TY - JOUR T1 - Rab GTPases Bind at a Common Site within the Angiotensin II Type I Receptor Carboxyl-Terminal Tail: Evidence that Rab4 Regulates Receptor Phosphorylation, Desensitization, and Resensitization JF - Molecular Pharmacology JO - Mol Pharmacol SP - 175 LP - 184 DO - 10.1124/mol.110.068379 VL - 79 IS - 1 AU - Jessica L. Esseltine AU - Lianne B. Dale AU - Stephen S. G. Ferguson Y1 - 2011/01/01 UR - http://molpharm.aspetjournals.org/content/79/1/175.abstract N2 - The human angiotensin II type 1 receptor (AT1R) is a member of the G protein-coupled receptor (GPCR) superfamily and represents an important target for cardiovascular therapeutic intervention. Agonist-activation of the AT1R induces β-arrestin-dependent endocytosis to early endosomes in which the receptor resides as a protein complex with the Rab GTPase Rab5. In the present study, we examined whether other Rab GTPases that regulate receptor trafficking through endosomal compartments also bind to the AT1R. We find that Rab4, Rab7, and Rab11 all bind to the last 10 amino acid residues of the AT1R carboxyl-terminal tail. Rab11 binds AT1R more effectively than Rab5, whereas Rab4 binds less effectively than Rab5. Alanine scanning mutagenesis reveals that proline 354 and cysteine 355 contribute to Rab protein binding, and mutation of these residues does not affect G protein coupling. We find that the Rab GTPases each compete with one another for receptor binding and that although Rab4 interacts poorly with the AT1R, it effectively displaces Rab11 from the receptor. In contrast, Rab11 overexpression does not prevent Rab4 binding to the AT1R. Overexpression of wild-type Rab4, but not Rab11, facilitates AT1R dephosphorylation, and a constitutively active Rab4-Q67L mutant reduces AT1R desensitization and promotes AT1R resensitization. Taken together, our data indicate that multiple Rab GTPases bind to a motif localized to the distal end of the AT1R tail and that increased Rab4 activity may contribute to the regulation AT1R desensitization and dephosphorylation. ER -