CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal excitability
CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal excitability
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DOI：
10.1096/fj.201500161
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发表时间：
2016-06-01
期刊：
影响因子：
4.8
通讯作者：
Laezza, Fernanda
中科院分区：
文献类型：
--
作者：
Hsu, Wei-Chun J.;Scala, Federico;Laezza, Fernanda
最近的数据显示，成纤维细胞生长因子14（FGF 14）结合并控制电压门控钠（Nav）通道的功能，其表型结果对神经元兴奋性具有影响。人类FGF 14基因突变与FGF 14（-/-）小鼠中部分重现的脑部疾病相关。因此，调节FGF 14：Nav通道相互作用的信号传导途径可能是重要的治疗靶点。FGF 14：Nav1.6复合物的小分子调节剂的基于生物发光的筛选鉴定了4，5，6，7-四溴苯并三唑（TBB），一种有效的酪蛋白激酶2（CK 2）抑制剂，作为FGF 14：Nav1.6相互作用的强抑制剂。通过TBB抑制CK 2降低了FGF 14与Nav1.6和Nav1.2通道的相互作用。质谱法证实了CK 2在S228和S230处直接磷酸化FGF 14，并且在这些位点突变为丙氨酸修饰了FGF 14对Nav1.6介导的电流的调节。在1 d的体外海马神经元中，TBB诱导FGF 14表达减少，瞬时Na+电流幅度降低，Nav通道稳态失活的电压依赖性超极化转变。在成熟神经元中，TBB降低FGF 14的轴树突极性。在野生型小鼠海马1区脑片中，TBB通过增加动作电位阈值和降低放电频率损害神经元兴奋性。重要的是，这些兴奋性的变化在Fgf 14（-/-）小鼠中重现，并且Fgf 14的缺失封闭了在野生型小鼠中观察到的TB依赖性表型。这些结果表明CK 2-FGF 14轴可以调节Nav通道和神经元兴奋性。C. J.，Scala，F.，Nenov，M. N.，Wildburger，N. C.的方法，Elferink，H.，辛格A. K.，切森角B.，Buzhdygan，T.，Sohail，M.，Shavkunov，A.美国，帕诺瓦，N。一、尼尔森角L.，Rudra，J.S.，利希蒂角F.、Laezza，F. CK 2活性是FGF 14与电压门控钠通道和神经元兴奋性相互作用所必需的。
Recent data shows that fibroblast growth factor 14 (FGF14) binds to and controls the function of the voltage-gated sodium (Nav) channel with phenotypic outcomes on neuronal excitability. Mutations in the FGF14 gene in humans have been associated with brain disorders that are partially recapitulated in Fgf14(-/-) mice. Thus, signaling pathways that modulate the FGF14:Nav channel interaction may be important therapeutic targets. Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7-tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. In 1 d in vitro hippocampal neurons, TBB induced a reduction in FGF14 expression, a decrease in transient Na+ current amplitude, and a hyperpolarizing shift in the voltage dependence of Nav channel steady-state inactivation. In mature neurons, TBB reduces the axodendritic polarity of FGF14. In cornu ammonis area 1 hippocampal slices from wild-type mice, TBB impairs neuronal excitability by increasing action potential threshold and lowering firing frequency. Importantly, these changes in excitability are recapitulated in Fgf14(-/-) mice, and deletion of Fgf14 occludes TBB-dependent phenotypes observed in wild-type mice. These results suggest that a CK2-FGF14 axis may regulate Nav channels and neuronal excitability.Hsu, W.-C. J., Scala, F., Nenov, M. N., Wildburger, N. C., Elferink, H., Singh, A. K., Chesson, C. B., Buzhdygan, T., Sohail, M., Shavkunov, A. S., Panova, N. I., Nilsson, C. L., Rudra, J. S., Lichti, C. F., Laezza, F. CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal excitability.