Rab6. Consistently, Rab2Q65L and Rab2 siRNA inhibited α2B-AR and β2-AR signaling measured as ERK1/2 activation and cAMP production, respectively, whereas Rab6Q72L and Rab6 siRNA reduced signaling of β2-AR, but not α2B-AR. Similar to the β2-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 β2-AR and AT1R, but not α2B-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.
KW - Adrenergic receptor
KW - Angiotensin II receptor
KW - Export
KW - G protein-coupled receptor
KW - Intracellular trafficking
KW - Rab2
KW - Rab6
KW - Signaling
UR - http://www.scopus.com/inward/record.url?scp=34548426859&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34548426859&partnerID=8YFLogxK
U2 - 10.1016/j.cellsig.2007.07.017
DO - 10.1016/j.cellsig.2007.07.017
M3 - Article
C2 - 17716866
AN - SCOPUS:34548426859
SN - 0898-6568
VL - 19
SP - 2388
EP - 2399
JO - Cellular Signalling
JF - Cellular Signalling
IS - 11
ER -