Heterodimerization of V1a and V2 vasopressin receptors determines the interaction with beta-arrestin and their trafficking patterns.
V1a vasopressin receptor (V1aR) and V2 vasopressin receptor (V2R) present distinct mechanisms of agonist-promoted trafficking. Although both receptors are endocytosed by way of beta-arrestin-dependent processes, beta-arrestin dissociates rapidly from V1aR, allowing its rapid recycling to the plasma membrane while beta-arrestin remains associated with V2R in the endosomes, leading to their intracellular accumulation. Here, we demonstrate that, when coexpressed, the two receptors can be endocytosed as stable heterodimers. On activation with a nonselective agonist, both receptors cotrafficked with beta-arrestin in endosomes where the stable interaction inhibited the recycling of V1aR to the plasma membrane, thus conferring a V2R-like endocytotic/recycling pattern to the V1aR/V2R heterodimer. Coexpression of the constitutively internalized R137HV2R mutant with V1aR was sufficient to promote cointernalization of V1aR in beta-arrestin-positive vesicles even in the absence of agonist stimulation. This finding indicates that internalization of the heterodimer does not require activation of each of the protomers. Consistent with this notion, a V1aR-selective agonist led to the coendocytosis of V2R. In that case, however, the V1aR/V2R heterodimer was not stably associated with beta-arrestin, and both receptors were recycled back to the cell surface, indicating that the complex followed the V1aR endocytotic/recycling path. Taken together, these results suggest that heterodimerization regulates the endocytotic processing of G protein-coupled receptors and that the identity of the activated protomer within the heterodimer determines the fate of the internalized receptors.
Terrillon
Sonia
S
Département de Biochimie, Université de Montréal, Montréal, Quebec, Canada H3C 3J7.
Barberis
Claude
C
Bouvier
Michel
M
D019390:Arrestins / Q000378:metabolism*; D002460:Cell Line; D019281:Dimerization; D004705:Endocytosis; D006801:Humans; D008856:Microscopy, Fluorescence; D021381:Protein Transport; D017483:Receptors, Vasopressin / Q000378:metabolism*; D000071557:beta-Arrestins
D019390:Arrestins; D017483:Receptors, Vasopressin; D000071557:beta-Arrestins