Mechanisms of K+ Channel Modulation in Plasticity

K 通道可塑性调制机制

• 批准号: 6687714
• 负责人: Laura Schrader
• 金额: $ 13.91万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-17 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6687714
• 关键词: Xenopus oocyte; biological signal transduction; calcium binding protein; electrophysiology; enzyme activity; gene expression; hippocampus; immunocytochemistry; laboratory rabbit; laboratory rat; mutant; neural information processing; neural plasticity; neuroregulation; neurotransmitter receptor; phosphorylation; potassium channel; protein kinase; protein protein interaction; protein structure function; pyramidal cells; site directed mutagenesis; synapses; voltage /patch clamp; western blottings

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.

描述（由申请人提供）：K+频道在基本中起着至关重要的作用 神经元功能，并表示神经元活性的底物 可以动态调节神经元的兴奋性和发射特性。 该建议旨在确定磷酸化在 构成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 启动K+通道的磷酸化，这些激酶被激活 耦合到神经递质 受体。因此，通过激活激活对K+通道的调节可能不会 仅在信息处理和存储中发挥作用 学习和记忆，以及在突触的正常信号集成期间 传播。该项目建立在最近的发现，即电压门控 瞬态K+电流特别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 位于锥体神经元树突的亚基蛋白和 生理和药理证据表明，Kv4.2是 Shal型通道的孔形亚基。 KV4.2亚基助理 使用相互作用的蛋白质家族，K+通道相互作用的蛋白质 （kchips）在海马中。 Kchip是Ca2+结合蛋白的家族 与特征转录阻遏物同源的99％。这 KV4.2和KCHIP亚基的相互作用提供了多个基板 激酶磷酸化以在功能上调节通道。另外， Kchip的Ca2+结合特性传达了Kv4.2和Kchip的可能作用 CA2+介导的可塑性。该建议将决定 IC通道亚基在K+的动态调节中的磷酸化 电流。具体而言，我们将研究野生型的生物物理特性 和通过电生理的磷酸化位点突变体通道 卵母细胞的记录。此外，我们将研究他们的调制 海马神经元，通过生化和免疫组织化学技术测定。