Store-operated channels in the nervous system

Ca 2+信号调节发育中的神经系统的多种功能，包括增殖和 神经干细胞（NSC）的分化、新生神经元的迁移和凋亡。的作用虽然 Ca 2+信号在神经系统发育中的作用已被广泛认识，但对神经系统发育中的Ca 2+信号传导机制知之甚少。 负责在NSC中产生Ca 2+信号的机制。在各种机制中， 产生细胞Ca 2+信号，钙库操纵的Ca 2+释放激活的Ca 2+（CRAC）通道具有 作为一种广泛的途径出现，用于调节许多Ca 2+依赖性功能，包括转录， 运动和增殖。CRAC通道由奥赖基因编码，其产生三种高度依赖性的CRAC通道。 在大多数组织中广泛表达的同源蛋白质。我们实验室的新证据表明 由经典Orai 1-STIM 1通路编码的CRAC通道是神经干细胞中Ca 2+进入的主要途径。 此外，通过CRAC通道的Ca 2+内流强烈激活Ca 2+依赖性基因表达介导的细胞内钙离子转运。 通过转录因子NFAT调节神经干细胞的增殖。我们假设CRAC 通道是神经干细胞增殖和分化的关键关卡。当前的总体目标 该提案旨在阐明神经干细胞中CRAC通道的分子和功能特性，并阐明其 在神经干细胞的基因表达、增殖和分化中的作用。结合电生理学 和生物化学方法以及缺乏CRAC通道功能的基因工程小鼠，我们将：1） 确定神经干细胞中CRAC通道的电生理特性和分子机制，2）研究 在ER Ca 2+传感器STIM 1结合后孔开放中涉及的门控机制， CRAC通道，以及，3）阐明CRAC通道用于基因表达的下游功能， NSC的增殖和分化。这些研究的结果将大大加深我们的 了解神经干细胞中的Ca 2+信号通路和调控早期神经元的机制 发展此外，通过解决CRAC通道门控的机制，我们的研究可能会 影响针对CRAC通道的新药设计，并为新疗法提供基础， 神经退行性疾病和脑损伤。

Ca2+ signals regulate diverse functions in the developing nervous system, including proliferation and differentiation of neural stem cells (NSCs), migration of nascent neurons, and apoptosis. Although the role of Ca2+ signaling in the development of the nervous system is widely recognized, little is known about the mechanisms responsible for production of Ca2+ signals in NSCs. Among the various mechanisms by which cellular Ca2+ signals are generated, store-operated Ca2+ release-activated Ca2+ (CRAC) channels have emerged as a widespread pathway for regulating many Ca2+-dependent functions, including transcription, motility and proliferation. CRAC channels are encoded by the Orai genes, which give rise to three highly homologous proteins that are widely expressed in most tissues. Emerging evidence in our laboratory indicates that CRAC channels encoded by the canonical Orai1-STIM1 pathway are a major route of Ca2+ entry in NSCs. Moreover, Ca2+ influx through CRAC channels powerfully activates Ca2+-dependent gene expression mediated by the transcription factor, NFAT, and regulates the proliferation of NSCs. We hypothesize that CRAC channels are a key checkpoint for proliferation and differentiation of NSCs. The overall goal of the present proposal is to elucidate the molecular and functional properties of CRAC channels in NSCs and illuminate their role for gene expression, proliferation, and differentiation of NSCs. Using a combination of electrophysiological and biochemical approaches as well as genetically engineered mice lacking CRAC channel function, we will: 1) define the electrophysiolgical properties and molecular machinery of CRAC channels in NSCs, 2) investigate the gating mechanisms involved in the opening of the pore following binding of the ER Ca2+ sensor, STIM1, to CRAC channels, and, 3) illuminate the downstream functions of CRAC channels for gene expression, proliferation, and differentiation in NSCs. Findings from these studies will significantly deepen our understanding of Ca2+ signaling pathways in NSCs and the mechanisms regulating early neuronal development. In addition, by addressing the mechanisms of CRAC channel gating, our studies are likely to impact the design of new drugs against CRAC channels and provide a basis for new therapies for neurodegenerative diseases and brain injury.