Department of Neurology, Yale University, New Haven, CT, 06510, USA; Center for Neuroscience & Regeneration Research, Yale University, New Haven, CT, 06510, USA; Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT, 06516, USA.
Department of Neurology, Yale University, New Haven, CT, 06510, USA; Center for Neuroscience & Regeneration Research, Yale University, New Haven, CT, 06510, USA; Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT, 06516, USA; Integrated Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, The Catholic University of Korea, Bucheon, 14662, South Korea.
Neurosci Lett. 2021 Jan 10;741:135446. doi: 10.1016/j.neulet.2020.135446. Epub 2020 Nov 6.
Peripheral neuropathy is associated with enhanced activity of primary afferents which is often manifested as pain. Voltage-gated sodium channels (VGSCs) are critical for the initiation and propagation of action potentials and are thus essential for the transmission of the noxious stimuli from the periphery. Human peripheral sensory neurons express multiple VGSCs, including Nav1.7, Nav1.8, and Nav1.9 that are almost exclusively expressed in the peripheral nervous system. Distinct biophysical properties of Nav1.7, Nav1.8, and Nav1.9 underlie their differential contributions to finely tuned neuronal firing of nociceptors, and mutations in these channels have been associated with several inherited human pain disorders. Functional characterization of these mutations has provided additional insights into the role of these channels in electrogenesis in nociceptive neurons and pain sensation. Peripheral tissue damage activates an inflammatory response and triggers generation and release of inflammatory mediators, which can act through diverse signaling cascades to modulate expression and activity of ion channels including VGSCs, contributing to the development and maintenance of pathological pain conditions. In this review, we discuss signaling pathways that are activated by pro-nociceptive inflammatory mediators that regulate peripheral sodium channels, with a specific focus on direct phosphorylation of these channels by multiple protein kinases.
周围神经病变与初级传入活动增强有关，这种增强通常表现为疼痛。电压门控钠离子通道（VGSCs）对于动作电位的起始和传播至关重要，因此对于将有害刺激从外周传递至关重要。人类周围感觉神经元表达多种 VGSCs，包括 Nav1.7、Nav1.8 和 Nav1.9，它们几乎只在外周神经系统中表达。Nav1.7、Nav1.8 和 Nav1.9 的不同生物物理特性是它们对伤害感受器精细调谐的神经元放电的不同贡献的基础，这些通道的突变与几种遗传性人类疼痛障碍有关。对这些突变的功能特征分析为这些通道在伤害性神经元的电发生和疼痛感觉中的作用提供了更多的见解。周围组织损伤会激活炎症反应，并引发炎症介质的产生和释放，这些介质可以通过多种信号级联作用来调节包括 VGSCs 在内的离子通道的表达和活性，从而导致病理性疼痛状态的发展和维持。在这篇综述中，我们讨论了受伤害性炎症介质激活的信号通路，这些通路调节周围的钠离子通道，特别关注多种蛋白激酶对这些通道的直接磷酸化。
