Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2
Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2
复制标题
DOI：
10.1073/pnas.95.6.2985
复制
发表时间：
1998-03-17
影响因子：
11.1
通讯作者：
Mayor, F
中科院分区：
文献类型：
--
作者：
Aragay, AM;Mellado, M;Mayor, F
单核细胞趋化蛋白1 （MCP-1）是趋化因子细胞因子家族的一员，其生理功能通过与G蛋白偶联受体家族成员CCR2和CCR4受体结合介导。MCP-1在白细胞的激活和迁移中起关键作用。快速的趋化因子受体脱敏很可能是准确趋化的必要条件。在本报告中，我们发现MCP-1与单核细胞CCR2受体的结合促进了MCP-1诱导的钙通量反应的快速脱敏。这种脱敏与受体的丝氨酸/苏氨酸磷酸化以及G蛋白偶联受体激酶2 （GRK2，也称为β -肾上腺素能激酶1或β - ARK1）在膜上的瞬时易位有关。我们还证明GRK2和解偶联蛋白β -抑制素与受体结合，在MCP-1结合后不久形成大分子复合物。在表达CCR2B受体的HEK293细胞中，与GRK2或同源激酶GRK3共转染后，钙通量对MCP-1的反应也显著降低。然而，GRK2显性阴性突变体β ARK-K220R的表达并不影响初始钙反应，但有利于受体对随后激动剂的反应。GRK2对CCR2B受体的调节表明该激酶在单核细胞和淋巴细胞对趋化因子的反应调节中起重要作用。
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 beta ARK1) 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 beta 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.