The chemokine receptors CXCR1 and CXCR2 couple to distinct G protein-coupled receptor kinases to mediate and regulate leukocyte functions.
The chemokine receptors CXCR1 and CXCR2 couple to distinct G protein-coupled receptor kinases to mediate and regulate leukocyte functions.
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DOI：
10.4049/jimmunol.1201114
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发表时间：
2012-09-15
期刊：
影响因子：
--
通讯作者：
Richardson RM
中科院分区：
文献类型：
--
作者：
Raghuwanshi SK;Su Y;Singh V;Haynes K;Richmond A;Richardson RM
趋化因子受体CXCR 1和CXCR 2与Gαi偶联，诱导炎症部位的白细胞募集和活化。在被CXCL 8激活后，这些受体变得磷酸化、脱敏和内化。在这项研究中，我们研究了不同的G蛋白偶联受体激酶（GRKs）在CXCR 1和CXCR 2介导的细胞功能中的作用。为此，在稳定表达CXCR 1或CXCR 2的RBL-2 H3细胞中，使用shRNA抑制GRK 2、3、5和6，并评估CXCL 8介导的受体活化和调节。GRK 2和GRK 6的抑制分别增加了CXCR 1和CXCR 2对磷酸化、脱敏和内化的抗性，并增强了体外CXCL 8诱导的磷酸肌醇水解和胞吐作用。GRK 2耗竭减少CXCR 1诱导的ERK 1/2磷酸化，但对CXCR 2诱导的ERK 1/2磷酸化没有影响。GRK 6缺失对CXCR 1功能没有显著影响。然而，来自GRK 6缺陷小鼠（GRK 6-/-）的腹膜中性粒细胞显示CXCR 2介导的G蛋白活化增加，但在体外表现出相对于野生型（GRK 6 +/+）细胞的趋化性，受体脱敏和内化减少。相比之下，GRK 6 −/−小鼠体内的中性粒细胞募集增加，以响应通过气囊模型递送CXCL 1。在伤口闭合试验中，与GRK 6 +/+动物相比，GRK 6-/-小鼠显示出增强的髓过氧化物酶活性，表明增强的中性粒细胞募集和更快的伤口闭合。综上所述，结果表明CXCR 1和CXCR 2与不同的GRK同种型偶联以介导和调节炎症反应。CXCR 1主要与GRK 2偶联，而CXCR 2与GRK 6相互作用以负调节受体敏化和运输，从而影响细胞信号传导和血管生成。
The chemokine receptors, CXCR1 and CXCR2, couple to Gαi to induce leukocyte recruitment and activation at sites of inflammation. Upon activation by CXCL8, these receptors become phosphorylated, desensitized and internalized. In this study we investigated the role of different G protein-coupled receptor kinases (GRKs) in CXCR1- and CXCR2-mediated cellular functions. To that end, shRNA was used to inhibit GRK 2, 3, 5 and 6 in RBL-2H3 cells stably expressing CXCR1 or CXCR2, and CXCL8-mediated receptor activation and regulation were assessed. Inhibition of GRK2 and GRK6, respectively, increased CXCR1 and CXCR2 resistance to phosphorylation, desensitization and internalization, and enhanced CXCL8-induced phosphoinositide hydrolysis and exocytosis in vitro. GRK2 depletion diminished CXCR1-induced ERK1/2 phosphorylation but had no effect in CXCR2-induced ERK1/2 phosphorylation. GRK6 depletion had no significant effect on CXCR1 function. However, peritoneal neutrophils from mice deficient in GRK6 (GRK6−/−) displayed an increase in CXCR2-mediated G-protein activation, but in vitro exhibited a decrease in chemotaxis, receptor desensitization and internalization relative to wild type (GRK6+/+) cells. In contrast, neutrophil recruitment in vivo in GRK6−/− mice was increased in response to delivery of CXCL1 through the air-pouch model. In a wound closure assay, GRK6−/− mice showed enhanced myeloperoxidase activity, suggesting enhanced neutrophil recruitment, and faster wound closure as compared to GRK6+/+ animals. Taken together, the results indicate that CXCR1 and CXCR2 couple to distinct GRK isoforms to mediate and regulate inflammatory responses. CXCR1 predominantly couples to GRK2, whereas CXCR2 interacts with GRK6 to negatively regulate receptor sensitization and trafficking, thus affecting cell signaling and angiogenesis.
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影响因子：
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作者：
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发表时间：
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期刊：
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影响因子：
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