Mechanisms of K+ Channel Modulation in Plasticity

描述（由申请人提供）：K 通道在基本功能中发挥着关键作用 神经元功能，并代表神经元活动的基质 可以动态调节神经元的兴奋性和放电特性。 该提案旨在确定磷酸化在 构成 K 通道的蛋白质亚基的功能调节。 各种激酶的激活，特别是 PKA、CaMKII、PKC 和 ERK/MAPK 可以 启动 K 通道磷酸化，这些激酶被激活 与神经递质耦合的各种第二信使系统 受体。因此，激酶激活对 K 通道的调节可能不会 只在信息处理和存储过程中发挥作用 学习和记忆，而且在突触的正常信号整合过程中 传输。该项目建立在最近发现电压门控的基础上 瞬态 K 电流尤其强烈调节海马神经元 兴奋性和信息处理。 Kv4.2是Shal型K通道 亚基蛋白定位于锥体神经元树突和 生理学和药理学证据表明 Kv4.2 是 Shal 型通道的成孔亚基。 Kv4.2 亚基关联 具有相互作用蛋白家族，K 通道相互作用蛋白 (KChIPs) 在海马体中。 KChIP 是 Ca2 结合蛋白家族 与特定的转录抑制子有 99% 的同源性。的 Kv4.2 和 KChIP 亚基的相互作用为 激酶磷酸化以功能性调节通道。此外， KChIP 的 Ca2 结合特性传达了 Kv4.2 和 KChiP 在以下方面的可能作用： Ca2 介导的可塑性。该提案将确定以下角色： IC通道亚基磷酸化在K动态调节中的作用 电流。具体来说，我们将研究野生型的生物物理特性 和通过电生理学的磷酸化位点突变通道 卵母细胞中的记录。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进行测定。

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.