MECHANISMS OF BLOCK OF NMDA ACTIVATED CHANNELS

L激活的一类神经递质受体分子--谷氨酸 似乎在脊椎动物中介导了最快的突触传递 中枢神经系统。这里描述的项目的总体目标是 是为了加深我们的药理学和生物物理学方面的理解 重要的一类受体被激活和调节。 谷氨酸受体在几乎每一类正常的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 在皮质中发现密度较高，似乎对较高的 学习和记忆等功能。它们还在以下方面发挥重要作用 大脑功能障碍；谷氨酸受体在病因中有牵连 许多大脑疾病，包括癫痫，阿尔茨海默病， 亨廷顿氏病和精神分裂症。此外，低氧还会导致 例如，中风导致的神经元死亡可能是由 谷氨酸受体过度激活。 对正常或病理性脑功能的描述将需要 详细了解谷氨酸受体是如何工作的。这项研究 在此提出的建议旨在促进这一理解。具体来说， 将追求五个主要目标：1)活性谷氨酸的新药 2)受体结合的动力学 通过一类药物调节一种类型的谷氨酸反应将是 测量；3)谷氨酸离开其受体的速度 4)谷氨酸受体特性的变化 在大脑的不同部位进行研究，并通过以下方式研究其机制 哪些谷氨酸反应可以被调节将被调查。这个 神经元和单受体-通道复合分子的反应将 膜片钳电生理技术的研究 与一种灌流技术相结合，使细胞外快速 解决方案更改。 这项研究计划将为科学研究提供相当大的发展。 首席调查员。功能强大且适用范围广泛的新技术 将开展脑片完整神经元的膜片钳研究。 对谷氨酸反应长期调节的研究将 将首席调查员的研究视角拓宽为一门专业 膜通道研究领域。 这个项目有助于理解神经元是如何 交流，对药理和医学的发展 治疗上有用的药物。所获得的知识应该有助于提供 洞察各种生理学疾病背后的机制 谷氨酸受体参与的过程和大脑紊乱。

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.