MECHANISMS OF BLOCK OF NMDA ACTIVATED CHANNELS

NMDA 激活通道的阻断机制

• 批准号: 6653196
• 负责人: Jon W. Johnson
• 金额: $ 9.08万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6653196
• 关键词: NMDA receptors; brain cell; ion channel blocker; magnesium ion; membrane channels; membrane potentials; neural transmission; recombinant proteins; sodium ion; voltage /patch clamp; voltage gated channel

The class of neurotransmitter receptor molecules activated by L-glutamate appears to mediate most fast synaptic transmission in the vertebrate central nervous system. The broad objective of the project described here is to further our pharmacological and biophysical understanding of how this important class of receptors is activated and regulated. Glutamate receptors function in nearly every category of normal central nervous system activity. There is evidence for their involvement at multiple levels in sensory and motor systems. Glutamate receptors are found at high density in the cortex and appear to be essential for higher functions such as learning and memory. They also play important roles in brain dysfunction; glutamate receptors have been implicated in the etiology of many brain disorders including epilepsy, Alzheimer's disease, Huntington's disease, and schizophrenia. In addition, hypoxia induced neuronal death, as a consequence, for example, of stroke, may result from excessive activation of glutamate receptors. A description of either normal or pathological brain function will require detailed understanding of how glutamate receptors work. The research proposed here is intended to advance that understanding. Specifically, five major goals will be pursued: 1) New drugs active at glutamate receptor sites will be characterized; 2) the kinetics of receptor binding by a class of drugs that modulate one type of glutamate response will be measured; 3) the speed with which glutamate leaves one of its receptor sites will be measured; 4) the variation in glutamate receptor properties in different parts of the brain will be studied, and 5) the mechanisms by which glutamate responses can be regulated will be investigated. The responses of neurons and of single receptor-channel complex molecules will be studied with the electrophysiological technique of patch clamp in combination with a perfusion technique that allows rapid extracellular solution changes. The research plan will provide considerable scientific development for the Principal Investigator. Powerful and broadly applicable new techniques for the patch clamp study of intact neurons in brain slices will be developed. Investigation of the long-term regulation of glutamate responses will broaden the research perspective of the Principal Investigator into a major field of membrane channel research. This project can contribute to the understanding of how neurons communicate, and to the development of pharmacologically and therapeutically useful drugs. The knowledge gained should help provide insight into the mechanisms that underlie the wide variety of physiological processes and brain disorders in which glutamate receptors are involved.

L-谷氨酸激活的神经递质受体分子类别 似乎介导脊椎动物中最快的突触传递 中枢神经系统。 此处描述的项目的总体目标 是为了进一步了解我们的药理学和生物物理学如何 一类重要的受体被激活和调节。 谷氨酸受体在正常中枢的几乎所有类别中都有功能 神经系统活动。 有证据表明他们参与了 感觉和运动系统的多个层次。 谷氨酸受体是 在皮质中以高密度存在，并且似乎对于更高的功能至关重要 学习和记忆等功能。 他们也发挥着重要作用 脑功能障碍；谷氨酸受体与病因学有关 许多脑部疾病，包括癫痫、阿尔茨海默氏病、 亨廷顿舞蹈症和精神分裂症。 另外，缺氧引起 神经元死亡，例如中风的后果，可能是由于 谷氨酸受体过度激活。 需要描述正常或病理的大脑功能 详细了解谷氨酸受体如何工作。 研究 这里提出的建议旨在促进这种理解。 具体来说， 我们将追求五个主要目标： 1) 谷氨酸活性新药 受体位点将被表征； 2) 受体结合动力学 通过一类调节一种谷氨酸反应的药物将 测量； 3) 谷氨酸离开其受体之一的速度 将测量场地； 4) 谷氨酸受体特性的变化 将研究大脑不同部位的作用，5）其机制 将研究哪些谷氨酸反应可以被调节。 这 神经元和单一受体通道复合分子的反应将 采用膜片钳电生理技术进行研究 与灌注技术相结合，允许快速细胞外 解决方案发生变化。 该研究计划将为该领域的科学发展提供重大帮助 首席研究员。 强大且广泛适用的新技术 将开发对脑切片中完整神经元的膜片钳研究。 对谷氨酸反应的长期调节的研究将 拓宽首席研究员的研究视野 膜通道研究领域。 该项目有助于理解神经元如何 沟通，并促进药理学和 有治疗作用的药物。 获得的知识应该有助于提供 深入了解各种生理现象背后的机制 涉及谷氨酸受体的过程和大脑疾病。

项目成果

Asynchrony of mossy fibre inputs and excitatory postsynaptic currents in rat hippocampus.

大鼠海马苔藓纤维输入和兴奋性突触后电流的异步。

• 发表时间: 1993-12
• 作者: Langdon, R B;Johnson, J W;Barrionuevo, G
• 通讯作者: Barrionuevo, G