Specificity of calcium channels in neuronal signaling

电压门控Ca通道（VGCC）是跨膜蛋白，允许Ca进入 在激活时。除了它们的生电作用，VGCC还提供了与细胞凋亡之间的关键联系。 膜去极化和广泛的非电活动。Ca 2+通过不同途径内流 不同类型的VGCC可以激活/调节不同的细胞信号传导级联。VGCC也是目标 用于由多种第二信使调节。磷酸化和去磷酸化是 快速调节Ca 2+通道活性的重要手段。新出现的证据表明， 大分子信号复合物的形成是特异性的机制之一， Ca 2+通道作用以及蛋白激酶对通道活性的快速调节，和/或 磷酸酶本项目的长期目标是了解Ca 2+通道的独特作用 神经元信号传导中的伴侣蛋白。在本申请中，我们将集中在三个新的Ca 2+通道 通过酵母双杂交筛选鉴定的伴侣蛋白，用于它们在PKC形成中的作用 信号传导复合物以及将mRNA靶向树突和/或轴突，以进行活性依赖性 局部蛋白质合成几个不同的假设将被测试，使用组合 分子和细胞生物学、生物化学、荧光成像和电生理学的方法。 我们将讨论：（1）生理因素，如蛋白激酶磷酸化，调节 PKCe-ENH-N型Ca 2+通道复合物的形成。(2)存在新的Ca 2+结合结构域， 负责PKCe-ENH和ENH-N-型Ca 2+之间相互作用的差异调节 渠道(3)功能性PKC信号传导复合物包括蛋白磷酸酶PP 2ca， 直接与Ca 2+通道的C末端结合。(4)一种新的通道伴侣蛋白PQ-46， 是一种RNA结合蛋白，与N-和P/Q-型Ca 2+通道结合，可能参与活性 依赖性地将mRNA靶向树突和/或轴突。研究结果将揭示 通过蛋白质-蛋白质相互作用建立的细胞信号传导网络实现其特异性。 本研究的结果将提供大脑中信号转导的分子机制， 将有助于了解正常的神经功能，如学习和记忆，并提供 神经系统疾病的原因，如阿尔茨海默病。

Voltage-gated Ca channels (VGCCs) are transmembrane proteins, which allow Ca entry upon activation. In addition to their electrogenic role, VGCCs provide a pivotal link between membrane depolarization and a wide range of nonelectrical activities. Ca2+ influx through different types of VGCCs can activate/regulate distinct cellular signaling cascades. VGCCs are also targets for modulation by a variety of second messengers. Phosphorylation and dephosphorylation are important means of rapid regulation of the Ca2+ channel activity. Emerging evidence shows that formation of macromolecular signaling complexes is one the of the mechanisms for the specificity of the Ca2+ channel action as well as rapid regulation of the channel activity by protein kinases and/or phosphatases. The long term goal of this project is to understand the unique role of Ca2+ channel partner proteins in neuronal signaling. In this application we will focus on three novel Ca2+ channel partner proteins, identified via yeast two-hybrid screening, for their roles in formation of a PKC signaling complex as well as in targeting mRNAs to dendrites and/or axons for activity-dependent localized protein synthesis. Several different hypotheses will be tested, using the combined approaches of molecular and cell biology, biochemistry, fluorescent imaging and electrophysiology. We will address: (1) Physiological factors, such as phosphorylation by protein kinases, regulate formation of the PKCe-ENH-N-type Ca2+ channel complex. (2) Novel Ca2+ binding domains exist, responsible for differential regulation of the interactions between PKCe-ENH and ENH-N-type Ca2+ channels. (3) The functional PKC signaling complex includes a protein phosphatase, PP2ca, which binds directly to the C-terminus of Ca2+ channels. (4) A novel channel partner protein, PQ-46, which is an RNA binding protein and binds to N- and P/Q-type Ca2+ channels, may be involved in activity dependent targeting of mRNAs to dendrites and/or axons. The results will shed light on how the cellular signaling network, established via protein-protein interactions, achieves its specificity. Results of this study will provide molecular mechanisms of signal transduction in the brain and will help understand normal neurological functions, such as learning and memory, and provide reasons for neurological disorders, such as Alzheimer's disease.