Slow inactivation of nociceptive sodium channels: crucial gating mechanism and its role in the origin of pain

慢性疼痛是一种严重的、使人衰弱的疾病。尽管全球高达10%的人口受到影响，但目前的治疗策略往往不足。最近，在外周伤害感受器中表达的人类电压门控钠通道Nav1.7的功能突变丧失与对疼痛的完全不敏感有关。反之亦然，Nav1.7功能突变的获得会导致遗传性慢性神经性疼痛综合征，即红斑性肢痛症。所有红斑性肢痛症突变都将通道激活转移到更多的负电位，使表达细胞更容易兴奋。它们中的大多数也显示出缓慢失活的显著增强，这是一种减少可用通道数量的门控模式，最近已成为疼痛相关药物开发的兴趣。本项目旨在通过电生理学和分子生物学方法探讨慢失活的结构和功能及其在动作电位和疼痛相关重复性放电产生中的作用。我计划回答三个问题：1。哪些通道结构导致了不同类型的痛觉钠通道的缓慢失活特性？2. 缓慢失活对疼痛神经元动作电位形成和重复放电的贡献是什么？3. 调节钠通道的缓慢失活是否适合作为小鼠神经性疼痛模型的治疗原则？回答这些问题将进一步加深我们对分子钠通道门控的理解，并有助于开发针对疼痛的副作用更小的靶向药物。

Chronic pain represents a severe, debilitating condition. Although up to 10% of the worldwide population is affected, current treatment strategies are often inadequate. Recently, loss of function mutations in human voltage-gated sodium channel Nav1.7, which is expressed in peripheral nociceptors, has been linked to complete insensitivity to pain. Vice versa, gain of function mutations in Nav1.7 lead to an inherited chronic neuropathic pain syndrome, erythromelalgia. All erythromelalgia mutations shift the channel s activation to more negative potentials, rendering the expressing cells more excitable. Most of them also show prominent enhancement of slow inactivation, a gating mode that reduces the number of available channels and that recently has become of interest for pain-related drug development. This project aims to explore the structure and function of slow inactivation and its role in the generation of action potential and pain-related repetitive firing with electrophysiology and molecular biology methods. I plan to address three questions: 1. Which channel structures are responsible for the different slow inactivation properties of subtypes of nociceptive sodium channels? 2. What is the contribution of slow inactivation to action potential formation and repetitive firing in pain neurons? 3. Is modulation of slow inactivation in sodium channels suitable as therapeutic principle in a mouse model of neuropathic pain? Answering these questions will further our understandings of molecular sodium channel gating and help developing targeted medication with fewer side effects against pain.