FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons.
FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons.
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DOI：
10.1007/s00424-016-1911-9
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发表时间：
2017-02
期刊：
影响因子：
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通讯作者：
Cummins TR
中科院分区：
文献类型：
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作者：
Barbosa C;Xiao Y;Johnson AJ;Xie W;Strong JA;Zhang JM;Cummins TR
Nav1.6和Nav1.6介导的复苏性电流与多种疼痛病理有关。然而，我们对神经元中复活电流的调制速度的了解是有限的。我们的研究探索了成纤维细胞生长因子同源因子2(FHF2)的异构体对Nav1.6介导的复苏性电流的潜在调节，以努力弥补我们知识上的差距。在外周感觉神经元中，FHF2亚型与Nav1.6共存。细胞系研究表明，这些蛋白质对失活有不同的调节作用。特别是，FHF2a介导了长期失活，这一机制被认为是为了与介导复活电流的开放通道阻滞剂机制竞争。另一方面，FHF2B缺乏调节长期失活的能力，可能会延迟失活，有利于开放通道阻断。基于这些观察，我们假设FHF2A限制复苏电流，而FHF2B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。相反，FHF2B正向调节复苏电流，并不改变长期失活。FHF2A和NAVβ4的嵌合结构(可能是感觉神经元中的内源性开放通道阻滞剂)对复苏电流显示出不同的作用，提示FHF2A和NAVβ4中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亚型的表达是不同的，相关的神经元超兴奋性显著地被FHFA多肽减弱。因此，这些发现表明，FHF2A和FHF2B调节感觉神经元的复苏性电流，并可能与某些疼痛病理相关的过度兴奋有关。
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 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.