Molecular mechanisms of dendritic K channel function

树突状K通道功能的分子机制

• 批准号: 6999731
• 负责人: LiLian Yuan
• 金额: $ 7.3万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6999731
• 关键词: action potentials; biological signal transduction; calcium flux; dendrites; genetically modified animals; hippocampus; laboratory mouse; neural plasticity; neuroregulation; phosphorylation; potassium channel; protein structure function; pyramidal cells; site directed mutagenesis

DESCRIPTION (provided by applicant): With the ability to directly measure electrical signals from the neuronal dendrites, we have learned a great deal about the active properties of the dendrites over the past ten years. The most remarkable finding is that action potentials (b-APs) initiated at soma also actively propagate back into dendrites, reversing the conventional direction of information flow. Emerging evidence suggests that b-APs are involved in NMDA-receptor dependent plasticity by providing a large enough membrane depolarization to unblock NMDA receptors in synapses. Thus, factors determining b-AP back-propagation, b-AP amplitude and duration are likely to have an important impact on this signaling pathway. The fast activation kinetics, near-threshold activation profile, and a high current density in dendrites of CA1 pyramidal neurons have made A-type K+ channels the ideal determining factor of b-AP. The regulation, however, can be further complicated as A-type K+ channels themselves are subject to modulation by various protein kinases, neurotransmitters, and modulators, greatly extending the computational power of this system. Thus, A-type K+ channels represent a key regulatory component in hippocampal plasticity. Although quite some evidence suggests Kv4.2 is the major subunits underlying dendritic A-type K+ currents, this hypothesis has never been directly tested. We would like to know what mechanisms underlie the regulation and establishment of the unique dendritic gradient of A-type K+ channel distribution. Our recent work suggests the involvement of CaMKII activity in regulating surface expression of Kv4.2-mediated currents in the soma. These results formulate the intriguing hypotheses we wish to test: dendritic A-type K+ channels contribute to synaptic plasticity and neuronal activity helps to establish and maintain the characteristic dendritic distribution of this channel. Combining two unique techniques (dendritic recordings in mouse preparation and the use of a mutant form of sindbis virus that allows quick gene delivery in vivo with minimized neuronal toxicity), the studies proposed above should allow us to define the molecular mechanisms of A-type K+ channel mediated signal propagation and neuronal plasticity in dendrites.

描述（由申请人提供）：具有直接测量神经元树突的电信号的能力，在过去十年中，我们已经了解了大量有关树突的活动性能的知识。最引人注目的发现是，在SOMA发起的动作电位（B-APS）也会积极地传播回树突，从而逆转了信息流的常规方向。新兴的证据表明，通过提供足够大的膜去极化以解开突触中的NMDA受体，BAP与NMDA受体依赖性可塑性有关。因此，确定B-AP后传播，B-AP振幅和持续时间的因素可能会对该信号通路产生重要影响。 CA1锥体神经元的树突中的快速激活动力学，接近阈值激活曲线和高电流密度使A型K+通道成为B-AP的理想决定因素。但是，随着A型K+通道本身受到各种蛋白激酶，神经递质和调节剂的调节，该调节可能会更加复杂，从而大大扩展了该系统的计算能力。因此，A型K+通道代表海马可塑性中的关键调节成分。尽管有很多证据表明KV4.2是树突状A型K+电流的主要亚基，但该假设从未直接检验。我们想知道哪些机制是基于A型K+通道分布的独特树突梯度的调节和建立。我们最近的工作表明，CAMKII活性参与了调节SOMA中KV4.2介导的电流的表面表达。这些结果提出了我们希望测试的有趣的假设：树突A型K+通道有助于突触可塑性和神经元活性，有助于建立和维持该通道的特征性树突状分布。结合两种独特的技术（小鼠制备中的树突状记录和使用突变形式的sindbis病毒形式，可以在体内快速递送基因递送具有最小的神经元毒性），上面提出的研究应允许我们定义A-Type K+ K+ K+ K+的分子机制树突中的通道介导的信号传播和神经元可塑性。