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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Low nociceptor GRK2 prolongs prostaglandin E2 hyperalgesia via biased cAMP signaling to Epac/Rap1, protein kinase Cepsilon, and MEK/ERK.
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Low nociceptor GRK2 prolongs prostaglandin E2 hyperalgesia via biased cAMP signaling to Epac/Rap1, protein kinase Cepsilon, and MEK/ERK.

机译：低伤害感受器GRK2通过偏向epac / Rap1，蛋白激酶Cepsilon和MEK / ERK的cAMP信号传导延长前列腺素E2痛觉过敏。

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摘要

Hyperexcitability of peripheral nociceptive pathways is often associated with inflammation and is an important mechanism underlying inflammatory pain. Here we describe a completely novel mechanism via which nociceptor G-protein-coupled receptor kinase 2 (GRK2) contributes to regulation of inflammatory hyperalgesia. We show that nociceptor GRK2 is downregulated during inflammation. In addition, we show for the first time that prostaglandin E2 (PGE2)-induced hyperalgesia is prolonged from <6 h in wild-type (WT) mice to 3 d in mice with low GRK2 in Nav1.8+ nociceptors (SNS-GRK2+/- mice). This prolongation of PGE2 hyperalgesia in SNS-GRK2+/- mice does not depend on changes in the sensitivity of the prostaglandin receptors because prolonged hyperalgesia also developed in response to 8-Br-cAMP. PGE2 or cAMP-induced hyperalgesia in WT mice is PKA dependent. However, PKA activity is not required for hyperalgesia in SNS-GRK2+/- mice. SNS-GRK2+/- mice developed prolonged hyperalgesia in response to the Exchange proteins directly activated by cAMP (Epac) activator 8-pCPT-2'-O-Me-cAMP (8-pCPT). Coimmunoprecipitation experiments showed that GRK2 binds to Epac1. In vitro, GRK2 deficiency increased 8-pCPT-induced activation of the downstream effector of Epac, Rap1, and extracellular signal-regulated kinase (ERK). In vivo, inhibition of MEK1 or PKCepsilon prevented prolonged PGE2, 8-Br-cAMP, and 8-pCPT hyperalgesia in SNS-GRK2+/- mice. In conclusion, we discovered GRK2 as a novel Epac1-interacting protein. A reduction in the cellular level of GRK2 enhances activation of the Epac-Rap1 pathway. In vivo, low nociceptor GRK2 leads to prolonged inflammatory hyperalgesia via biased cAMP signaling from PKA to Epac-Rap1, ERK/PKCepsilon pathways.
机译：周围伤害感受途径的过度兴奋性通常与炎症相关，并且是引起炎症性疼痛的重要机制。在这里，我们描述了伤害感受器G蛋白偶联受体激酶2（GRK2）有助于调节炎症性痛觉过敏的全新机制。我们表明，伤害感受器GRK2在炎症过程中被下调。此外，我们首次展示了前列腺素E2（PGE2）引起的痛觉过敏从Nav1.8 +伤害感受器（SNS-GRK2 + /- 老鼠）。 SNS-GRK2 +/-小鼠中PGE2痛觉过敏的这种延长不取决于前列腺素受体敏感性的变化，因为长期的痛觉过敏也响应于8-Br-cAMP而发展。 WT小鼠中的PGE2或cAMP诱导的痛觉过敏是PKA依赖性的。但是，SKA-GRK2 +/-小鼠的痛觉过敏不需要PKA活性。 SNS-GRK2 +/-小鼠对cAMP（Epac）激活剂8-pCPT-2'-O-Me-cAMP（8-pCPT）直接激活的交换蛋白产生了长时间的痛觉过敏。免疫共沉淀实验表明，GRK2与Epac1结合。在体外，GRK2缺乏症增加了8-pCPT诱导的Epac，Rap1和细胞外信号调节激酶（ERK）下游效应子的激活。在体内，抑制MEK1或PKCepsilon可以防止SNS-GRK2 +/-小鼠中延长的PGE2、8-Br-cAMP和8-pCPT痛觉过敏。总之，我们发现GRK2是一种新型的Epac1相互作用蛋白。 GRK2的细胞水平降低会增强Epac-Rap1途径的激活。在体内，低伤害感受器GRK2通过从PKA到Epac-Rap1，ERK / PKCepsilon通路的cAMP信号偏向导致长时间的炎性痛觉过敏。

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