Ionotropic glutamate receptors mediate the majority of excitatory signal transmission in the mammalian nervous system and are essential to its normal development and function. There are three distinct and well defined receptor subtypes that are the AMPA, kainate and NMDA receptors. Ionotropic glutamate receptors 'work' by coupling the binding of glutamate to gating, or opening, of a transmembrane ion channel. Because ionotropic glutamate receptors are linchpins of the human nervous system, they have been the target of a large number of pharmacological investigations and, therefore, a vast number of agonists, antagonists and allosteric effectors are known. Because in many cases these molecules elicit specific functional responses, they serve as excellent probes of the relationships between receptor structure and function. A substantial portion of the research proposed in this application is aimed at determining atomic resolution structures of the extracellular domains of AMPA and NMDA receptors, and understanding how agonists, antagonists and allosteric modulators exert their functional effects on the receptor. In addition, we have recently discovered bacterial homologs of the eukaryotic receptors and these molecules are promising species for over expression, crystallization and structure determination. Thus, a second element of the research proposed in this application is concentrated on determining the high resolution, three-dimensional structure of a bacterial receptor, in order to understand how ligand-binding is coupled to channel gating. A final element of the research proposed in this application is related to testing structure-based mechanistic hypotheses using site-directed mutagenesis and electrophysiology. By carrying out two electrode voltage clamp experiments in my laboratory, we will be able to evaluate the validity of specific mechanistic hypotheses. ? ? Taken together, the overall aims of the proposed research are to provide new and deep insights into the relationships between structure and function in ionotropic glutamate receptors. The resulting atomic structures and the mechanistic schemes will likely prove useful in the design of novel molecules that may have significant therapeutic value. ? ? ?
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