Esseltine JL, Dale LB, Ferguson SS

The human angiotensin II type 1 receptor (AT?R) is a member of the G protein-coupled receptor (GPCR) superfamily and represents an important target for cardiovascular therapeutic intervention. Agonist-activation of the AT?R induces ?-arrestin-dependent endocytosis to early endosomes in which the receptor resides as a protein complex with the Rab GTPase ...

Read More

Rab5. In the present study, we examined whether other Rab GTPases that regulate receptor trafficking through endosomal compartments also bind to the AT?R. We find that Rab4, Rab7, and Rab11 all bind to the last 10 amino acid residues of the AT?R carboxyl-terminal tail. Rab11 binds AT?R 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 AT?R, it effectively displaces Rab11 from the receptor. In contrast, Rab11 overexpression does not prevent Rab4 binding to the AT?R. Overexpression of wild-type Rab4, but not Rab11, facilitates AT?R dephosphorylation, and a constitutively active Rab4-Q67L mutant reduces AT?R desensitization and promotes AT?R resensitization. Taken together, our data indicate that multiple Rab GTPases bind to a motif localized to the distal end of the AT?R tail and that increased Rab4 activity may contribute to the regulation AT?R desensitization and dephosphorylation.

Date: Jan. 01, 2011

View in: Pubmed Google Scholar

239751