Phosphorylation of histone H3 at serine 10 (p-H3S10) is a marker of active gene transcription. Using cognitive models of neural plasticity, p-H3S10 was shown to be downstream of extracellular signal-regulated kinase (ERK) signalling in the hippocampus. In this study, we show that nociceptive signalling after peripheral formalin injection increased p-H3S10 expression in the ipsilateral dorsal horn. This increase was maximal 30 minutes after formalin injection and occurred mainly within p-ERK-positive neurons. Spinal p-H3S10-enhanced expression was also observed in neurokinin 1 receptor (NK1R), c-Fos, and Zif268 positive neurons and was inhibited by ablation of serotonergic descending controls. The mitogen and stress-activated protein kinase 1 (MSK1) is downstream of ERK and can induce p-H3S10. We found that, after formalin injection, most phospho-MSK1 (p-MSK1)-positive cells (87% ± 3%) expressed p-ERK and the majority of p-H3S10-positive cells (85% ± 5%) expressed p-MSK1. Inhibition of ERK activity with the MEK inhibitor SL327 reduced formalin-induced p-ERK, p-MSK1, and p-H3S10, demonstrating that spinal p-MSK1 and p-H3S10 were at least partly downstream of ERK signalling. Crucially, pharmacological blockade of spinal MSK1 activity with the novel MSK1 inhibitor SB727651A inhibited formalin-induced spinal p-H3S10 and nocifensive behaviour. These findings are the first to establish the involvement of p-H3S10 and its main kinase, MSK1, in ERK regulation of nociception. Given the general importance of ERK signalling in pain processing, our results suggest that p-H3S10 could play a role in the response to injury.

译文

:丝氨酸10(p-H3S10)处的组蛋白H3磷酸化是活性基因转录的标志。使用神经可塑性的认知模型,p-H3S10显示为海马中细胞外信号调节激酶(ERK)信号的下游。在这项研究中,我们显示注射福尔马林外围药后的伤害性信号传导会增加同侧背角中p-H3S10的表达。注射福尔马林后30分钟,这种增加最大,主要发生在p-ERK阳性神经元内。在神经激肽1受体(NK1R),c-Fos和Zif268阳性神经元中也观察到了脊髓p-H3S10增强的表达,并被消融的血清素能下降对照所抑制。有丝分裂原和应激激活蛋白激酶1(MSK1)在ERK的下游,可以诱导p-H3S10。我们发现,注射福尔马林后,大多数磷酸-MSK1(p-MSK1)阳性细胞(87%±3%)表达p-ERK,而大多数p-H3S10阳性细胞(85%±5%)表达p-ERK。 -MSK1。用MEK抑制剂SL327抑制ERK活性可降低福尔马林诱导的p-ERK,p-MSK1和p-H3S10,表明脊髓p-MSK1和p-H3S10至少部分位于ERK信号传导的下游。至关重要的是,用新型MSK1抑制剂SB727651A阻断脊柱MSK1活性的药理作用抑制了福尔马林诱导的脊柱p-H3S10和伤害行为。这些发现是第一个确定p-H3S10及其主要激酶MSK1参与ERK伤害感受调节的研究。考虑到ERK信号在疼痛处理中的重要性,我们的研究结果表明p-H3S10可能在伤害反应中发挥作用。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录