The NMDA subtype of glutamate receptor is fundamental for the normal function of the nervous system. Excessive NMDA receptor activity, however, can lead to neurological diseases, such as hypoxic-ischemic brain injury, epilepsy, Huntington's disease, Parkinson's disease, or AIDS-related dementia. The central role of NMDA receptors in the normal and abnormal functioning of the nervous system imposes important constraints on possible therapeutic strategies aimed at ameliorating or abating developmental disorders and neurological disease. Block of NMDA receptor overactivity should be achieved without interference with its normal function. Drugs that interact with modulatory sites on the NMDA receptor or use-dependent antagonists are likely to show the greatest promise for safe pharmacological intervention. Recently, we have characterized members of two families of drugs that block NMDA receptor mediated neuronal death by either blocking the NMDA receptor gated ion- channel in a use-dependent manner or by interaction with redox modulatory sites. The first group is represented by the drug memantine that has been used for the treatment of, Parkinson's disease in humans for more than a dozen years. The second group of drugs encompasses nitroso-compounds, including nitroglycerin, that interact with a so- called redox-modulatory site of the NMDA receptor. These drugs generate redox-related congeners of nitric oxide. With the cloning, and functional expression of recombinant NMDA receptor subunits, it has now become possible to begin to characterize the precise structural determinants and the molecular substrate for the therapeutic effects of these drugs. Studies with both recombinant and native NMDA receptors indicate that NMDA receptors are likely to be a heterogenous group of receptors, and as yet undiscovered subunits may be part of native NMDA receptor complexes in neurons. Our recent discovery and isolation of a novel gene from the rat CNS that shares homology with other NMDA receptor subunits is, therefore, of significance. This novel subunit was discovered using a PCR strategy based upon the presumed structure of the NMDA receptor redox site.
The specific aims of this proposal are: 1) To characterize the structural determinants of the open channel block by memantine and its interaction with Mg2+ block in recombinant NMDA receptor subunits. 2) To characterize the molecular basis of the effects of nitroso- compounds, redox-related congeners of nitric oxide, in recombinant NMDA receptor subunits. 3) To characterize a novel, putative NMDA receptor subunit gene that is developmentally regulated in the CNS. The proposed studies will contribute to a better understanding of the molecular structure of the NMDA receptor complex and will facilitate the development of selective drugs with fewer untoward side effects.
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