L-type Calcium Channel Mediated Gene Expression

描述(申请人提供)：我们主要感兴趣的是确定L类型的钙通道，而不是其他钙进入途径，通过基因表达和蛋白质合成的变化来影响神经元可塑性的机制。具体地说，我们认为L类钙通道的不同α1亚基是唯一负责激活转录因子CREB和NFATC4的，这两个转录因子都调节细胞的兴奋性。我们将用来解决这个问题的实验分为三个具体目标： 1)确定(α1C)激活CREB所必需和充分的分子组成。 2)确定调控NFATC4激活的是否是(α1C和/或α1D组成的L型钙通道)。 3)阐明L类钙通道调控NFAT依赖转录的机制。 我们的总体目标是理解为什么许多影响细胞兴奋性的基因的表达受到钙内流的严格调控，特别是通过L类型的钙通道。因此，我们将深入了解各种细胞事件的机制，包括那些与发育、学习和记忆、痛觉过敏、药物成瘾和衰老有关的事件。

DESCRIPTION (provided by applicant): We are primarily interested in determining the mechanisms by which L-type calcium channels, and not other calcium entry routes, influence neuronal plasticity via changes in gene expression and protein synthesis. Specifically, we believe different alpha1 subunits of L-type calcium channels are uniquely responsible for activation of the transcription factors CREB and NFATc4, both of which regulate cellular excitability. The experiments we will use to address this question are organized into three specific aims: 1) Determine the molecular components of (alpha1C that are necessary and sufficient for activation of CREB. 2) Establish whether it is the (alpha1C and/or alpha1D comprised L-type calcium channel that regulates NFATc4 activation. 3) Elucidate the mechanism by which L-type calcium channels regulate NFAT-dependent transcription. Our overall goal is to comprehend why the expression of many genes influencing cell excitability are tightly regulated by calcium entry specifically through L-type calcium channels. Thus, we will gain insight into the mechanisms surrounding a variety of cellular events, including those linked to development, learning and memory, hyperalgesia, drug addiction and aging.