Ionotropic glutamate receptors (iGluRs) are the primary mediators of excitatory neuronal events. iGluRs form transmembrane, cation permeable channels that open in response to agonist binding. The three different iGluR subtypes are the AMPA, NMDA and kainate receptors, named according to their ligand sensitivity. iGluRs are linchpins of the nervous system and participate in learning and memory. Consistent with the central roles of iGluRs in the nervous system, disruption of receptor function has been implicated in brain disease and trauma ranging from epilepsy to stroke. Hyperactivation of iGluRs may lead neuronal death in degenerative conditions such as Huntington's disease, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Therefore, an understanding of the structure of iGluRs may lead to the development of valuable therapeutic agents. The proposed research involves the elucidation of molecular mechanisms for the function of iGluRs based on high resolution, three-dimensional structures determined by x-ray crystallography and on selected biochemical and biophysical techniques. Mechanisms to describe (i) ligand specificity and affinity, (ii) channel selectivity, (iii) ligand-gated channel opening and closing and (v) channel desensitization will be developed. These hypotheses will be probed by site-directed mutagenesis, measurements of biological function, and evaluation of biophysical behavior and three-dimensional structure. Achievement of the long term objectives is founded on determining the structures of (i) the ligand binding domains, (ii) constructs containing the extracellular domains and (iii) species incorporating the extracellular and channel-forming domains of the AMPA, NMDA and kainate receptor subtypes. These structures will be determined in the presence of a wide range of agonists, antagonists and allosteric effectors. Methods for the folding of water-soluble and membrane proteins and strategies for the crystallization of membrane proteins will be developed. Since there is currently no structural information on an iGluR or a domain of an iGluR, the proposed studies will significantly increase our understanding of these essential ligand gated ion channels.
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