Alternative Splicing Regulates Kv3.1 Polarized Targeting to Adjust Maximal Spiking Frequency
Alternative Splicing Regulates Kv3.1 Polarized Targeting to Adjust Maximal Spiking Frequency
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DOI：
10.1074/jbc.m111.299305
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发表时间：
2012-01-13
影响因子：
4.8
通讯作者：
Gu, Chen
中科院分区：
文献类型：
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作者：
Gu, Yuanzheng;Barry, Joshua;Gu, Chen
在树突处接收到的突触输入被转换成由大多数神经元中的轴突起始段处产生的动作电位编码的数字输出。在这里，我们报告说，选择性剪接调节极化靶向Kv3.1电压门控钾（KV）通道，以调整输入输出关系。培养海马神经元的峰发放频率与内源性Kv 3通道的水平相关。轴突Kv3.1b（Kv3.1剪接变体的较长形式）的表达有效地将慢速尖峰的年轻神经元转化为快速尖峰的神经元; Kv1.2或Kv4.2通道结构的情况并非如此。尽管与Kv3.1b具有相同的生物物理特性，但树突状Kv3.1a在增加最大放电频率方面的效果明显较差。这表明通道靶向在调节尖峰频率中的可能作用。突变研究表明，Kv3.1b N/C末端之间的静电排斥，由其C-末端剪接结构域，揭露Kv3.1b轴突靶向基序。Kv3.1b轴突靶向增加响应于延长去极化的最大尖峰频率。这一发现进一步支持的结果，本地应用的通道阻滞剂和计算机模拟。总之，我们的研究表明，选择性剪接通过调节Kv3.1通道的极化靶向来控制神经元的放电速率。
Synaptic inputs received at dendrites are converted into digital outputs encoded by action potentials generated at the axon initial segment in most neurons. Here, we report that alternative splicing regulates polarized targeting of Kv3.1 voltage-gated potassium (Kv) channels to adjust the input-output relationship. The spiking frequency of cultured hippocampal neurons correlated with the level of endogenous Kv3 channels. Expression of axonal Kv3.1b, the longer form of Kv3.1 splice variants, effectively converted slow-spiking young neurons to fast-spiking ones; this was not the case for Kv1.2 or Kv4.2 channel constructs. Despite having identical biophysical properties as Kv3.1b, dendritic Kv3.1a was significantly less effective at increasing the maximal firing frequency. This suggests a possible role of channel targeting in regulating spiking frequency. Mutagenesis studies suggest the electrostatic repulsion between the Kv3.1b N/C termini, created by its C-terminal splice domain, unmasks the Kv3.1b axonal targeting motif. Kv3.1b axonal targeting increased the maximal spiking frequency in response to prolonged depolarization. This finding was further supported by the results of local application of channel blockers and computer simulations. Taken together, our studies have demonstrated that alternative splicing controls neuronal firing rates by regulating the polarized targeting of Kv3.1 channels.