Ion Channel Regulation of Excitability in Immature Brain

建议的研究重点是信号通路调节兴奋性的分子机制。 未成熟海马神经元。信号级联激活蛋白激酶，对其进行生化修饰 底物蛋白质通过磷酸化。离子通道亚基的激酶磷酸化是一个很好的- 其特点是调节神经元的通道功能，从而调节细胞膜的兴奋性。尽管 这些洞察力，是调控未成熟膜特性的分子机制 神经元仍不清楚。我们提出了一个重要的调节兴奋性神经调节的基因座。 未成熟海马神经元是通过以下方式调节钾(K+)通道活性的 磷酸化。这项建议关注的是钙激活的K+通道，称为小电导 频道。这些亚单位构成电流的一个分量，称为后超极化 (AHP)。AHP遵循单个动作电位或一系列动作电位。因此，AHP法具有较强的实用性 在海马神经元早期形成电反应的关键作用，以及 这种电流的调制可以极大地影响神经元的兴奋性。鉴于K*通道对 神经元兴奋性的调节、K+通道表达和激酶的发育差异 调节可能在幼年期的正常可塑性和病理过程中发挥作用，如癫痫 大脑。对于这些研究，我们将集中在SK2和它所支持的电流，阿帕明敏感的AHP。 这一建议的中心假设是cAMP依赖的蛋白激酶(PKA)途径调节 SK2通道通过直接磷酸化发挥作用，这种翻译后机制以及 SK2通道和潜在的mAHP表达的发育调节有助于 发育中海马区神经元兴奋性的调节。作为我们研究的一部分，我们将调查 SK2通道亚单位的表达和调控存在发育差异的可能性 以及对阿帕明敏感的AHP，这可能是未成熟大脑良好特征观察的基础 表现出兴奋性增强的时期。这一特征可能有助于发育过程中的正常可塑性。 中枢神经系统以及病理，如未成熟脑内癫痫易感性增加。

The proposed studies focus on molecular mechanisms of signaling pathway modulation of excitability in neurons of immature hippocampus. Signaling cascades activate protein kinases, which biochemically modify substrate proteins via phosphorylation. Kinase phosphorylation of ion channel subunits is a well- characterized means of regulating channel function in neurons and therefore, membrane excitability. Despite these insights, the molecular mechanisms underlying the regulation of the membrane properties of immature neurons remain unclear. We propose that an important locus for mediating neuromodulation of excitability of neurons from immature hippocampus is through regulation of potassium (K+) channel activity by phosphorylation. This proposal focuses on Ca2+-activated K+ channels known as the small conductanceSK channels. These subunits contribute to a component of the current known as the afterhyperpolarization (AHP). The AHP follows a single action potential or a series of action potentials. Therefore, the AHP playsa critical role in shaping the electrical responsiveness of hippocampal neurons beginning early in life, and modulation of this current can dramatically affect neuronal excitability. Given that K* channels are critical to the regulation of neuronal excitability, developmental differences in K+ channel expression and kinase regulation may play a role in normal plasticity and pathological processes such as epilepsy in the immature brain. For these studies we will focus on SK2 and the current that it underlies, the apamin-sensitive AHP. The central hypothesis of this proposal is that the cAMP-dependent protein kinase (PKA) pathway regulates SK2 channel function through direct phosphorylation and that this post-translational mechanism as well as the developmental regulation of the expression of SK2 channels and the underlying mAHP contributes to the regulation of neuronal excitability in developing hippocampus. As part of our studies we will investigate the possibility that there are developmental differences in the expression and regulation of SK2 channel subunits and the apamin-sensitive AHP that may underlie the well-characterized observation that immature brain exhibits periods of increased excitability. This feature likely contributes to normal plasticity in developing CNS as well as pathology, such as increased seizure susceptibility in immature brain.