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首页> 外文期刊>The European Journal of Neuroscience >Modulation by the BK accessory beta4 subunit of phosphorylation-dependent changes in excitability of dentate gyrus granule neurons.
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Modulation by the BK accessory beta4 subunit of phosphorylation-dependent changes in excitability of dentate gyrus granule neurons.

机译：BK辅助beta4亚基的齿状回颗粒神经元兴奋性的磷酸化依赖性变化的调制。

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摘要

Large-conductance voltage- and calcium-activated potassium (BK) channels are large-conductance calcium- and voltage-activated potassium channels critical for neuronal excitability. Some neurons express so called fast-gated, type I BK channels. Other neurons express BK channels assembled with the accessory beta4 subunit conferring slow gating of type II BK channels. However, it is not clear how protein phosphorylation modulates these two distinct BK channel types. Using beta4-knockout mice, we compared fast- or slow-gated BK channels in response to changes in phosphorylation status of hippocampus dentate gyrus granule neurons. We utilized the selective PP2A/PP4 phosphatase inhibitor Fostriecin to study changes in action potential shape and firing properties of the neurons. In beta4-knockout neurons, Fostriecin increases BK current, speeds up BK channel activation and reduces action potential amplitudes. Fostriecin increases spiking during early components of an action potential train. In contrast, inhibition of BK channels through beta4 in wild-type neurons or by the BK channel inhibitor Paxilline opposes Fostriecin effects. Voltage clamp recordings of neurons reveal that Fostriecin increases both calcium and BK currents. However, Fostriecin does not activate BK alpha channels in transfected HEK293 cells lacking calcium channels. In summary, these results suggest that fast-gating, type I BK channels lacking beta4 can increase neuronal excitability in response to reduced phosphatase activity and activation of calcium channels. By opposing BK channel activation, the beta4 subunit plays an important role in moderating firing frequency regardless of changes in phosphorylation status.
机译：大电导的电压和钙激活钾（BK）通道是对神经元兴奋性至关重要的大电导的钙和电压激活的钾通道。一些神经元表达所谓的快速门控I型BK通道。其他神经元表达与辅助beta4亚基组装在一起的BK通道，赋予II型BK通道缓慢的门控。但是，尚不清楚蛋白质的磷酸化如何调节这两种不同的BK通道类型。使用beta4基因敲除小鼠，我们比较了快速或慢速门控BK通道响应海马齿状回颗粒神经元的磷酸化状态变化。我们利用选择性PP2A / PP4磷酸酶抑制剂Fostriecin来研究神经元的动作电位形状和放电特性的变化。在beta4基因敲除的神经元中，新霉素增加BK电流，加速​​BK通道激活并降低动作电位振幅。 Fostriecin在动作电位训练的早期阶段会增加峰值。相反，在野生型神经元中通过beta4抑制BK通道或通过BK通道抑制剂Paxilline抑制Fostriecin的作用。神经元的电压钳记录显示，去甲鸟精增加钙和BK电流。但是，在缺乏钙通道的转染HEK293细胞中，伏斯特霉素不能激活BKα通道。总之，这些结果表明，缺乏β4的快速门控I型BK通道可响应磷酸酶活性降低和钙通道激活而增加神经元兴奋性。通过对抗BK通道激活，无论磷酸化状态如何变化，β4亚基在调节触发频率中都起着重要作用。

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