Mechanisms of K+ Channel Modulation in Plasticity

描述（由申请人提供）：K+通道在基础代谢中起关键作用。 神经元功能，并表示通过其神经元活动的底物 可以动态调节神经元的兴奋性和放电特性。 该建议旨在确定磷酸化在以下方面的作用： 构成K+通道的蛋白质亚基的功能调节。 各种激酶，特别是PKA、CaMKII、PKC和ERK/MAPK的活化可 启动K+通道的磷酸化，这些激酶被 各种第二信使系统与神经递质 受体。因此，通过激酶激活对K+通道的调节可能不 只在信息处理和存储中起作用， 学习和记忆，而且在正常的信号整合突触 传输这个项目建立在最近的发现，电压门控 瞬时K+电流特别强烈地调节海马神经元 兴奋性和信息处理。Kv4.2为Shal型钾通道 一种定位于锥体神经元树突的亚单位蛋白， 生理和药理学证据表明，Kv4.2是 页岩型通道的成孔亚基。Kv4.2亚基与 K+通道相互作用蛋白 （KChIPs）在海马体中。KChIP是钙离子结合蛋白家族 与一个特定的转录抑制子有99%的同源性。的 Kv4.2和KChIP亚基的相互作用提供了多种底物， 激酶磷酸化以功能性地调节通道。此外该 KChIP的Ca 2+结合特性传达了Kv4.2和KChiPs在以下方面的可能作用： Ca 2+介导的可塑性。这一建议将决定 钾离子动态调节中IC通道亚基的磷酸化 水流具体来说，我们将研究野生型的生物物理特性， 和磷酸化位点突变通道通过电生理学 记录在卵母细胞中。此外，我们将研究它们的调制， 海马神经元，通过生化和免疫组织化学技术测定。

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.