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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >The leukotriene B4 receptors BLT1 and BLT2 form an antagonistic sensitizing system in peripheral sensory neurons
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The leukotriene B4 receptors BLT1 and BLT2 form an antagonistic sensitizing system in peripheral sensory neurons

机译：白三烯B4受体BLT1和BLT2在周围感觉神经元中形成拮抗敏化系统

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摘要

Sensitization of the heat-activated ion channel transient receptor potential vanilloid 1 (TRPV1) through lipids is a fundamental mechanism during inflammation-induced peripheral sensitization. Leukotriene B4 is a proinflammatory lipid mediator whose role in peripheral nociceptive sensitization is not well understood to date. Two major G-protein-coupled receptors for leukotriene B4 have been identified: the high-affinity receptor BLT1 and the low-affinity receptor BLT2. Transcriptional screening for the expression G-protein-coupled receptors in murine dorsal root ganglia showed that both receptors were among the highest expressed in dorsal root ganglia. Calcium imaging revealed a sensitization of TRPV1-mediated calcium increases in a relative narrow concentration range for leukotriene B4 (100–200 nm). Selective antagonists and neurons from knock-out mice demonstrated a BLT1-dependent sensitization of TRPV1-mediated calcium increases. Accordingly, leukotriene B4-induced thermal hyperalgesia was mediated through BLT1 and TRPV1 as shown using the respective knock-out mice. Importantly, higher leukotriene B4 concentrations (>0.5 μm) and BLT2 agonists abolished sensitization of the TRPV1-mediated calcium increases. Also, BLT2 activation inhibited protein kinase C- and protein kinase A-mediated sensitization processes through the phosphatase calcineurin. Consequently, a selective BLT2-receptor agonist increased thermal and mechanical withdrawal thresholds during zymosan-induced inflammation. In accordance with these data, immunohistochemical analysis showed that both leukotriene B4 receptors were expressed in peripheral sensory neurons. Thus, the data show that the two leukotriene B4 receptors have opposing roles in the sensitization of peripheral sensory neurons forming a self-restricting system.
机译：通过脂质对热激活离子通道瞬态受体电位香草酸1（TRPV1）的敏化是炎症引起的外周致敏过程中的基本机制。白三烯B4是一种促炎性脂质介体，迄今为止其在外周伤害感受敏化中的作用尚不十分清楚。已经确定了白三烯B4的两个主要的G蛋白偶联受体：高亲和力受体BLT1和低亲和力受体BLT2。转录筛选小鼠背根神经节中G蛋白偶联受体的表达表明，这两种受体均在背根神经节中表达最高。钙成像显示，在相对狭窄的白三烯B4（100-200 nm）浓度范围内，TRPV1介导的钙增敏。来自基因敲除小鼠的选择性拮抗剂和神经元显示出TRPV1介导的钙增加的BLT1依赖性致敏作用。因此，如分别使用敲除小鼠所示，白三烯B4诱导的热痛觉过敏通过BLT1和TRPV1介导。重要的是，较高的白三烯B4浓度（> 0.5μm）和BLT2激动剂消除了TRPV1介导的钙增高的敏感性。而且，BLT2激活通过磷酸钙调磷酸酶抑制了蛋白激酶C和蛋白激酶A介导的致敏过程。因此，在酵母聚糖诱导的炎症过程中，选择性BLT2受体激动剂增加了热和机械退缩阈值。根据这些数据，免疫组织化学分析显示，白三烯B4受体均在周围感觉神经元中表达。因此，数据显示两种白三烯B4受体在形成自我限制系统的周围感觉神经元致敏中具有相反的作用。

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