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， 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响应突触输入。在 这个建议，我们将研究适当的分子基础， 调节神经元树突功能。海马ca 1区 神经元，一个位于远端树突的A通道， 由多个蛋白激酶系统，是一个关键的网站， 树突的活性许多重要的问题仍然存在， 然而，为了了解控制这些疾病的分子过程， 树突状细胞的功能第一个重要的问题是关于 这些通道的组成。Shal亚基蛋白已经被 提出构成神经元中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 鉴定用于形成蛋白质的特定亚基蛋白质的方法 海马树突状细胞A通道。另一个重要的问题是， 产生树突状定位的机制 渠道对于其他通道和受体，PDZ结合序列具有 与膜蛋白的特异性锚定有关， 细胞骨架在特定目标2中，我们将测试Shal亚基蛋白 在它们的C-末端含有新的PDZ结合序列。最后我们 想了解激酶系统如何调节A通道。 在具体目标3中，我们将继续研究磷酸化位点， Shal亚基蛋白rKv4.2，以确定功能性后果 这些通道被不同的激酶系统磷酸化。

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.