Oncostatin M induces hyperalgesic priming and amplifies signaling of cAMP to ERK by RapGEF2 and PKA
Oncostatin M induces hyperalgesic priming and amplifies signaling of cAMP to ERK by RapGEF2 and PKA
复制标题
DOI：
10.1111/jnc.15172
复制
发表时间：
2020-09-20
影响因子：
4.7
通讯作者：
Hucho，Tim
中科院分区：
文献类型：
--
作者：
Garza Carbajal，Anibal;Ebersberger，Andrea;Hucho，Tim
痛觉过敏启动的特征在于由原伤害感受介质（原型为PGE 2）增强的伤害感受器敏化。引发作为向慢性疼痛转变的潜在机制已经引起了人们的兴趣。哪些刺激诱导启动以及采用何种细胞机制仍不完全清楚。在成年雄性大鼠中，我们提出了细胞因子OncostatinM（OSM），IL-6家族的一员，通过一种新的机制作为引发的诱导剂。我们使用基于高含量显微镜的方法来量化培养物中数千个感觉神经元的内源性PKA-II和ERK的激活。与OSM孵育增加并延长了增加cAMP产生的试剂（如PGE 2、毛喉素和cAMP类似物）对ERK的激活。这些变化特异于IB 4/CaMKIIα阳性神经元，需要蛋白质翻译，并增加cAMP至ERK信号传导。在对照和OSM处理的神经元中，cAMP/ERK信号转导涉及RapGEF 2和PKA，但不涉及Epac。GDNF可以诱导cAMP-ERK信号的类似增强，GDNF主要作用于IB 4/CaMKIIα阳性神经元，而NGF则不诱导cAMP-ERK信号的增强，NGF主要作用于IB 4/CaMKIIα阴性神经元。在体外，OSM预处理使基线TTX-R电流ERK依赖性，并在小型/中型神经元中将毛喉素增加的电流从部分ERK依赖性转换为完全ERK依赖性。总之，由OSM诱导的引发使用新的机制来增强和延长cAMP/PKA与ERK 1/2信号传导的偶联，而不改变整体通路结构。
Hyperalgesic priming is characterized by enhanced nociceptor sensitization by pronociceptive mediators, prototypically PGE2. Priming has gained interest as a mechanism underlying the transition to chronic pain. Which stimuli induce priming and what cellular mechanisms are employed remains incompletely understood. In adult male rats, we present the cytokine OncostatinM(OSM), a member of the IL‐6 family, as an inducer of priming by a novel mechanism. We used a high content microscopy based approach to quantify the activation of endogenous PKA‐II and ERK of thousands sensory neurons in culture. Incubation with OSM increased and prolonged ERK activation by agents that increase cAMP production such as PGE2, forskolin, and cAMP analogs. These changes were specific to IB4/CaMKIIα positive neurons, required protein translation, and increased cAMP‐to‐ERK signaling. In both, control and OSM‐treated neurons, cAMP/ERK signaling involved RapGEF2 and PKA but not Epac. Similar enhancement of cAMP‐to‐ERK signaling could be induced by GDNF, which acts mostly on IB4/CaMKIIα‐positive neurons, but not by NGF, which acts mostly on IB4/CaMKIIα‐negative neurons. In vitro, OSM pretreatment rendered baseline TTX‐R currents ERK‐dependent and switched forskolin‐increased currents from partial to full ERK‐dependence in small/medium sized neurons. In summary, priming induced by OSM uses a novel mechanism to enhance and prolong coupling of cAMP/PKA to ERK1/2 signaling without changing the overall pathway structure.