Protein kinase A regulates inflammatory pain sensitization by modulating HCN2 channel activity in nociceptive sensory neurons
Protein kinase A regulates inflammatory pain sensitization by modulating HCN2 channel activity in nociceptive sensory neurons
复制标题
DOI：
10.1097/j.pain.0000000000001005
复制
发表时间：
2017-10-01
期刊：
影响因子：
7.4
通讯作者：
Ludwig, Andreas
中科院分区：
文献类型：
--
作者：
Herrmann, Stefan;Rajab, Hamsa;Ludwig, Andreas
一些研究表明环磷酸腺苷（cAMP）作为一个重要的第二信使调节伤害感受器敏化，但下游的目标，这有助于神经元的可塑性信号通路还没有得到很好的理解。我们使用了Cre/loxP为基础的策略，以禁用HCN 2或PKA的功能选择性外周伤害性神经元的子集，并分析了两个转基因系的伤害性反应。当皮内注射8br-cAMP诱导外周炎症时，在两种突变株中观察到几乎完全缺乏致敏性。HCN 2的缺乏以及PKA的抑制消除了背根神经节神经元中cAMP介导的钙瞬变增加。Ih通过cAMP的便利化，Ih电流的标志，在没有PKA活性的神经元中被废除。总的来说，这些结果显示了两种基因对炎性疼痛的显著贡献，并表明PKC依赖性的HCN 2激活是cAMP触发的神经元致敏的基础。
Several studies implicated cyclic adenosine monophosphate (cAMP) as an important second messenger for regulating nociceptor sensitization, but downstream targets of this signaling pathway which contribute to neuronal plasticity are not well understood. We used a Cre/loxP-based strategy to disable the function of either HCN2 or PKA selectively in a subset of peripheral nociceptive neurons and analyzed the nociceptive responses in both transgenic lines. A near-complete lack of sensitization was observed in both mutant strains when peripheral inflammation was induced by an intradermal injection of 8br-cAMP. The lack of HCN2 as well as the inhibition of PKA eliminated the cAMP-mediated increase of calcium transients in dorsal root ganglion neurons. Facilitation of Ih via cAMP, a hallmark of the Ih current, was abolished in neurons without PKA activity. Collectively, these results show a significant contribution of both genes to inflammatory pain and suggest that PKA-dependent activation of HCN2 underlies cAMP-triggered neuronal sensitization.