Ion Channel Regulation of Excitability in Immature Brain

这些研究主要集中在神经元兴奋性信号通路调节的分子机制上， 未成熟海马神经元。信号级联激活蛋白激酶， 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- 其特征在于调节神经元中的通道功能，从而调节膜兴奋性。尽管 这些见解，未成熟的细胞膜特性调节的分子机制， 神经元仍然不清楚。我们认为，一个重要的位点介导的神经调制的兴奋性， 来自未成熟海马的神经元是通过调节钾（K+）通道活性， 磷酸化该建议关注被称为小电导SK的Ca 2+激活的K+通道 渠道这些亚单位构成了称为后超极化的电流成分 （AHP）。AHP遵循单个动作电位或一系列动作电位。因此，层次分析法发挥了 在塑造海马神经元在生命早期开始的电反应性中起关键作用， 该电流的调节可显著影响神经元兴奋性。考虑到K* 通道对于 神经元兴奋性的调节，K+通道表达和激酶的发育差异 调节可能在未成熟儿童的正常可塑性和癫痫等病理过程中发挥作用 个脑袋对于这些研究，我们将重点放在SK 2和它所依据的电流，apamin敏感的AHP。 该建议的中心假设是cAMP依赖性蛋白激酶（PKA）途径调节 SK2通道通过直接磷酸化发挥功能，这种翻译后机制以及 SK2通道表达的发育调节和潜在的mAHP有助于 发育中海马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通道亚基的表达和调节可能存在发育差异 以及对apamin敏感的AHP，这可能是未成熟的大脑 表现出兴奋性增加的时期。这一特征可能有助于发育过程中的正常可塑性。 CNS以及病理学，如未成熟大脑中癫痫发作易感性增加。

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.