Sodium channels and electrogenesis in sensory neurons

描述(申请人提供)：疼痛是一个严重的医学问题。虽然众所周知，背根神经节(DRG)感觉神经元的超兴奋性可导致神经病理性和炎症性疼痛，但这种超兴奋性背后的细胞和分子变化尚不完全清楚。这种知识的缺乏阻碍了更好的疗法的发展。研究表明，炎症和神经损伤会改变钠通道的特性。钠电流的改变可以显著改变DRG神经元的兴奋性。我们发现，导致阵发性极端疼痛障碍(PEPD)的突变可以显著增加由Nav1.7在DRG神经元上产生的复苏性钠电流。此外，我们有令人兴奋的新数据表明，引起疼痛增加的脊髓损伤可以显著增加DRG神经元的复苏电流。我们认为，复苏性钠电流有助于DRG感觉神经元的自发放电、超兴奋性和痛觉的启动。不幸的是，我们对复活电流背后的分子机制的了解很差，特别是在DRG神经元中。我们已经开发了一个用于重组电压门控钠通道的神经元表达系统，它为我们研究这些电流提供了独特的位置。在本项目中，我们将：1)建立DRG神经元复苏电流的分子决定因素。2)确定复苏性电流如何受磷酸化、炎症介质、活性氧物种、酸度和其他调节剂的调节，这些调节剂阻碍钠通道的快速失活并促进痛觉增强。3)确定复苏性电流是否对局部麻醉剂、抗惊厥剂和其他针对电压门控钠通道的药物的调制敏感。4)研究复苏电流对感觉神经元兴奋性的影响。识别复发性电流产生的分子机制将增强我们识别这些电流在疼痛和其他兴奋性障碍中的作用的能力，并开发专门针对复发性电流的治疗策略。

DESCRIPTION (provided by applicant): Pain is a serious medical problem. While it is well known that hyperexcitability of dorsal root ganglion (DRG) sensory neurons can contribute to neuropathic and inflammatory pain, the cellular and molecular changes that underlie this hyperexcitability are not fully understood. This lack of knowledge has hindered the development of better therapeutics. Studies indicate that sodium channel properties are altered by inflammation and nerve injury. Changes in sodium currents can substantially alter the excitability of DRG neurons. We have found that mutations that cause paroxysmal extreme pain disorder (PEPD) can significantly increase resurgent sodium currents produced by Nav1.7 in DRG neurons. Furthermore, we have exciting new data indicating that a spinal cord injury that causes increased pain can significantly increase resurgent currents in DRG neurons. We propose that resurgent sodium currents contribute to spontaneous firing, hyperexcitability and the initiation of pain sensations in DRG sensory neurons. Unfortunately, our understanding of the molecular mechanisms that underlie resurgent currents, especially in DRG neurons, is poor. We have developed a neuronal expression system for recombinant voltage-gated sodium channels that uniquely positions us to investigate these currents. In this project we will: 1) Establish the molecular determinants of resurgent currents in DRG neurons. 2) Determine how resurgent currents are regulated by phosphorylation, inflammatory mediators, reactive oxygen species, acidity, and other modulators that impede fast-inactivation of sodium channels and contribute to enhanced pain sensations. 3) Determine if resurgent currents are sensitive to modulation by local anesthetics, anti-convulsants and other agents that target voltage-gated sodium channels. 4) Investigate the consequences of resurgent currents on sensory neuronal excitability. Identifying the molecular mechanisms underlying resurgent current generation will enhance our ability to identify the roles of these currents in pain and other disorders of excitability, and to develop therapeutic strategies specifically targeting resurgent currents.