Barbosa Cindy, Xiao Yucheng, Johnson Andrew J, Xie Wenrui, Strong Judith A, Zhang Jun-Ming, Cummins Theodore R
Department of Pharmacology and Toxicology, Indiana University, Indianapolis, IN, USA.
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
Pflugers Arch. 2017 Feb;469(2):195-212. doi: 10.1007/s00424-016-1911-9. Epub 2016 Dec 20.
Nav1.6 and Nav1.6-mediated resurgent currents have been implicated in several pain pathologies. However, our knowledge of how fast resurgent currents are modulated in neurons is limited. Our study explored the potential regulation of Nav1.6-mediated resurgent currents by isoforms of fibroblast growth factor homologous factor 2 (FHF2) in an effort to address the gap in our knowledge. FHF2 isoforms colocalize with Nav1.6 in peripheral sensory neurons. Cell line studies suggest that these proteins differentially regulate inactivation. In particular, FHF2A mediates long-term inactivation, a mechanism proposed to compete with the open-channel blocker mechanism that mediates resurgent currents. On the other hand, FHF2B lacks the ability to mediate long-term inactivation and may delay inactivation favoring open-channel block. Based on these observations, we hypothesized that FHF2A limits resurgent currents, whereas FHF2B enhances resurgent currents. Overall, our results suggest that FHF2A negatively regulates fast resurgent current by enhancing long-term inactivation and delaying recovery. In contrast, FHF2B positively regulated resurgent current and did not alter long-term inactivation. Chimeric constructs of FHF2A and Navβ4 (likely the endogenous open channel blocker in sensory neurons) exhibited differential effects on resurgent currents, suggesting that specific regions within FHF2A and Navβ4 have important regulatory functions. Our data also indicate that FHFAs and FHF2B isoform expression are differentially regulated in a radicular pain model and that associated neuronal hyperexcitability is substantially attenuated by a FHFA peptide. As such, these findings suggest that FHF2A and FHF2B regulate resurgent current in sensory neurons and may contribute to hyperexcitability associated with some pain pathologies.
Nav1.6及Nav1.6介导的复苏电流与多种疼痛病理状态有关。然而，我们对神经元中复苏电流的调节速度了解有限。我们的研究探索了成纤维细胞生长因子同源因子2（FHF2）的亚型对Nav1.6介导的复苏电流的潜在调节作用，以填补我们在这方面知识的空白。FHF2亚型在外周感觉神经元中与Nav1.6共定位。细胞系研究表明，这些蛋白质对失活的调节存在差异。特别是，FHF2A介导长期失活，这是一种被认为与介导复苏电流的开放通道阻断机制相竞争的机制。另一方面，FHF2B缺乏介导长期失活的能力，可能会延迟失活，有利于开放通道阻断。基于这些观察结果，我们推测FHF2A会限制复苏电流，而FHF2B会增强复苏电流。总体而言，我们的结果表明，FHF2A通过增强长期失活和延迟恢复来负向调节快速复苏电流。相比之下，FHF2B正向调节复苏电流，且不改变长期失活。FHF2A与Navβ4（可能是感觉神经元中的内源性开放通道阻断剂）的嵌合构建体对复苏电流表现出不同的影响，表明FHF2A和Navβ4内的特定区域具有重要的调节功能。我们的数据还表明，在神经根性疼痛模型中，FHFAs和FHF2B亚型的表达受到不同调节，并且一种FHFA肽可显著减轻相关的神经元兴奋性过高。因此，这些发现表明，FHF2A和FHF2B调节感觉神经元中的复苏电流，并可能导致与某些疼痛病理状态相关的兴奋性过高。
