MECHANISM OF SODIUM DEPENDENT METABOLITE TRANSPORT

钠依赖性代谢物转运机制

• 批准号: 6177072
• 负责人: GEORGE A KIMMICH
• 金额: $ 24.67万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-03-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6177072
• 关键词: astrocytes; biological signal transduction; cell membrane; extracellular matrix; glutamate transporter; glutamates; neural transmission; neuroregulation; neurotransmitter transport; phosphoprotein phosphatase; protein kinase C; protein tyrosine kinase; sodium; synapses; tissue /cell culture

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.

谷氨酸是主要的兴奋性神经递质，由 中枢神经系统中的神经元。尽管……很突出 谷氨酸作为正常中枢功能的载体，它也是一种 当突触水平保持在高于 正常静息浓度(约1微米)，即使在很短的时间内 时间间隔。神经毒性可因递质的释放而发生 谷氨酸超过了通常机制的能力 谷氨酸从突触的清除，和/或当 清除机制本身就会受到损害。我们的前期工作 显示局部生化信号通过改变谷氨酸再摄取 大鼠脑内星形胶质细胞的作用方式可以妥协或增强 通关程序。 已知星形胶质细胞在清除 突触谷氨酸。这项建议的重点是星形胶质细胞 谷氨酸转运系统在维持胞外谷氨酸中的作用 在允许适当的持续功能的水平上 神经传递事件。主要目标是定义生物化学 调控星形胶质细胞主动和被动的调控机制 谷氨酸转运系统决定体内和体内的稳定状态 胞外中枢谷氨酸水平。更新建立在最近的基础上 我们已经证明了星形细胞中的谷氨酸 GLAST共转运蛋白可以清除突触 明显受到各种“信号分子”的刺激，这些分子暗示着 涉及蛋白激酶C、蛋白质的细胞事件的重要性 酪氨酸激酶、磷酸蛋白磷酸酶和靶向 将蛋白质运输到质膜。具体目标是 描述了哪些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体中起作用 活动，并因此缓和兴奋毒性“风险”增加 突触谷氨酸水平在其他方面代表着。我们的观察结果表明 对健康的重大影响，因为它们提高了有趣的 谷氨酸突触清除上调的可能性或 对作用于细胞内或细胞上的分子信号作出反应而下调 星形细胞。这项建议旨在提供机械性的定义 这些监管机制。