MECHANISMS OF BLOCK OF NMDA ACTIVATED CHANNELS

NMDA 激活通道的阻断机制

• 批准号: 6528034
• 负责人: Jon W. Johnson
• 金额: $ 8.81万
• 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/6528034
• 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.

由L-谷氨酸激活的神经递质受体分子类 似乎介导脊椎动物中最快的突触传递 中枢神经系统 这里描述的项目的广泛目标 是为了进一步加深我们的药理学和生物物理学的理解， 一类重要的受体被激活和调节。 谷氨酸受体在几乎所有类型的正常中枢神经系统中发挥作用。 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 在大脑皮层中发现高密度的，似乎是必不可少的， 学习和记忆等功能。 他们还发挥重要作用， 脑功能障碍;谷氨酸受体与病因有关 包括癫痫，阿尔茨海默病， 亨廷顿氏病和精神分裂症。 此外，缺氧诱导 神经元死亡，例如中风的结果，可能是由于 谷氨酸受体的过度激活。 对正常或病理性脑功能的描述需要 详细了解谷氨酸受体的工作原理 研究 在此提出的建议旨在促进这一理解。 具体地说， 将追求五个主要目标：1）谷氨酸活性新药 将表征受体位点; 2）受体结合的动力学 一类调节谷氨酸反应的药物 测量; 3）谷氨酸离开其受体之一的速度 将测量位点; 4）谷氨酸受体特性的变化 在大脑的不同部分将被研究，和5）的机制， 将研究哪些谷氨酸反应可以被调节。 的 神经元和单个受体通道复合物分子的反应将 应用膜片钳电生理技术， 与灌注技术相结合， 解决方案变化。 这项研究计划将为科学发展提供相当大的帮助。 首席研究员。 强大且广泛适用的新技术， 将开展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角，使其成为一个专业 膜通道研究领域。 这个项目有助于理解神经元 沟通，并为发展中国家和 治疗上有用的药物。 获得的知识应该有助于提供 深入了解各种生理机制的基础 谷氨酸受体参与的过程和大脑疾病。