Activation of Mast Cells by Trimeric G Protein Gi3; Coupling to the A3 Adenosine Receptor Directly and upon T Cell Contact
Activation of Mast Cells by Trimeric G Protein Gi3; Coupling to the A3 Adenosine Receptor Directly and upon T Cell Contact
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DOI：
10.4049/jimmunol.0901333
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发表时间：
2010-04-01
影响因子：
4.4
通讯作者：
Sagi-Eisenberg, Ronit
中科院分区：
文献类型：
--
作者：
Baram, Dana;Dekel, Ornit;Sagi-Eisenberg, Ronit
肥大细胞是介导和放大过敏和炎症反应的关键参与者。以前，我们确定了G-蛋白，Gi 3，作为受体模拟基本促分泌素的细胞靶点，其独立于IgE激活肥大细胞。在这项研究中，我们证明了Gi 3是腺苷A3受体（A3 R）的细胞靶点，A3 R是一种参与炎症和哮喘病理生理的G蛋白偶联受体。通过使用包含与输入序列（ALL 1）融合的G α 13的C-末端的细胞可渗透肽作为Gi 3信号传导的选择性抑制剂，我们表明，通过与GO偶联，A3 R刺激人肥大细胞中的多种信号传导途径，导致细胞因子、趋化因子和生长因子的上调。我们进一步表明，在与活化的T细胞膜接触后，内源性腺苷结合并激活A3 R，导致GO介导的信号传导。具体而言，通过与活化的T细胞膜接触而启动的大多数ERK 1/2信号传导由Gi 3介导，引起ALL 1-可应答的细胞应答。这些结果揭示了与Gi 3偶联的生理性G蛋白偶联受体，并确立了该G蛋白在涉及腺苷激活的肥大细胞的炎症条件中所起的重要作用。免疫学杂志，2010，184：3677-3688。
Mast cells are key players in mediating and amplifying allergic and inflammatory reactions. Previously, we identified the G-protein, Gi3, as the cellular target of receptor mimetic basic secretagogues that activate mast cell independently of IgE. In this study, we demonstrate that Gi3 is the cellular target of the adenosine A3 receptor (A3R), a G-protein coupled receptor involved in inflammation and the pathophysiology of asthma. By using a cell permeable peptide comprising the C-terminal end of G alpha i3 fused to an importation sequence (ALL1) as a selective inhibitor of Gi3 signaling, we show that by coupling to GO, the A3R stimulates multiple signaling pathways in human mast cells, leading to upregulation of cytokines, chemokines, and growth factors. We further show that after contact with activated T cell membranes, endogenous adenosine binds to and activates the A3R, resulting in GO-mediated signaling. Specifically, the majority of ERK1/2 signaling initiated by contact with activated T cell membranes, is mediated by Gi3, giving rise to ALL1-inhibitable cellular responses. These results unveil the physiological G-protein coupled receptor that couples to Gi3 and establish the important role played by this G-protein in inflammatory conditions that involve adenosine-activated mast cells. The Journal of Immunology, 2010, 184: 3677-3688.