MECHANISMS OF BLOCK OF NMDA ACTIVATED CHANNELS

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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.