The FGF14F145S mutation disrupts the interaction of FGF14 with voltage-gated Na+ channels and impairs neuronal excitability
The FGF14F145S mutation disrupts the interaction of FGF14 with voltage-gated Na+ channels and impairs neuronal excitability
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DOI：
10.1523/jneurosci.2282-07.2007
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发表时间：
2007-10-31
影响因子：
5.3
通讯作者：
Nerbonne, Jeanne M.
中科院分区：
文献类型：
--
作者：
Laezza, Fernanda;Gerber, Benjamin R.;Nerbonne, Jeanne M.
成纤维细胞生长因子14（FGF 14）属于FGF蛋白（iFGF）的细胞内FGF同源因子亚家族，其不分泌并且不激活酪氨酸激酶受体。然而，iFGF已显示与电压门控Na+（Na-v）通道的成孔（α）亚基相互作用。在Fgf 14（-/-）小鼠中观察到的神经学表型以及在呈现认知障碍和脊髓小脑共济失调的荷兰家族中鉴定到的FGF 14错义突变（FGF 14（F145 S））表明FGF 14与神经元功能之间的联系。在这里，我们证明了FGF 14（F145 S）的表达减少了轴突起始段的Na-v α亚基表达，减弱了Nav通道电流，并降低了海马神经元的兴奋性。此外，与野生型FGF 14相反，FGF 14（F145 S）不直接与Na-v通道α亚基相互作用。相反，FGF 14（F145 S）与野生型FGF 14缔合并破坏野生型FGF 14和Nav通道α亚基之间的相互作用，表明突变型FGF 14（F145 S）蛋白充当显性负性，干扰野生型FGF 14和Nav通道α亚基之间的相互作用并改变神经元兴奋性。
Fibroblast growth factor 14 ( FGF14) belongs to the intracellular FGF homologous factor subfamily of FGF proteins ( iFGFs) that are not secreted and do not activate tyrosine kinase receptors. The iFGFs, however, have been shown to interact with the pore-forming ( alpha) subunits of voltage-gated Na+ ( Na-v) channels. The neurological phenotypes seen in Fgf14(-/-) mice and the identification of an FGF14 missense mutation ( FGF14(F145S)) in a Dutch family presenting with cognitive impairment and spinocerebellar ataxia suggest links between FGF14 and neuronal functioning. Here, we demonstrate that the expression of FGF14(F145S) reduces Na-v alpha subunit expression at the axon initial segment, attenuates Nav channel currents, and reduces the excitability of hippocampal neurons. In addition, and in contrast with wild-type FGF14, FGF14(F145S) does not interact directly with Na-v channel alpha subunits. Rather, FGF14(F145S) associates with wild-type FGF14 and disrupts the interaction between wild-type FGF14 and Na-v alpha subunits, suggesting that the mutant FGF14(F145S) protein acts as a dominant negative, interfering with the interaction between wild- type FGF14 and Nav channel alpha subunits and altering neuronal excitability.