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Activation of Sodium-Activated Potassium Channels by Sodium Influx.

机译：钠流入激活钠激活的钾通道。

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摘要

Sodium-activated potassium channels (KNa channels) are a small family of high-conductance K+-channels activated by increases in the intracellular sodium concentration. KNa channels are broadly expressed in the nervous system, but the role, and even existence, of K Na channels has been overlooked or doubted by neurophysiologists for many years. In the face of evidence to suggest a role for KNa channels in normal physiology, resting Na+ concentrations are lower than reported to be sufficient for activation of KNa channels. This contradiction coupled with methodological shortcomings of some investigations into KNa channels tempered acceptance of a contribution of K Na channels in normal conditions. The goal of my dissertation research has been to determine if KNa channels are participants in the normal physiology of neurons.;I have demonstrated the prominent activation of KNa channels by sodium influx under normal physiological conditions in neurons of the rat central nervous system. Large KNa currents were revealed by preventing sodium influx using multiple experimental manipulations in neurons prepared from multiple brain regions. Transfection of neurons with siRNA directed against Slack was used to demonstrate its contribution to the encoding of KNa channels.;Many of my experiments emphasize the importance of the persistent sodium current (INaP) as a source of sodium to activate KNa channels. One line of these experiments entailed the recording and measurement of the activity of individual KNa channel in membranes isolated from neurons. This work is the first demonstration of KNa channel activation by sodium-influx using single channel recordings. I also present results demonstrating that INaP is active across a broad range of voltages, including membrane resting potentials, using both whole cell recordings as well as recordings of individual sodium-channels from isolated patches.;Finally, I've demonstrated that after blocking sodium influx, the resulting decrease in KNa channel activity is a slow process (tau ∼ 13 seconds). I developed a strategy to isolate KNa channel activity in neurons by taking advantage of this slow decrease in KNa channel activity. Isolation of neuronal KNa currents has not previously been possible due to a lack of specific antagonists for K Na channels.
机译：钠激活钾通道（KNa通道）是一小家族的高电导K +通道，可通过细胞内钠浓度的增加来激活。 KNa通道在神经系统中广泛表达，但是多年来，神经生理学家一直忽略或怀疑K Na通道的作用，甚至存在。面对表明KNa通道在正常生理中起作用的证据，静息的Na +浓度低于所报道的足以激活KNa通道的浓度。这种矛盾加上对KNa通道的某些研究的方法学缺陷，在正常情况下抑制了对K Na通道贡献的接受。本论文的研究目的是确定KNa通道是否参与神经元的正常生理。我已经证明了在正常生理条件下钠中流在大鼠中枢神经系统神经元中KNa通道的显着激活。通过在多个大脑区域制备的神经元中进行多种实验操作来防止钠流入，揭示出了较大的KNa电流。用针对Slack的siRNA转染神经元来证明其对KNa通道编码的贡献。;我的许多实验都强调了持续钠电流（INaP）作为激活KNa通道的钠源的重要性。这些实验中的一条需要在从神经元分离的膜中记录和测量单个KNa通道的活性。这项工作是使用单通道录音通过钠流入激活KNa通道的首次演示。我还提供了结果，证明了全细胞记录以及来自分离斑块的单个钠通道的记录，表明INaP在很宽的电压范围内都具有活性，包括膜静止电位。最后，我证明了在阻断钠后大量涌入后，KNa通道活性降低是一个缓慢的过程（τ〜13秒）。我开发了一种策略，可以利用这种KNa通道活性的缓慢降低来隔离神经元中的KNa通道活性。由于缺乏K Na通道的特异性拮抗剂，以前不可能分离神经元KNa电流。

著录项

  • 作者

    Hage, Travis Allen.;

  • 作者单位

    Washington University in St. Louis.;

  • 授予单位 Washington University in St. Louis.;
  • 学科 Biology Neuroscience.;Biology Physiology.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 181 p.
  • 总页数 181
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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