Molecular mechanisms of dendritic K channel function

描述（由申请人提供）：由于能够直接测量来自神经元树突的电信号，在过去的十年中，我们已经了解了大量关于树突的活性特性。最引人注目的发现是，动作电位（b-AP）发起的索马也积极传播回树突，扭转了传统的方向的信息流。新出现的证据表明，b-AP通过提供足够大的膜去极化以解除突触中NMDA受体的阻滞而参与NMDA受体依赖性可塑性。因此，决定b-AP反向传播、b-AP振幅和持续时间的因素可能对该信号通路具有重要影响。CA 1区锥体神经元树突的快速激活动力学、近阈值激活曲线和高电流密度使A型钾通道成为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，这种调节可以进一步复杂化，从而大大扩展了该系统的计算能力。因此，A型K+通道代表了海马可塑性的关键调控成分。虽然有相当多的证据表明Kv4.2是树突状细胞A型K+电流的主要亚基，但这一假设从未得到直接验证。我们想知道是什么机制的调节和建立独特的树突状梯度的A型钾通道分布。我们最近的工作表明，参与调节表面表达的Kv4.2介导的电流在索马的CaMK Ⅱ活性。这些结果制定有趣的假设，我们希望测试：树突状A型K+通道有助于突触可塑性和神经元活动有助于建立和维持该通道的特征树突状分布。结合两种独特的技术（树突状记录在小鼠制备和使用的辛德毕斯病毒的突变形式，允许快速基因传递在体内与最小的神经元毒性），上述研究建议应允许我们定义的分子机制A型K+通道介导的信号传播和神经元的可塑性树突。

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.