Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT 06520.
Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510.
Proc Natl Acad Sci U S A. 2023 Mar 14;120(11):e2215417120. doi: 10.1073/pnas.2215417120. Epub 2023 Mar 10.
Inflammation causes pain by shifting the balance of ionic currents in nociceptors toward depolarization, leading to hyperexcitability. The ensemble of ion channels within the plasma membrane is regulated by processes including biogenesis, transport, and degradation. Thus, alterations in ion channel trafficking may influence excitability. Sodium channel Na1.7 and potassium channel K7.2 promote and oppose excitability in nociceptors, respectively. We used live-cell imaging to investigate mechanisms by which inflammatory mediators (IM) modulate the abundance of these channels at axonal surfaces through transcription, vesicular loading, axonal transport, exocytosis, and endocytosis. Inflammatory mediators induced a Na1.7-dependent increase in activity in distal axons. Further, inflammation increased the abundance of Na1.7, but not of K7.2, at axonal surfaces by selectively increasing channel loading into anterograde transport vesicles and insertion at the membrane, without affecting retrograde transport. These results uncover a cell biological mechanism for inflammatory pain and suggest Na1.7 trafficking as a potential therapeutic target.
炎症通过将伤害感受器中离子电流的平衡向去极化转移，导致过度兴奋，从而引起疼痛。等离子膜内的离子通道的集合由包括生物发生、运输和降解在内的过程调节。因此，离子通道运输的改变可能会影响兴奋性。钠通道 Na1.7 和钾通道 K7.2 分别促进和抑制伤害感受器的兴奋性。我们使用活细胞成像技术研究了炎症介质（IM）通过转录、囊泡装载、轴突运输、胞吐和胞吞作用，调节这些通道在轴突表面丰度的机制。炎症介质诱导了远端轴突中 Na1.7 依赖性活性增加。此外，炎症通过选择性地增加正向运输囊泡中的通道装载和插入膜，而不影响逆行运输，增加了轴突表面 Na1.7 的丰度，但不增加 K7.2 的丰度，从而增加了 Na1.7 的丰度，但不增加 K7.2 的丰度。这些结果揭示了炎症性疼痛的细胞生物学机制，并表明 Na1.7 运输可能是一个潜在的治疗靶点。
