PROPERTIES & REGULATION OF GLUTAMATE RECEPTORS

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 感觉系统，通常在从感觉器官到 皮质联合区谷氨酸反应的存在， 小脑，纹状体和脊髓表明广泛参与 运动系统谷氨酸受体在大脑皮层高密度分布 似乎对更高的功能，如学习和 记忆一组与正常大脑深度相关的受体类型 功能也可以发挥重要作用，在脑功能障碍;谷氨酸 受体与许多脑部疾病的病因有关 包括癫痫、阿尔茨海默病、亨廷顿病，以及 精神分裂症此外，缺氧诱导神经元死亡， 过度激活可能导致中风等后果 谷氨酸受体。 对正常或病理性脑功能的描述需要 对谷氨酸受体如何工作的详细了解。研究 在此提出的建议旨在促进这一理解。 具体地说， 主要目标有五个：1）谷氨酸受体活性新药 位点将被表征; 2）受体结合的动力学由一类 将测量调节一种类型的谷氨酸反应的药物的量; 3） 谷氨酸离开它的一个受体位点的速度 4）谷氨酸受体特性的变化-在不同的 部分大脑将被研究;和，5）的机制， 谷氨酸反应可以被调节。的答复 神经元和单一受体通道复合物分子的研究 与膜片钳的电生理技术结合， 一种允许细胞外溶液快速变化的灌注技术。 几种推广膜片钳应用的新方法 还将利用各种技术， 这项研究有助于理解突触是如何 传输发生，以及它的强度是如何调节的， 开发能够改变突触传递的药物。知识 获得的信息应该有助于深入了解 各种各样的生理过程和大脑疾病， 谷氨酸受体也参与其中。

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 in all sensory systems, often at multiple levels from the sensory organ to cortical association areas. The presence of glutamate responses in cerebellum, striatum, and spinal cord suggest extensive involvement in 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. A group of receptors types so deeply involved in normal brain function can 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. Several new approaches that generalize the utility of the patch clamp technique will also be taken advantage of This research can contribute to the understanding of how synaptic transmission takes place and how its strength is regulated, and to the development of drugs that can modify synaptic transmission. 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.