Rab1 GTPase and Dimerization in the Cell Surface Expression of Angiotensin II Type 2 Receptor
- 8 April 2009
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Journal of Pharmacology and Experimental Therapeutics
- Vol. 330 (1), 109-117
- https://doi.org/10.1124/jpet.109.153460
Abstract
The physiological function of angiotensin II (Ang II) is mediated through the Ang II type 1 (AT1R) and type 2 (AT2R) receptors. Our previous studies have demonstrated that cell surface targeting of AT1R is regulated by Rab and Sar1 GTPases and the F(x)6LL motif in the membrane-proximal C terminus. However, the molecular mechanisms underlying the export of nascent AT2R remain poorly defined. In this report, we determined the role of Rab1 GTPase, which specifically controls protein transport from the endoplasmic reticulum (ER) to the Golgi, and receptor dimerization in the biosynthesis of AT2R. Cell surface expression of AT2R was augmented by transient expression of Rab1 and attenuated by dominant-negative Rab1 mutants and small interfering RNA-mediated knockdown of Rab1. Consistently, AT2R inhibition of epidermal growth factor-activated extracellular signal-regulated kinase 1/2 was significantly reduced by the Rab1 mutants, indicating that endogenous Rab1 modulates the cell surface targeting and signaling of AT2R. It is of interest to note that Rab1 augmented the overall expression of AT2R and its mRNA, whereas the Rab1 mutants attenuated the total AT2R expression and enhanced ubiquitin-dependent AT2R degradation. Furthermore, our previously characterized ER export-deficient AT1R mutant in which the F(x)6LL motif was mutated formed both homodimers and heterodimers with AT2R. Dimerization of the AT1R mutant with AT2R blocked AT2R trafficking to the cell surface, suggesting constitutive dimerization of both receptors in the ER and an important role of dimerization in ER export of the receptors. These data demonstrate for the first time that Rab1 GTPase and dimerization modulate export traffic from the ER to the cell surface of newly synthesized AT2R.Keywords
This publication has 41 references indexed in Scilit:
- A Single Conserved Leucine Residue on the First Intracellular Loop Regulates ER Export of G Protein‐Coupled ReceptorsTraffic, 2009
- Endoplasmic reticulum export of adrenergic and angiotensin II receptors is differentially regulated by Sar1 GTPaseCellular Signalling, 2008
- Regulation of anterograde transport of adrenergic and angiotensin II receptors by Rab2 and Rab6 GTPasesCellular Signalling, 2007
- Regulation of G protein-coupled receptor export traffickingBiochimica et Biophysica Acta (BBA) - Biomembranes, 2006
- Molecular Mechanism Underlying Inverse Agonist of Angiotensin II Type 1 ReceptorJournal of Biological Chemistry, 2006
- Cell-surface targeting of α2-adrenergic receptors — Inhibition by a transport deficient mutant through dimerizationCellular Signalling, 2006
- Golgi Inheritance in Mammalian Cells Is Mediated through Endoplasmic Reticulum Export ActivitiesMolecular Biology of the Cell, 2006
- Reconstitution of Coat Protein Complex II (COPII) Vesicle Formation from Cargo-reconstituted Proteoliposomes Reveals the Potential Role of GTP Hydrolysis by Sar1p in Protein SortingJournal of Biological Chemistry, 2004
- Rab1a and Multiple Other Rab Proteins Are Associated with the Transcytotic Pathway in Rat LiverPublished by Elsevier BV ,1996
- The AT2 Receptor Selectively Associates with Giα2 and Giα3 in the Rat FetusJournal of Biological Chemistry, 1996