Regulation of Angiotensin II Type 1A Receptor Intracellular Retention, Degradation, and Recycling by Rab5, Rab7, and Rab11 GTPases

Abstract

Previous studies have demonstrated that the interaction of the angiotensin II type 1A receptor (AT1AR) carboxyl-terminal tail with Rab5a may modulate Rab5a activity, leading to the homotypic fusion of endocytic vesicles. Therefore, we have investigated whether AT1AR/Rab5a interactions mediate the retention of AT1AR·β-arrestin complexes in early endosomes and whether the overexpression of Rab7 and Rab11 GTPases influences AT1AR lysosomal degradation and plasma membrane recycling. We found that internalized AT1AR was retained in Rab5a-positive early endosomes and was neither targeted to lysosomes nor recycled back to the cell surface, whereas a mutant defective in Rab5a binding, AT 1AR-(1-349), was targeted to lysosomes for degradation. However, the loss of Rab5a binding to the AT1AR carboxyl-terminal tail did not promote AT1AR recycling. Rather, it was the stable binding of β-arrestin to the AT1AR that prevented, at least in part, AT1AR recycling. The overexpression of wild-type Rab7 and Rab7-Q67L resulted in both increased AT1AR degradation and AT1AR targeting to lysosomes. The Rab7 expression-dependent transition of "putative" AT1AR·β-arrestin complexes to late endosomes was blocked by the expression of dominant-negative Rab5a-S34N. Rab11 overexpression established AT1AR recycling and promoted the redistribution of AT1AR·β-arrestin complexes from early to recycling endosomes. Taken together, our data suggest that Rab5, Rab7, and Rab11 work in concert with one another to regulate the intracellular trafficking patterns of the AT1AR.