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首页> 外文期刊>Molecular pain >F-actin links Epac-PKC signaling to purinergic P2X3 receptor sensitization in dorsal root ganglia following inflammation
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F-actin links Epac-PKC signaling to purinergic P2X3 receptor sensitization in dorsal root ganglia following inflammation

机译：F-肌动蛋白将Epac-PKC信号转导与发炎后背根神经节的嘌呤能P2X3受体致敏

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Sensitization of purinergic P2X3 receptors (P2X3Rs) contributes to the production of exaggerated nociceptive responses following inflammatory injury. We showed previously that prostaglandin E2 (PGE2) potentiates P2X3R-mediated ATP currents in dorsal root ganglion neurons isolated from both control and complete Freund’s adjuvant-induced inflamed rats. PGE2 potentiation of ATP currents depends only on PKA signaling in control neurons, but it depends on both PKA and PKC signaling in inflamed neurons. We further found that inflammation evokes an increase in exchange proteins directly activated by cAMP (Epacs) in dorsal root ganglions. This increase promotes the activation of PKC to produce a much enhanced PGE2 effect on ATP currents and to elicit Epac-dependent flinch nocifensive behavioral responses in complete Freund’s adjuvant rats. The link between Epac-PKC signaling and P2X3R sensitization remains unexplored. Here, we show that the activation of Epacs promotes the expression of phosphorylated PKC and leads to an increase in the cytoskeleton, F-actin, expression at the cell perimeter. Depolymerization of F-actin blocks PGE2-enhanced ATP currents and inhibits P2X3R-mediated nocifensive responses after inflammation. Thus, F-actin is dynamically involved in the Epac-PKC-dependent P2X3R sensitization. Furthermore, Epacs induce a PKC-dependent increase in the membrane expression of P2X3Rs. This increase is abolished by F-actin depolymerization, suggesting that F-actin mediates Epac-PKC signaling of P2X3R membrane expression. Thus, after inflammation, an Epac-PKC dependent increase in F-actin in dorsal root ganglion neurons enhances the membrane expression of P2X3Rs to bring about sensitization of P2X3Rs and abnormal pain behaviors.
机译：嘌呤能P2X3受体（P2X3Rs）的致敏作用导致炎性损伤后产生过大的伤害感受。先前我们发现，前列腺素E2（PGE2）增强了从对照和完全弗氏佐剂诱发的发炎大鼠中分离出的背根神经节神经元中P2X3R介导的ATP电流。 ATP电流的PGE2增强仅取决于对照神经元中的PKA信号，但取决于发炎神经元中的PKA和PKC信号。我们进一步发现炎症引起了背根神经节中由cAMP（Epacs）直接激活的交换蛋白的增加。这种增加促进了PKC的激活，从而大大增强了对ATP电流的PGE2效应，并在完全的弗氏佐剂大鼠中引发了Epac依赖性的雀斑伤害行为反应。 Epac-PKC信号转导与P2X3R致敏之间的联系尚未探索。在这里，我们显示Epacs的激活促进了磷酸化PKC的表达，并导致细胞骨架F-肌动蛋白在细胞周围的表达增加。 F-肌动蛋白的解聚反应可阻止PGE2增强的ATP电流，并抑制炎症后P2X3R介导的伤害反应。因此，F-肌动蛋白动态参与Epac-PKC依赖的P2X3R致敏。此外，Epacs诱导PKC依赖的P2X3Rs膜表达增加。 F-肌动蛋白解聚取消了这种增加，表明F-肌动蛋白介导了P2X3R膜表达的Epac-PKC信号传导。因此，发炎后，背根神经节神经元中F-肌动蛋白的Epac-PKC依赖性增加会增强P2X3Rs的膜表达，从而引起P2X3Rs的致敏和异常的疼痛行为。

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