Functional consequences of chemically-induced β-arrestin binding to chemokine receptors CXCR4 and CCR5 in the absence of ligand stimulation.
- Resource Type
- Academic Journal
- Authors
- Liebick M; Department of Cellular and Molecular Immunology, University of Göttingen, Göttingen, Niedersachsen, Germany. Electronic address: marcel.liebick@med.uni-goettingen.de.; Henze S; Department of Cellular and Molecular Immunology, University of Göttingen, Göttingen, Niedersachsen, Germany.; Vogt V; Department of Cellular and Molecular Immunology, University of Göttingen, Göttingen, Niedersachsen, Germany.; Oppermann M; Department of Cellular and Molecular Immunology, University of Göttingen, Göttingen, Niedersachsen, Germany.
- Source
- Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 8904683 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-3913 (Electronic) Linking ISSN: 08986568 NLM ISO Abbreviation: Cell Signal Subsets: MEDLINE
- Subject
- Language
- English
Chemokine receptor signaling is a tightly regulated process which was for a long time exclusively attributed to heterotrimeric G proteins. β-Arrestins constitute a separable signaling arm from classical heterotrimeric G proteins, in addition to their well-established roles in receptor desensitization and endocytosis. In order to clearly dissect β-arrestin- from G protein-dependent effects we forced the recruitment of β-arrestin to CXCR4 and CCR5 independently of agonist-promoted receptor activation through chemically-induced dimerization. Targeting β-arrestins to receptors at the plasma membrane prior to chemokine stimulation attenuated G protein-mediated calcium release. Association of β-arrestins to the receptors was sufficient to induce their internalization in the absence of ligand and this effect could be further enhanced by translocation of a constitutively active β-arrestin 1 variant. CXCR4 and CCR5 were targeted to different intracellular compartments upon chemical-induced dimerization with β-arrestins and reproduced the intracellular distribution of receptors after activation with their respective ligands. Our data further provide evidence for direct β-arrestin-mediated signaling via MAP kinases ERK 1/2. These results provide clear evidence that CXCR4- or CCR5-β-arrestin complexes induce receptor endocytosis and signaling in the absence of G protein coupling and ligand-induced conformational changes of the receptor.
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