The DRY
motif is a triplet a
mino acid sequence (aspartic acid, arginine, and tyrosine) that ishighly conserved in G protein-coupled receptors (GPCRs). Recently, we have shown that a
moleculardeter
minant for nephrogenic diabetes insipidus, the vasopressin receptor with a substitution at the DRY
motif arginine (V2R R137H), is a constitutively desensitized receptor that is unable to couple to G proteinsdue to its constitutive association with
![](/i<font color=)
mages/gifchars/beta2.gif" BORDER=0 ALIGN="
middle">-arrestin [Barak, L. S. (2001)
Proc. Natl. Acad. Sci. U.S.A. 98,93-98]. Additionally, the
mutant receptors are localized in endocytic vesicles, identical to wild-typereceptors sti
mulated with agonist. In this study, we asked whether the constitutively desensitized phenotypeobserved in the V2R R137H represents a general paradig
m that
may be extended to other GPCRs. Weshow that arginine substitutions in the DRY
motifs of the
![](/i<font color=)
mages/gifchars/alpha.gif" BORDER=0>
1B adrenergic receptor (
![](/i<font color=)
mages/gifchars/alpha.gif" BORDER=0>
1B-AR) and angiotensinII type 1A receptor (AT
1AR) result in receptors that are uncoupled fro
m G proteins, associated with
![](/i<font color=)
mages/gifchars/beta2.gif" BORDER=0 ALIGN="
middle">-arrestins, and found localized in endocytic vesicles rather than at the plas
ma
me
mbrane in the absenceof agonists. The localization of the
![](/i<font color=)
mages/gifchars/alpha.gif" BORDER=0>
1B-ARs and AT
1ARs with arginine substitutions can be restored tothe plas
ma
me
mbrane by either using selective antagonists or preventing the endocytosis of the
![](/i<font color=)
mages/gifchars/beta2.gif" BORDER=0 ALIGN="
middle">-arrestin-receptor co
mplexes. These results indicate that the arginine residue of the DRY
motif is essential forpreserving the localization of the inactive receptor co
mplex. Further
more, constitutive desensitization
may underlie so
me loss-of-function receptor phenotypes and represent an unappreciated
mechanis
m ofhor
monal resistance.