Molecular mechanisms of dendritic K channel function

描述(申请人提供)：有了直接测量神经元树突电信号的能力，我们在过去的十年里对树突的活性特性有了很大的了解。最值得注意的发现是，在胞体启动的动作电位(b-AP)也积极地传播回树突，扭转了传统的信息流方向。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，参与了NMDA受体依赖的可塑性。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这一信号通路产生重要影响。CA1区锥体神经元的快速激活动力学、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，这种调节可能会更加复杂，因为A型K+通道本身受到各种蛋白激酶、神经递质和调制器的调节，从而极大地扩展了这个系统的计算能力。因此，A型K+通道是海马可塑性的关键调节成分。尽管有相当多的证据表明Kv4.2是树突状A型K+电流的主要亚基，但这一假说从未被直接验证过。我们想知道调节和建立独特的A型K+通道分布树突状梯度的机制是什么。我们最近的工作表明，CaMKII活性参与了调节Kv4.2介导的胞体电流的表面表达。这些结果阐明了我们希望检验的耐人寻味的假设：树突状A型K+通道有助于突触可塑性，神经元活动有助于建立和维持该通道特有的树突状分布。结合两种独特的技术(小鼠制备中的树突记录和使用Sindbis病毒的突变形式，允许在体内快速传递基因并将神经元毒性降至最低)，上述研究应使我们能够确定A-型K+通道介导的信号传播和树突中神经元可塑性的分子机制。

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.