Regulation of Nav1.2 channels by brain-derived neurotrophic factor, TrkB, and associated fyn kinase
Regulation of Nav1.2 channels by brain-derived neurotrophic factor, TrkB, and associated fyn kinase
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DOI：
10.1523/jneurosci.5005-06.2007
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发表时间：
2007-10-24
影响因子：
5.3
通讯作者：
Catterall, William A.
中科院分区：
文献类型：
--
作者：
Ahn, Misol;Beacham, Daniel;Catterall, William A.
电压门控钠通道负责神经元中动作电位的起始和传播，并且其功能的调节对神经元兴奋性具有重要影响。钠通道由Src家族酪氨酸激酶途径调节，并且这种调节可以被特异性结合的受体磷蛋白酪氨酸磷酸酶-β逆转。然而，具体的酪氨酸激酶和信号通路是未知的。我们发现，大鼠脑中的钠通道与Fyn相互作用，Fyn是在脑中表达的四种Src家族酪氨酸激酶之一。Na（V）1.2通道和Fyn一起定位于培养的海马神经元的轴突、海马的苔藓纤维以及许多其他脑区域中的神经元的细胞体、树突和轴突中，并且它们与来自共转染的tsA-201细胞的Fyn共免疫沉淀。Fyn与Na（V）1.2通道的共表达通过增加失活速率并引起失活电压依赖性的负移来降低钠电流。通过酪氨酸受体激酶B（Trk B）/p75神经营养因子受体和Fyn激酶在转染细胞中重建从脑源性神经营养因子（BDNF）到钠通道的信号通路，导致钠通道失活速率增加，BDNF处理后失活的电压依赖性负移。这些结果表明，Fyn激酶与脑神经元中的钠通道相关，并且可以在BDNF激活TrkB/p75信号转导后通过酪氨酸磷酸化调节NaV1.2通道。
Voltage-gated sodium channels are responsible for action potential initiation and propagation in neurons, and modulation of their function has an important impact on neuronal excitability. Sodium channels are regulated by a Src-family tyrosine kinase pathway, and this modulation can be reversed by specifically bound receptor phosphoprotein tyrosine phosphatase-beta. However, the specific tyrosine kinase and signaling pathway are unknown. We found that the sodium channels in rat brain interact with Fyn, one of four Src-family tyrosine kinases expressed in the brain. Na(V)1.2 channels and Fyn are localized together in the axons of cultured hippocampal neurons, the mossy fibers of the hippocampus, and cell bodies, dendrites, and axons of neurons in many other brain areas, and they coimmunoprecipitate with Fyn from cotransfected tsA-201 cells. Coexpression of Fyn with Na(V)1.2 channels decreases sodium currents by increasing the rate of inactivation and causing a negative shift in the voltage dependence of inactivation. Reconstitution of a signaling pathway from brain-derived neurotrophic factor ( BDNF) to sodium channels via the tyrosine receptor kinase B (TrkB)/p75 neurotrophin receptor and Fyn kinase in transfected cells resulted in an increased rate of inactivation of sodium channels and a negative shift in the voltage dependence of inactivation after treatment with BDNF. These results indicate that Fyn kinase is associated with sodium channels in brain neurons and can modulate NaV1.2 channels by tyrosine phosphorylation after activation of TrkB/p75 signaling by BDNF.