A role for translational regulation by S6 kinase and a downstream target in inflammatory pain.
A role for translational regulation by S6 kinase and a downstream target in inflammatory pain.
复制标题
DOI：
10.1111/bph.15646
复制
发表时间：
2021-12
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
翻译控制遍及神经生物学。伤害感受器在疼痛信号的检测和传播中起着不可或缺的作用。伤害感受器的内在兴奋性可以发生持续变化。新生蛋白质合成的药理学破坏减少了急性和慢性形式的疼痛相关行为。然而，促进伤害感受器可塑性的翻译控制的靶点尚不清楚。我们使用核糖体分析来探测雄性Swiss-Webster小鼠在用神经生长因子和IL-6处理后背根神经节（DRG）神经元的翻译景观。采用免疫印迹和免疫组化法观察c-Fos的表达动态。核糖体蛋白S6激酶1（S6 K1），mTOR信号传导的下游组分，在控制c-Fos水平的参与进行了评估，低分子量抑制剂S6 K1（DG 2）或c-Fos（T-5224），研究其对伤害感受器活性的体外使用多电极阵列（MEA）和疼痛行为在体内的Swiss-Webster小鼠使用痛觉过敏引发模型。c-Fos在感觉神经元表达。在人类和啮齿动物中促进疼痛的炎症介质促进c-Fos翻译。mTOR效应子S6 K1是c-Fos生物合成所必需的。用低分子量化合物抑制S6 K1或c-Fos可降低对炎症信号的机械和热超敏反应。此外，这两种抑制剂都降低了诱发的伤害感受器活性。我们的数据显示S6 K1在调节对炎症介质的快速反应中具有新的作用，其中c-Fos是一个关键的下游靶点。靶向S6激酶通路或c-Fos是一种令人兴奋的疼痛调节化合物的新途径。
Translational controls pervade neurobiology. Nociceptors play an integral role in the detection and propagation of pain signals. Nociceptors can undergo persistent changes in their intrinsic excitability. Pharmacological disruption of nascent protein synthesis diminishes acute and chronic forms of pain-associated behaviours. However, the targets of translational controls that facilitate plasticity in nociceptors are unclear. We used ribosome profiling to probe the translational landscape in dorsal root ganglion (DRG) neurons from male Swiss-Webster mice, after treatment with nerve growth factor and IL-6. Expression dynamics of c-Fos were followed with immunoblotting and immunohistochemistry. The involvement of ribosomal protein S6 kinase 1 (S6K1), a downstream component of mTOR signalling, in the control of c-Fos levels was assessed with low MW inhibitors of S6K1 (DG2) or c-Fos (T-5224), studying their effects on nociceptor activity in vitro using multielectrode arrays (MEAs) and pain behaviour in vivo in Swiss-Webster mice using the hyperalgesic priming model. c-Fos was expressed in sensory neurons. Inflammatory mediators that promote pain in both humans and rodents promote c-Fos translation. The mTOR effector S6K1 is essential for c-Fos biosynthesis. Inhibition of S6K1 or c-Fos with low MW compounds diminished mechanical and thermal hypersensitivity in response to inflammatory cues. Additionally, both inhibitors reduced evoked nociceptor activity. Our data show a novel role of S6K1 in modulating the rapid response to inflammatory mediators, with c-Fos being one key downstream target. Targeting the S6 kinase pathway or c-Fos is an exciting new avenue for pain-modulating compounds.
登录
查看更多内容
影响因子：
5.3
作者：
Gandolfi D;Cerri S;Mapelli J;Polimeni M;Tritto S;Fuzzati-Armentero MT;Bigiani A;Blandini F;Mapelli L;D'Angelo E
通讯作者：
D'Angelo E
DOI：
10.1016/s0165-1838(97)00105-7
发表时间：
1997-12-03
期刊：
JOURNAL OF THE AUTONOMIC NERVOUS SYSTEM
影响因子：
--
作者：
Avelino, A;Cruz, F;Coimbra, A
通讯作者：
Coimbra, A
影响因子：
2
作者：
Antion, Marcia D.;Merhav, Maayan;Klann, Eric
通讯作者：
Klann, Eric
DOI：
10.1073/pnas.1600587113
发表时间：
2016-07-12
影响因子：
11.1
作者：
Bhatt, Aadra Prashant;Wong, Jason P.;Damania, Blossom
通讯作者：
Damania, Blossom
影响因子：
11.2
作者：
Alain, Tommy;Morita, Masahiro;Sonenberg, Nahum
通讯作者：
Sonenberg, Nahum