CHARACTERIZE MOLECULAR PROPERTIES OF MAMMALIAN NEURONAL DENDRITIC K CHANNEL

正常的神经元功能需要适当的组装、定位和 离子通道蛋白的调节。当这些系统崩溃时， 神经元不再能够正确地对突触输入做出反应。在……里面 这项提议，我们将研究分子基础的适当 神经元树突功能的调节。在海马CA1区锥体细胞 神经元，一种位于树突远端的A通道，并受到调节 通过多个蛋白激酶系统，是控制的关键部位 枝晶的活性性质。许多重要的问题仍然存在， 然而，要了解参与控制的分子过程 树突功能第一个重要的问题与分子有关 这些A频道的组成。Shal亚单位蛋白已经被 被认为是神经元A通道的重要组成部分。 在具体目标1中，我们将使用分子遗传学和免疫学 鉴定特定亚基蛋白质的方法 海马树突状A通道。另一个重要的问题涉及 为A产生树枝状局部化的操作机制 频道。对于其他通道和受体，PDZ结合序列具有 与膜蛋白的特定锚定有关 细胞骨架。在特定的目标2中，我们将测试Shal亚单位蛋白 在其C末端含有一个新的PDZ结合序列。最后，我们 我想了解激酶系统是如何调节A通道的。 在具体目标3中，我们将继续在#年进行磷酸化位点的工作。 Shal亚单位蛋白rKv4.2以确定功能后果 不同的激酶系统对这些通道的磷酸化的影响。

Normal neuronal function requires the proper assembly, localization, and regulation of ion channel proteins. When these systems break down, neurons are no longer able to properly respond to synaptic inputs. In this proposal, we will be examining the molecular basis for the proper regulation of neuronal dendritic function. In hippocampal CA1 pyramidal neurons, an A channel that is located in distal dendrites, and regulated by multiple protein kinase systems, is a critical site for controlling the active properties of dendrites. Many important questions remain, however, to understand the molecular processes involved in controlling dendritic function The first important question concerns the molecular composition of these A channels. Shal subunit proteins have been proposed to constitute an important component of A channels in neurons. In Specific Aim 1, we will use molecular genetic and immunological methods to identify specific subunit proteins that are used to form the hippocampal dendritic A channel. Another important question concerns the mechanisms operating to produce a dendritic localization for the A channels. For other channels and receptors, PDZ binding sequences have been implicated in specific anchoring of membrane proteins to the cytoskeleton. In Specific Aim 2, we will test if Shal subunit proteins contain a novel PDZ binding sequence at their C-terminus. Finally, we would like to understand how kinase systems act to regulate A channels. In Specific Aim 3, we will continue our work on phosphorylation sites in the Shal subunit protein rKv4.2 to determine the functional consequences of phosphorylation of these channels by different kinase systems.