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Unité d'Immunologie Virale, Institut Pasteur, Paris, France (B.L., T.P., K.B., Y.P., I.S., F.B.); Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (S.B., C.B., G.V., M.P.), Service de Génétique Médicale (G.V.), Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium; Euroscreen, Gosselies, Belgium (E.L.P.); and Department of Immunology, Georg-August-University, Göttingen, Germany (M.O.)
CC chemokine receptor 5 (CCR5) is a G protein-coupled receptor that governs migration of leukocytes and serves as a coreceptor for the R5 tropic strains of human immunodeficiency virus (HIV). CCR5-mediated signaling in response to CC chemokines relies on G protein activation. Desensitization, which rapidly turns off G protein-dependent signaling, involves phosphorylation of CCR5 that promotes interaction of the receptor with 
-arrestins for endocytosis. Whether coupling to G proteins, desensitization, and endocytosis of CCR5 require the same structural determinants remains a matter of investigation. Here, we show that CCR5 displayed agonist-independent coupling to G proteins. This constitutive activity of the receptor was abrogated by TAK779 (N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride), a nonpeptidic CCR5 ligand that inhibits HIV infection and was found to depend on the integrity of the Asp-Arg-Tyr (DRY) motif. Changing Arg-126 by the neutral residue Asn (R126N-CCR5 mutant) abolished CCR5-mediated activation of G proteins, either constitutively or in response to agonists. In contrast, R126N-CCR5 not only retained agonist-promoted phosphorylation and -arrestin-dependent endocytosis but also displayed a higher basal phosphorylation than wild-type CCR5. Expression of -arrestin in R126N-CCR5-expressing cells resulted in receptor down-regulation, thereby suggesting that R126N-CCR5 spontaneously interacts with -arrestins. However, although expression of -arrestin favored wild-type CCR5-mediated chemotaxis, it failed to promote migration of cells expressing R126N-CCR5. Overall, these data indicate that structural requirements for CCR5-mediated activation of G proteins, albeit not involved in receptor desensitization and internalization, are needed for -arrestin-mediated chemotaxis. These results have implications for how distinct biological responses of CCR5 might rely on a different set of receptor conformations.
Received for publication November 26, 2004.
Accepted for publication March 10, 2005.
Address correspondence to: Dr. Françoise Bachelerie, Institut Pasteur, Unité d'Immunologie Virale, 28 rue du Dr Roux, 75015 Paris, France. E-mail: fbachele{at}pasteur.fr.
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