Store-operated channels in the nervous system

神经系统中的Ca2+信号介导多种细胞功能，包括 神经递质释放、膜兴奋性和增殖。控件的动态功能 由这种多功能信使介导的信号并产生特异性，神经元被赋予了一种 大量的离子通道、泵和细胞器，它们共同作用以塑造Ca2+信号。在 在这一指令库中，最不为人所知的是商店运营渠道（SOC）。SOC，定义为通道 在响应于来自内质网（ER）的Ca 2+耗尽而打开的质膜中， 是触发Ca2+流入细胞的广泛机制。在神经系统中，已知SOC 影响神经递质释放和突触可塑性，涉及SOC的异常信号传导是 与老年痴呆症有关然而，对神经元的基本性质知之甚少。 SOC和连接存储耗尽到通道激活的机制。这项工作的长期目标是 了解神经元的生物物理特征，分子基础和功能组织， SOC，以确定触发其激活的刺激，并阐明其下游的后果， 激活神经元功能。荧光钙指示剂和显微镜的最新进展提供了 有机会深入了解SOC激活过程的性质。当前的总体趋势 一项提议是利用新的工具来探测神经元中钙库操纵的Ca2+信号网络， 包括SOC和ER，并探索这种信号传导的下游后果， 表情我们的近期目标是：（1）定义神经元SOC的生物物理特性， 膜片钳电生理学(2)通过采用以下方法定义SOC激活的ER Ca2+依赖性： Cameleon测量ER Ca 2+信号。这与ER Ca2+依赖性激活相比如何？ STIM1是一种钙离子传感器的候选分子，可以将[Ca2+]ER的信息传递给SOC。 (3)研究SOC在启动转录介导的Ca2+依赖性基因表达中的作用。 因子，NFAT。最近的研究表明，NFAT参与了几个重要的功能，如轴突， 生长、神经元存活和突触可塑性。更好地理解生物物理学 SOC在神经系统中的特性、激活机制和功能最终可以揭示 新的检查点调节神经元功能的钙离子，导致新的战略， 预防和治疗阿尔茨海默病等疾病。

Ca2+ signals in the nervous system mediate a remarkable variety of cellular functions, including neurotransmitter release, membrane excitability, and proliferation. To control the dynamic features of the signals mediated by this multifunctional messenger and generate specificity, neurons are endowed with a large repertoire of ion channels, pumps, and cellular organelles that work together to sculpt Ca2+ signals. In this repertoire, one of the least understood is the store-operated channel (SOC). SOCs, defined as channels in the plasma membrane that open in response to depletion of Ca2+ from the endoplasmic reticulum (ER), are a widespread mechanism for triggering Ca2+ influx into the cell. In the nervous system, SOCs are known to influence neurotransmitter release and synaptic plasticity, and aberrant signaling involving SOCs is associated with Alzheimer's disease. However, very little is known about the basic properties of neuronal SOCs and the mechanisms linking store depletion to channel activation. The long-term goals of this work are to understand the biophysical characteristics, molecular basis, and functional organization of neuronal SOCs, to identify stimuli that trigger their activation, and to elucidate the downstream consequences of their activation for neuronal function. Recent advances in fluorescent calcium indicators and microscopy provide an opportunity to gain insight into the nature of the SOC activation process. The overall thrust of present proposal is to exploit new tools to probe the store-operated Ca2+ signaling network in neurons, which is comprised of SOCs and the ER, and to explore downstream consequences of this signaling for gene expression. Our immediate objectives are: (1) Define the biophysical properties of neuronal SOCs using patch-clamp electrophysiology. (2) Define the ER Ca2+-dependence of SOC activation by employing cameleon to measure ER Ca2+ signals. How does this compare to the ER Ca2+-dependence of the activation of STIM1, a candidate molecule for the Ca2+ sensor that communicates information about [Ca2+]ER to SOCs? (3) Investigate the role of SOCs in initiating Ca2+-dependent gene expression mediated by the transcription factor, NFAT. Recent work indicates that NFAT is involved in several essential functions such as axonal outgrowth, neuronal survival, and synapse plasticity. An improved understanding of the biophysical properties, activation mechanisms, and functions of SOCs in the nervous system could ultimately reveal novel check points for the regulation of neuronal function by Ca2+, leading to new strategies for the prevention and treatment of diseases such as Alzheimer's disease.