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Apparent Loss-of-Function Mutant GPCRs Revealed as Constitutively Desensitized Receptors

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Howard Hughes Medical Institute Laboratories and Departments of Cell Biology and Medicine, Duke University Medical Center, Durham, North Carolina 27710
Cite this: Biochemistry 2002, 41, 40, 11981–11989
Publication Date (Web):September 11, 2002
https://doi.org/10.1021/bi020275m
Copyright © 2002 American Chemical Society

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    Abstract

    The DRY motif is a triplet amino acid sequence (aspartic acid, arginine, and tyrosine) that is highly conserved in G protein-coupled receptors (GPCRs). Recently, we have shown that a molecular determinant 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 proteins due to its constitutive association with β-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-type receptors stimulated with agonist. In this study, we asked whether the constitutively desensitized phenotype observed in the V2R R137H represents a general paradigm that may be extended to other GPCRs. We show that arginine substitutions in the DRY motifs of the α1B adrenergic receptor (α1B-AR) and angiotensin II type 1A receptor (AT1AR) result in receptors that are uncoupled from G proteins, associated with β-arrestins, and found localized in endocytic vesicles rather than at the plasma membrane in the absence of agonists. The localization of the α1B-ARs and AT1ARs with arginine substitutions can be restored to the plasma membrane by either using selective antagonists or preventing the endocytosis of the β-arrestin−receptor complexes. These results indicate that the arginine residue of the DRY motif is essential for preserving the localization of the inactive receptor complex. Furthermore, constitutive desensitization may underlie some loss-of-function receptor phenotypes and represent an unappreciated mechanism of hormonal resistance.

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     This work was supported by National Institutes of Health Grants HL61365 (to L.S.B.), DA14600 (to L.M.B.), and NS19576 (to M.G.C.). S.A.L. is a Research Fellow from the Canadian Institutes of Health Research. M.G.C. is an investigator at the Howard Hughes Medical Institute.

    *

     To whom correspondence should be addressed:  Howard Hughes Medical Institute Laboratories and Departments of Cell Biology and Medicine, Duke University Medical Center, Box 3287, Durham, NC 27710. E-mail:  [email protected].

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