Sodium channels and electrogenesis in sensory neurons

描述（由申请人提供）：疼痛是一个严重的医学问题。虽然众所周知背根神经节（DRG）感觉神经元的过度兴奋可导致神经性疼痛和炎性疼痛，但是作为这种过度兴奋的基础的细胞和分子变化尚未完全理解。这种知识的缺乏阻碍了更好的治疗方法的发展。研究表明，钠通道的特性会因炎症和神经损伤而改变。钠电流的变化可以显著改变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DRG神经元中Nav1.7产生的复苏钠电流。此外，我们有令人兴奋的新数据表明，导致疼痛增加的脊髓损伤可以显着增加DRG神经元中的复活电流。我们认为，复苏的钠电流有助于自发放电，超兴奋性和启动的DRG感觉神经元的疼痛感觉。不幸的是，我们对复活电流的分子机制的理解，特别是在DRG神经元中，是穷人。我们已经开发了一个神经元表达系统的重组电压门控钠通道，独特的定位，我们调查这些电流。本研究主要包括以下几个方面：1）建立DRG神经元复活电流的分子决定因素。2)确定复活电流如何被磷酸化、炎症介质、活性氧、酸度和其他阻碍钠通道快速失活并有助于增强疼痛感觉的调节剂调节。3)确定复苏电流是否对局部麻醉药、抗惊厥药和其他靶向电压门控钠通道的药物的调节敏感。4)研究复苏电流对感觉神经元兴奋性的影响。确定复活电流产生的分子机制将提高我们识别这些电流在疼痛和其他兴奋性疾病中的作用的能力，并开发专门针对复活电流的治疗策略。

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.