Molecular mechanisms of dendritic K channel function

树突状K通道功能的分子机制

• 批准号: 6870420
• 负责人: LiLian Yuan
• 金额: $ 7.48万
• 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/6870420
• 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）：凭借直接测量神经元树突电信号的能力，我们在过去十年中对树突的活性特性有了很多了解。最引人注目的发现是，体细胞启动的动作电位（b-AP）也主动传播回树突，扭转了信息流的传统方向。新的证据表明，b-AP 通过提供足够大的膜去极化来解锁突触中的 NMDA 受体，从而参与 NMDA 受体依赖性可塑性。因此，决定 b-AP 反向传播、b-AP 幅度和持续时间的因素可能对该信号传导途径产生重要影响。 CA1 锥体神经元树突中的快速激活动力学、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。然而，由于 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，调节可能会更加复杂，从而极大地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的关键调节成分。尽管相当多的证据表明 Kv4.2 是树突 A 型 K+ 电流的主要亚基，但这一假设从未得到直接检验。我们想知道A型K+通道分布的独特树突梯度的调节和建立背后的机制是什么。我们最近的工作表明 CaMKII 活性参与调节体细胞中 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假设：树突 A 型 K+ 通道有助于突触可塑性，而神经元活动有助于建立和维持该通道的特征性树突分布。结合两种独特的技术（小鼠制备中的树突记录和使用辛德毕斯病毒的突变形式，该病毒可以在体内快速进行基因传递，同时将神经元毒性降至最低），上述研究应该使我们能够定义 A 型 K+ 的分子机制通道介导的信号传播和树突中的神经元可塑性。