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。尽管全球有高达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电压门控钠通道Nav1.7的功能突变的丧失与对疼痛的完全不敏感性有关。反之亦然，Nav1.7中的功能突变的获得导致遗传性慢性神经性疼痛综合征，红斑性肢痛症。所有红斑性肢痛症突变都将通道的激活转移到更负的电位，使表达细胞更易兴奋。它们中的大多数还显示出显著的慢失活增强，这是一种门控模式，可减少可用通道的数量，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放电产生中的作用。我打算回答三个问题：1。哪些通道结构负责伤害性钠通道亚型的不同慢失活特性？2.慢失活对痛觉神经元动作电位的形成和重复放电有什么作用？3.调节钠通道的慢失活是否适合作为神经性疼痛小鼠模型的治疗原则？这些问题的解决将进一步加深我们对分子钠通道门控的理解，并有助于开发具有更少副作用的针对疼痛的靶向药物。

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.