Mechanisms of K+ Channel Modulation in Plasticity

描述(申请人提供)：K+通道在基础 神经元的功能，并代表神经元活动的底物 可以动态调节神经元的兴奋性和放电特性。 这一建议旨在确定磷酸化在细胞内的作用 组成K+通道的蛋白质亚基的功能调节。 激活各种激酶，特别是PKA、CaMKII、PKC和ERK/MAPK可以 启动K+通道的磷酸化，这些激酶被激活 与神经递质偶联的各种第二信使系统 感受器。因此，通过激活激酶来调节K+通道可能不会 仅在信息处理和存储过程中起作用 学习和记忆，也是在正常信号整合期间的突触 变速箱。该项目建立在最近发现的电压门控的基础上 瞬时K+电流对海马神经元的调制作用尤其强烈 兴奋性和信息处理。Kv4.2是一种Shal类型的K+通道 亚基蛋白定位于锥体神经元树突和 生理和药理学证据表明，Kv4.2是 砂岩型河道成孔亚单位。Kv4.2亚基关联 与一家族相互作用的蛋白，K+通道相互作用蛋白 (KChIPs)在海马区。KChIPs是一类钙结合蛋白家族 它们与一个特定的转录抑制因子有99%的同源性。这个 Kv4.2和KChIP亚基的相互作用提供了多种底物 激酶的磷酸化对通道进行功能调节。此外， KChIP的钙结合特性传达了Kv4.2和KChIPs在 钙离子介导的可塑性。这项提案将决定 IC通道亚基在K+动态调节中的磷酸化 洋流。具体地说，我们将研究野生型的生物物理性质 和通过电生理的磷酸化位点突变通道 卵母细胞中的录音。此外，我们还将研究它们在 用生化和免疫组织化学技术检测海马神经元。

DESCRIPTION (provided by applicant): K+ channels play a critical role in basic neuronal function, and represent a substrate through which neuronal activity can dynamically regulate the excitability and firing properties of neurons. This proposal is designed to determine the role of phosphorylation in functional modulation of the protein subunits that constitute K+ channels. Activation of various kinases, specifically PKA, CaMKII, PKC and ERK/MAPK can initiate phosphorylation of K+ channels, and these kinases are activated by various second messenger systems that are coupled to neurotransmitter receptors. Thus, the regulation of K+ channels by kinase activation may not only play a role in information processing and storage that occurs during learning and memory, but also during the normal signal integration of synaptic transmission. This project builds on the recent discovery that voltage gated transient K+ currents in particular strongly modulate hippocampal neuron excitability and information processing. Kv4.2 is a Shal-type K+ channel subunit protein that is localized to pyramidal neuron dendrites and physiological and pharmacological evidence suggests that Kv4.2 is the pore-forming subunit of the Shal-type channels. The Kv4.2 subunits associate with a family of interacting proteins, the K+ Channel Interacting Proteins (KChIPs) in the hippocampus. The KChIPs are a family of Ca2+ binding proteins that are 99 percent homologous to a characterized transcription repressor. The interaction of the Kv4.2 and KChIP subunits provides multiple substrates for kinase phosphorylation to functionally regulate the channels. In addition, the Ca2+-binding properties of KChIP convey a possible role for Kv4.2 and KChiPs in Ca2+ mediated plasticity. This proposal will determine the role of phosphorylation of IC channel subunits in the dynamic regulation of K+ currents. Specifically, we will study the biophysical properties of wild-type and phosphorylation-site mutant channels through electrophysiological recordings in oocytes. In addition, we will study their modulation in hippocampal neurons, assayed by biochemical and immunohistochemical techniques.