Fibroblast growth factor homologous factor 2 attenuates excitability of DRG neurons.
Fibroblast growth factor homologous factor 2 attenuates excitability of DRG neurons.
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DOI：
10.1152/jn.00361.2022
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发表时间：
2022-11-01
影响因子：
2.5
通讯作者：
Dib-Hajj, Sulayman D.
中科院分区：
文献类型：
--
作者：
Effraim, Philip R.;Estacion, Mark;Zhao, Peng;Sosniak, Daniel;Waxman, Stephen G.;Dib-Hajj, Sulayman D.
成纤维细胞生长因子同源因子(FHFs)是成纤维细胞生长因子蛋白的胞浆成员。该亚家族的四个成员(FHF1-4)在多个组织中以异构体依赖的方式差异表达。FHF蛋白的突变与多种神经疾病有关。FHF蛋白与电压门控钠(Nav)通道的C末端结合，调节这些通道的电流幅度和门控特性。在DRG神经元中表达的FHF2有两种主要的剪接异构体，FHF2A和FHF2B，它们的N末端的长度和序列不同，已被证明对Nav1.7的门控特性有不同的调节作用，Nav1.7是DRG神经元放电的主要驱动因素。周围神经切断后，FHF2的表达水平下调，提示它们可能通过作用于损伤后的NAV通道来调节神经元的兴奋性。我们之前已经证明，FHF2的敲除会导致Nav1.7门控特性的功能增益变化：增强的重新启动、增加的电流密度和超极化的激活。由此我们推测，FHF2基因敲除也可能导致DRG过度兴奋。在这里，我们表明，无论是单独的FHF2A还是FHF2的所有异构体，都会导致DRG神经元兴奋性的增加。此外，我们证明补充FHF2A和FHF2B降低了DRG神经元的兴奋性。FHF2A或FHF2B的过表达也降低了用炎性介质鸡尾酒处理的DRG神经元的兴奋性，这是一种炎性疼痛的模型。我们的数据表明，神经损伤后神经元兴奋性的增加可能部分通过FHF2-Nav1.7相互作用的丧失而触发。
Fibroblast Growth Factor Homologous Factors (FHFs) are cytosolic members of the of the FGF proteins. Four members of this subfamily (FHF1–4) are differentially expressed in multiple tissues in an isoform-dependent manner. Mutations in FHF proteins have been associated with multiple neurological disorders. FHF proteins bind to the C-terminus of voltage-gated sodium (Nav) channels and regulate current amplitude and gating properties of these channels. FHF2, which is expressed in DRG neurons, has two main splicing isoforms, FHF2A and FHF2B, which differ in the length and sequence of their N-termini, have been shown to differentially regulate gating properties of Nav1.7, a channel that is a major driver of DRG neuron firing. FHF2 expression levels are downregulated following peripheral nerve axotomy, which suggests that they may regulate neuronal excitability via an action on Nav channels after injury. We have previously shown that knockdown of FHF2 leads to gain-of-function changes in Nav1.7 gating properties: enhanced repriming, increased current density and hyperpolarized activation. From this we posited that knockdown of FHF2 might also lead to DRG hyperexcitability. Here we show that knockdown of either FHF2A alone or all isoforms of FHF2 results in increased DRG neuron excitability. In addition, we demonstrate that supplementation of FHF2A and FHF2B reduces DRG neuron excitability. Overexpression of FHF2A or FHF2B also reduced excitability of DRG neurons treated with a cocktail of inflammatory mediators, a model of inflammatory pain. Our data suggest that increased neuronal excitability after nerve injury might be triggered, in part, via a loss of FHF2-Nav1.7 interaction.
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DOI：
10.1007/s00424-016-1911-9
发表时间：
2017-02
期刊：
Pflugers Archiv : European journal of physiology
影响因子：
--
作者：
Barbosa C;Xiao Y;Johnson AJ;Xie W;Strong JA;Zhang JM;Cummins TR
通讯作者：
Cummins TR
影响因子：
4
作者：
Devor, M
通讯作者：
Devor, M
影响因子：
5.3
作者：
Gecz, J;Baker, E;Mulley, JC
通讯作者：
Mulley, JC
影响因子：
3.3
作者：
Grubinska, B.;Chen, L.;Gingras, J.
通讯作者：
Gingras, J.
影响因子：
14.8
作者：
Dib-Hajj, Sulayman D.;Choi, Jin Sung;Waxman, Stephen G.
通讯作者：
Waxman, Stephen G.