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Monocyte Chemoattractant Protein-1-Induced CCR2B Receptor Desensitization Mediated by the G Protein-Coupled Receptor Kinase 2

Monocyte chemoattractant protein 1 (MCP-1) is a member of the chemokine cytokine family, whose physiological function is mediated by binding to the CCR2 and CCR4 receptors, which are members of the G protein-coupled receptor family. MCP-1 plays a critical role in both activation and migration of leu...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1998-03, Vol.95 (6), p.2985-2990
Main Authors: Aragay, A. M., Mellado, M., Frade, J. M. R., Martin, A. M., Jimenez-Sainz, M. C., C. Martinez-A, Mayor, F.
Format: Article
Language:English
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Summary:Monocyte chemoattractant protein 1 (MCP-1) is a member of the chemokine cytokine family, whose physiological function is mediated by binding to the CCR2 and CCR4 receptors, which are members of the G protein-coupled receptor family. MCP-1 plays a critical role in both activation and migration of leukocytes. Rapid chemokine receptor desensitization is very likely essential for accurate chemotaxis. In this report, we show that MCP-1 binding to the CCR2 receptor in Mono Mac 1 cells promotes the rapid desensitization of MCP-1-induced calcium flux responses. This desensitization correlates with the Ser/Thr phosphorylation of the receptor and with the transient translocation of the G protein-coupled receptor kinase 2 (GRK2, also called β -adrenergic kinase 1 or β ARK1) to the membrane. We also demonstrate that GRK2 and the uncoupling protein β -arrestin associate with the receptor, forming a macromolecular complex shortly after MCP-1 binding. Calcium flux responses to MCP-1 in HEK293 cells expressing the CCR2B receptor were also markedly reduced upon cotransfection with GRK2 or the homologous kinase GRK3. Nevertheless, expression of the GRK2 dominant-negative mutant β ARK-K220R did not affect the initial calcium response, but favored receptor response to a subsequent challenge by agonists. The modulation of the CCR2B receptor by GRK2 suggests an important role for this kinase in the regulation of monocyte and lymphocyte response to chemokines.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.95.6.2985