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      Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2.

      Proceedings of the National Academy of Sciences of the United States of America

      beta-Adrenergic Receptor Kinases, Arrestin, metabolism, Recombinant Proteins, Receptors, Cytokine, Receptors, Chemokine, Receptors, CCR2, genetics, Receptor Protein-Tyrosine Kinases, Protein-Serine-Threonine Kinases, Protein Binding, Phosphorylation, drug effects, Monocytes, Humans, G-Protein-Coupled Receptor Kinase 3, Cyclic AMP-Dependent Protein Kinases, pharmacology, Chemokine CCL2, Cell Compartmentation, Calcium, Biological Transport

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          Abstract

          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 beta-adrenergic kinase 1 or betaARK1) to the membrane. We also demonstrate that GRK2 and the uncoupling protein beta-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 betaARK-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.

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          Author and article information

          Journal
          19681
          9501202

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