Psychoses et affections nerveuses / par Gilbert Ballet,...

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Evidence for negative binding cooperativity within CCR5-CCR2b heterodimers.

It is well established that most G protein-coupled receptors are able to form homo- and heterodimers, although the functional consequences of this process often remain unclear. CCR5 is a chemokine receptor that plays an important role in inflammatory diseases and acts as a major coreceptor for human immunodeficiency viruses. CCR5 was previously shown to homodimerize and heterodimerize with CCR2b, a closely related receptor. In the present study, we have analyzed the functional consequences of this dimerization process, in terms of ligand binding, stimulation of intracellular cascades, and internalization. Bioluminescence resonance energy transfer and coimmunoprecipitation assays demonstrated that CCR5 and CCR2b heterodimerize with the same efficiency as they homodimerize. In contrast to what has been reported previously, no cooperative signaling was observed after costimulation of the two receptors by their respective ligands. However, we observed that CCR5-specific ligands that are unable to compete for monocyte chemoattractant protein (MCP-1) binding on cells expressing CCR2b alone efficiently prevented MCP-1 binding when CCR5 and CCR2b were coexpressed. The extent of this cross-competition was correlated with the amount of CCR5 expressed in cells, as determined by fluorescence-activated cell sorting analysis. Similar observations were made for the CCR2b-selective ligand MCP-1 that competed efficiently for macrophage inflammatory protein-1beta binding on cells expressing both receptors. Internalization assays did not allow us to demonstrate cointernalization of the receptors in response to agonist stimulation. Together, our observations suggest that CCR5 and CCR2b form homo- and heterodimers with similar efficiencies and that a receptor dimer can only bind a single chemokine.Comparative StudyJournal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

L'expertise médico-légale et la question de responsabilité /

Congrès des médecins aliénistes et neurologistes de France et des pays de langue française - XVIIe session, Genève-Lausanne, août 1907. Médicine légal

Mutation of the DRY motif reveals different structural requirements for the CC chemokine receptor 5-mediated signaling and receptor endocytosis.

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 beta-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 beta-arrestin-dependent endocytosis but also displayed a higher basal phosphorylation than wild-type CCR5. Expression of beta-arrestin in R126N-CCR5-expressing cells resulted in receptor down-regulation, thereby suggesting that R126N-CCR5 spontaneously interacts with beta-arrestins. However, although expression of beta-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 beta-arrestin-mediated chemotaxis. These results have implications for how distinct biological responses of CCR5 might rely on a different set of receptor conformations.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

The Infantilization of the Colonized: Medical and Psychiatric Descriptions of Drinking Habits in the Colonial Maghreb

French doctors and psychiatrists traveling through or working in the colonial Maghreb during the nineteenth and twentieth centuries commonly reported in their publications that the colonized they encountered reminded them of children. They also described practically every aspect of the behavior of the colonized as childlike in some respect. While this equation of the colonized with children was by no means restricted to the medico-psychiatric source material and can be found in a variety of different colonial publications, this chapter will focus on publications by doctors and psychiatrists, as their status as widely accepted experts and as alleged pillars of science and modernity made their statements, in the eyes of their French readership, more authoritative than those of other authors. Though this is usually not stated explicitly, the children imagined in these comparisons were presumably European, which accords with a long tradition of European medical and psychiatric experts comparing the colonized to an imaginary European normality. Yet comparisons of the colonized with children in the publications of French doctors and psychiatrists were more than just colorful and anecdotal descriptions of life in the colonies; they were part of an implicit, ongoing process of diagnosing the behavior of the colonized as intrinsically different from French behavior. These comparisons implicitly suggested that colonized adults and European children were roughly on the same developmental level, and concluded that both groups had a similar relationship to French adults: that is, receiving education from them, following their lead, and letting them make important decisions on their behalf. The framing of the colonized as children highlights the colonial understanding of there being a clear power imbalance in the colonies—with France as the undisputed paterfamilias, so to speak, and with the colonized unable to reach French levels of reason and modernity on their own

The TXP motif in the second transmembrane helix of CCR5. A structural determinant of chemokine-induced activation.

CCR5 is a G-protein-coupled receptor activated by the chemokines RANTES (regulated on activation normal T cell expressed and secreted), macrophage inflammatory protein 1alpha and 1beta, and monocyte chemotactic protein 2 and is the main co-receptor for the macrophage-tropic human immunodeficiency virus strains. We have identified a sequence motif (TXP) in the second transmembrane helix of chemokine receptors and investigated its role by theoretical and experimental approaches. Molecular dynamics simulations of model alpha-helices in a nonpolar environment were used to show that a TXP motif strongly bends these helices, due to the coordinated action of the proline, which kinks the helix, and of the threonine, which further accentuates this structural deformation. Site-directed mutagenesis of the corresponding Pro and Thr residues in CCR5 allowed us to probe the consequences of these structural findings in the context of the whole receptor. The P84A mutation leads to a decreased binding affinity for chemokines and nearly abolishes the functional response of the receptor. In contrast, mutation of Thr-82(2.56) into Val, Ala, Cys, or Ser does not affect chemokine binding. However, the functional response was found to depend strongly on the nature of the substituted side chain. The rank order of impairment of receptor activation is P84A > T82V > T82A > T82C > T82S. This ranking of impairment parallels the bending of the alpha-helix observed in the molecular simulation study.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe