Dynamic regulation of axonal trafficking and surface distribution of Nav1.7 in sensory neurons

慢性疼痛在退伍军人中很常见，仍然是一种未得到满足的医疗需求。电压门控钠 在初级传入中优先表达的通道在人类疼痛中起着关键作用。 疾病，并为开发携带最小中枢神经系统的新型疼痛治疗提供了合适的靶点 副作用和使人上瘾的潜力。Nav1.7是调节动作电位的外周阈值通道 激发和神经递质释放。我们过去15年的研究将Nav1.7与人类疼痛障碍联系在一起， 例如，遗传性红斑性肢痛症、小纤维神经病、痛性糖尿病神经病，并将NAV 1.7确认为 非常有吸引力的治疗疼痛的靶点。尽管在这方面已经取得了相当大的进展 开发用于治疗疼痛的新型Nav1.7阻滞剂，需要做大量的工作来改进其 特异性和有效性。同样，虽然现有的NAV阻滞剂可以缓解患者的症状，但他们的 由于非特异性和显著的中枢神经系统副作用，其实用性受到限制。 加巴喷丁类药物是目前治疗慢性疼痛的一线药物，它抑制突触前电压门控的运输 钙离子通道进入质膜或破坏Rab11依赖的循环，从而减少钙离子 电流和发射机释放。通过类比加巴喷丁治疗疼痛的作用模式，以及 最近关注贩运蛋白作为中枢神经系统障碍的治疗靶点，靶向贩运机制 Nav1.7可能代表了一种治疗疼痛的新方法。然而，人们对分子和 控制钠通道运输和表面沿感觉长度分布的机制 轴突--我们在这项提案中探索的机会目标。 在这项提案中，我们旨在阐明控制Nav1.7及其成员贩运的分子机制 在感觉神经元轴突质膜中的分布，以努力寻找潜在的新靶点 慢性疼痛的治疗。具体地说，我们将建立在我们开发的强大的新平台上，即 能够实时成像离胞体一定距离的活体感觉神经元内的单个钠通道 具有前所未有的空间和时间分辨率。 从这些研究中收集到的知识将提供前所未有的关于调节亚胺类药物的机制的澄清 正常人感觉神经元中钠通道的细胞分布，特别是沿轴突长度的分布 和疾病状态。这些研究反过来将使发现治疗慢性疼痛的新靶点成为可能。 我们的最终目标是开发更安全、更有效的治疗方法，而不会使人上瘾 严重的副作用。

Chronic pain is common among Veterans and remains an unmet medical need. Voltage-gated sodium channels (NaVs) that are expressed preferentially in primary afferents play a critical role in human pain disorders, and present opportune targets for the development of novel pain treatments that carry minimal CNS side effects and addictive potential. NaV1.7 is a peripheral threshold channel that regulates action potential firing and neurotransmitter release. Our work for the past 15 years has linked NaV1.7 to human pain disorders, e.g., inherited erythromelalgia, small fiber neuropathy, painful diabetic neuropathy, and validated NaV 1.7 as a highly attractive target for the treatment of pain. Although considerable progress has been made in the development of novel NaV1.7 blockers for the treatment of pain, much work is needed to improve their specificity and efficacy. Similarly, while existing NaV blockers can provide symptomatic relief in patients, their utility is limited due to non-specificity and significant CNS side effects. Gabapentinoids, the current first line treatment for chronic pain, inhibit trafficking of presynaptic voltage-gated calcium channel to the plasma membrane or disrupt Rab11-dependent recycling, thus reducing calcium currents and transmitter release. By analogy to gabapentinoids' mode of action for the treatment of pain, and recent focus on trafficking proteins as therapeutic targets in CNS disorder, targeting trafficking machinery of Nav1.7 might represent a novel approach to pain treatment. However, little is known about molecules and mechanisms that control sodium channel trafficking and surface distribution along the length of sensory axons—a target of opportunity that we explore in this proposal. In this proposal, we aim to elucidate molecular mechanisms that control trafficking of NaV1.7 and their distribution in the axonal plasma membrane of sensory neurons, in an effort to identify potential new targets for the treatment of chronic pain. Specifically, we will build upon a powerful new platform that we developed, that enables real-time imaging of single sodium channels within living sensory neurons at a distance from the soma with unprecedented spatial- and temporal-resolution. Knowledge gleaned from these studies will provide unprecedented clarity about mechanisms that regulate sub- cellular distribution of sodium channels in sensory neurons, particularly along the length of axons, in normal and disease states. These studies, in turn, will enable discovery of new targets for treatment of chronic pain. Our ultimate goal is to develop safer and more effective treatments without addictive potential and other serious side effects.