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首页> 外文期刊>Cellular Signalling >Downregulation of kinin B1 receptor function by B2 receptor heterodimerization and signaling
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Downregulation of kinin B1 receptor function by B2 receptor heterodimerization and signaling

机译：B2受体异二聚化和信号转导下调激肽B1受体功能

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Signaling through the G protein-coupled kinin receptors B1 (kB1R) and B2 (kB2R) plays a critical role in inflammatory responses mediated by activation of the kallikrein-kinin system. The kB2R is constitutively expressed and rapidly desensitized in response to agonist whereas kB1R expression is upregulated by inflammatory stimuli and it is resistant to internalization and desensitization. Here we show that the kB1R heterodimerizes with kB2Rs in co-transfected HEK293 cells and natively expressing endothelial cells, resulting in significant internalization and desensitization of the kB1R response in cells pre-treated with kB2R agonist However, pre-treatment of cells with kB1R agonist did not affect subsequent kB2R responses. Agonists of other G protein-coupled receptors (thrombin, lysophosphatidic acid) had no effect on a subsequent kB1R response. The loss of kB1R response after pretreatment with kB2R agonist was partially reversed with kB2R mutant Y129S, which blocks kB2R signaling without affecting endocytosis, or T342A, which signals like wild type but is not endocytosed. Co-endocytosis of the kB1R with kB2R was dependent on beta-arrestin and clathrin-coated pits but not caveolae. The sorting pathway of kB1R and kB2R after endocytosis differed as recycling of kB1R to the cell surface was much slower than that of kB2R. In cytokine-treated human lung microvascular endothelial cells, pre-treatment with kB2R agonist inhibited kB1R-mediated increase in transendothelial electrical resistance (TER) caused by kB1R stimulation (to generate nitric oxide) and blocked the profound drop in TER caused by kB1R activation in the presence of pyrogallol (a superoxide generator). Thus, kB1R function can be downregulated by kB2R co-endocytosis and signaling, suggesting new approaches to control kB1R signaling in pathological conditions. (C) 2014 Elsevier Inc. All rights reserved.
机译：通过G蛋白偶联激肽受体B1（kB1R）和B2（kB2R）发出的信号在激肽释放酶激肽系统激活介导的炎症反应中起关键作用。 kB2R响应激动剂而组成性表达并迅速脱敏，而kB1R的表达受炎性刺激上调，并且抗内在化和脱敏。在这里，我们显示在共同转染的HEK293细胞和天然表达的内皮细胞中，kB1R与kB2Rs异源二聚体，导致在用kB2R激动剂预处理的细胞中kB1R应答显着内在化和脱敏性。不会影响后续的kB2R响应。其他G蛋白偶联受体（凝血酶，溶血磷脂酸）的激动剂对随后的kB1R反应无影响。用kB2R激动剂预处理后，kB2R突变体Y129S可以部分逆转kB1R反应的丧失，该突变体可阻断kB2R信号传导而不影响内吞作用，或T342A，其信号类似于野生型，但不被内吞。 kB1R与kB2R的共胞吞作用取决于β-arrestin和网格蛋白包被的凹坑，但不依赖小窝。内吞作用后kB1R和kB2R的分选途径有所不同，因为kB1R向细胞表面的再循环比kB2R慢得多。在细胞因子处理的人肺微血管内皮细胞中，用kB2R激动剂进行预处理可抑制kB1R介导的由kB1R刺激引起的内皮电阻（TER）升高（产生一氧化氮），并阻止由kB1R激活引起的TER的大幅下降。邻苯三酚（超氧化物生成器）的存在。因此，kB1R的功能可以通过kB2R共内吞作用和信号传导而下调，这表明在病理条件下控制kB1R信号传导的新方法。 （C）2014 Elsevier Inc.保留所有权利。

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