Voltage-gated sodium channel Nav1.6 is modulated by p38 mitogen-activated protein kinase
Voltage-gated sodium channel Nav1.6 is modulated by p38 mitogen-activated protein kinase
复制标题
DOI：
10.1523/jneurosci.0541-05.2005
复制
发表时间：
2005-07-13
影响因子：
5.3
通讯作者：
Dib-Hajj, SD
中科院分区：
文献类型：
--
作者：
Wittmack, EK;Rush, AM;Dib-Hajj, SD
Na（v）1.6是有髓轴突中郎维氏结处的主要钠通道亚型，此外，还沿感觉神经元的无髓C纤维沿着分布。因此，由Na（v）1.6产生的钠电流的调制可能显著影响轴突传导。丝裂原活化蛋白激酶（MAPK）在神经元中表达，并且在损伤后被活化，例如在坐骨神经切断和缺氧后。虽然MAPK在信号转导和损伤诱导的基因表达调控中的作用已经得到了很好的证实，但是这些激酶磷酸化和调节电压门控钠通道的能力还没有报道。序列分析显示Na（v）1.6在胞质环（L1）中包含一个推定的MAP激酶识别模块，其连接结构域1和2。我们在这项研究中表明，钠通道和p38 MAP激酶共定位在大鼠脑组织中，激活的p38 α磷酸化Na（v）1.6的L1，特别是在丝氨酸553（S553），在体外。在这些试验中，通道的其他细胞质环和末端均未被活化的p38 α磷酸化。在用Na（v）1.6转染的神经元ND 7/23细胞系中，p38的激活导致Na（v）1.6峰电流幅度的显著降低，而对门控特性没有可检测的影响。在Na（v）1.6通道的L1内用丙氨酸取代S553阻止了p38介导的Na（v）1.6电流密度的降低。这是MAPK磷酸化和电压门控钠通道的调节的第一个证明，并且这种调节可能代表MAPK在调节神经元对损伤的反应中的额外作用。
Na(v)1.6 is the major sodium channel isoform at nodes of Ranvier in myelinated axons and, additionally, is distributed along unmyelinated C-fibers of sensory neurons. Thus, modulation of the sodium current produced by Na(v)1.6 might significantly impact axonal conduction. Mitogen-activated protein kinases (MAPKs) are expressed in neurons and are activated after injury, for example, after sciatic nerve transection and hypoxia. Although the role of MAPK in signal transduction and in injury-induced regulation of gene expression is well established, the ability of these kinases to phosphorylate and modulate voltage-gated sodium channels has not been reported. Sequence analysis shows that Na(v)1.6 contains a putative MAP kinase-recognition module in the cytoplasmic loop (L1), which joins domains 1 and 2. We show in this study that sodium channels and p38 MAP kinase colocalize in rat brain tissue and that activated p38 alpha phosphorylates L1 of Na(v)1.6, specifically at serine 553 (S553), in vitro. None of the other cytoplasmic loops and termini of the channel are phosphorylated by activated p38 alpha in these assays. Activation of p38 in the neuronal ND7/23 cell line transfected with Na(v)1.6 leads to a significant reduction in the peak Na(v)1.6 current amplitude, without a detectable effect on gating properties. The substitution of S553 with alanine within L1 of the Na(v)1.6 channel prevents p38-mediated reduction of Na(v)1.6 current density. This is the first demonstration of MAPK phosphorylation and modulation of a voltage-gated sodium channel, and this modulation may represent an additional role for MAPK in regulating the neuronal response to injury.