Members of FGF Family Associate with Na+ Channel Nav1.6

描述（由申请人提供）：电压门控钠通道Nav1.6在成体髓鞘轴突的中枢神经系统和PNS、初始段和Ranvier节点均有表达（Burgess et al., 1995; Schaller et al., 1995; Boiko et al., 2001; Black et al., 2002）。Nav1.6与其他钠离子通道的不同之处是，它表达复苏和持续电流（Raman and Bean, 1997; Smith et al., 1998），这两种电流都是细胞类型依赖的，表明存在细胞特异性调节剂（Grieco et al., 2002）。确定和表征蛋白质与Nav1.6的相互作用对于确定生物物理调节背后的机制以及该通道的分布和聚集性至关重要。利用Nav1.6的c端进行酵母双杂交筛选发现，成纤维细胞生长因子家族的成员FHF2b （FGF13b）与Nav1.6相互作用。在本研究中，Nav1.6和FHF2b之间的相互作用将在哺乳动物细胞中进行表征。在第二个目标中，将确定这种相互作用对通道和通道定位的生物物理特性的调节作用。第三个目标是确定Nav1.6/FHF2b复合体是否招募激酶，以及该通道的生物物理特性是否受到激酶相互作用或激活的调节。最后，本提案将研究另一种c端结合蛋白钙调蛋白（calmodulin）对Nav1.6和FHF2b相互作用的影响。这些关于Nav1.6调节的研究可能具有临床应用价值，因为该通道参与神经系统疾病。

DESCRIPTION (provided by applicant): The voltage-gated sodium channel Nav1.6 is expressed in both the CNS and PNS, the initial segment, and nodes of Ranvier of adult myelinated axons (Burgess et al., 1995; Schaller et al., 1995; Boiko et al., 2001; Black et al., 2002). Nav1.6 is distinct from the other sodium channels in that it expresses resurgent and persistent currents (Raman and Bean, 1997; Smith et al., 1998), both of which have been shown to be cell-type dependent, suggesting a cell-specific modulator (Grieco et al., 2002). Determination and characterization of the interaction of proteins with Nav1.6 is crucial in order to ascertain the mechanisms behind the biophysical modulation, and the distribution and clustering of this channel. A yeast two-hybrid screen using the C-terminus of Nav1.6 found that a member of the fibroblast growth factor family, FHF2b (FGF13b), interacts with Nav1.6. In this study, the interaction between Nav1.6 and FHF2b will be characterized in mammalian cells. In the second aim, the modulatory effects of this interaction on the biophysical properties of the channel and channel localization will be determined. The third aim will determine if the Nav1.6/FHF2b complex recruits a kinase, and if the biophysical properties of the channel are modulated by kinase interactions or activation. Finally, this proposal will look at the effect of calmodulin, another C-terminal binding protein, on the interaction between Nav1.6 and FHF2b. These studies on the modulation of Nav1.6 may have clinical application due to the involvement of this channel in neurological disorders.