MECHANISM OF SODIUM DEPENDENT METABOLITE TRANSPORT

谷氨酸是主要的兴奋性神经递质， 中枢神经系统中的神经元。 尽管突出的 谷氨酸作为正常中枢神经系统功能的载体，它也是一种 当突触水平保持在高于 正常的静息浓度（约1 μ M），即使是短暂的 interval. 神经毒性可能是由于释放递质 谷氨酸超过了通常机制的能力， 从突触清除谷氨酸，和/或当功能的突触， 清除机制本身也会受到损害。我们的前期工作 显示局部生化信号通过以下方式改变谷氨酸再摄取： 大鼠脑星形胶质细胞的方式，可以妥协或增强 清除过程。 已知星形胶质细胞在清除 突触谷氨酸 这项提案的重点是星形胶质细胞的作用 谷氨酸转运系统在维持细胞外谷氨酸 浓度水平允许适当的持续功能， 神经传输事件主要目的是定义生物化学 调节主动和被动星形胶质细胞 谷氨酸转运系统，决定稳态内， 细胞外CNS谷氨酸水平。 更新建立在最近 我们的初步研究表明星形胶质细胞谷氨酸 通过GLAST共转运蛋白从突触的清除可以 受到各种“信号分子”的明显刺激， 涉及蛋白激酶C、蛋白质 酪氨酸激酶，磷蛋白磷酸酶，和'靶向'的 将蛋白质运输到质膜。 具体的目标是 描述的内容侧重于提供每个角色的详细信息， 这些过程在调节星形胶质细胞谷氨酸转运蛋白中起作用 活动，因此缓和兴奋性毒性“风险”， 突触谷氨酸水平则代表。 我们的观察表明 健康的影响，因为他们提出了有趣的 谷氨酸的突触清除上调的可能性， 下调的分子信号作用于 星形胶质细胞该建议旨在为以下方面提供机械定义： 这些监管机制。

Glutamate is the primary excitatory neurotransmitter utilized by neurons in the central nervous system. Despite the prominence of glutamate as a vehicle for normal CNS function, it is also a potent neurotoxin when synaptic levels remain elevated above normal resting concentrations (approximately 1 muM) even for a short interval. Neural toxicity can occur due to release of transmitter glutamate that exceeds the capacity of the usual mechanisms for clearance of glutamate from the synapse, and/or when function of the clearance mechanisms themselves become compromised. Our preliminary work shows that localized biochemical signals modify glutamate reuptake by rat brain astrocytes in ways that can either compromise or enhance the clearance process. Astrocytes are known to play a prominent role in the clearance of synaptic glutamate. This proposal focuses on the role that astrocyte glutamate transport systems play in maintaining extracellular glutamate concentrations at levels which allow appropriate ongoing function of neural transmission events. Primary aims are to define the biochemical regulatory mechanisms which modulate active and passive astrocytic glutamate transport systems that determine steady state intra- and extra-cellular CNS glutamate levels. The renewal builds on recent preliminary work in which we have shown that astrocytic glutamate clearance from the synapse by the GLAST cotransport protein can be markedly stimulated by various 'signal molecules' which implicate the importance of cellular events involving protein kinase C, protein tyrosine kinase, phosphoprotein phosphatases, and 'targeting' of transport protein to the plasma membrane. Specific aims are described which focus on providing detail for the role each of these processes plays in regulating astrocytic glutamate transporter activity and therefore of tempering the excitotoxic 'risk' that elevated synaptic glutamate levels otherwise represent. Our observations carry substantial health ramifications because they raise the interesting likelihood that synaptic clearance of glutamate is up-regulated or down-regulated in response to molecular signals acting in or on the astrocyte. This proposal aims at providing mechanistic definition for those regulatory mechanisms.