N-methyl-D-aspartate (NMDA) receptor over-stimulation has been linked to the neuropathological aftermath of stroke. Consequently, the modulation of the activity of the NMDA receptor is likely to influence the injurious outcome in this and related disorders. The investigations proposed here are directed at characterizing the detailed molecular properties of a modulatory site on the NMDA receptor that is sensitive to redox-active substances.
The specific aims of this project are: (1) To investigate the biophysical properties of the NMDA receptor following alterations of the redox site. (2) To identify physiological modulators of the NMDA receptor redox modulatory site. (3) To determine the redox properties of recombinant NMDA receptors expressed in mammalian cell lines. (4) To predict the subunit composition of native NMDA receptors based on developmental changes in their redox properties. Experiments outlined here utilize the well-defined system of rat cerebral cortex in dissociated cell culture. Electrophysiological measurements will utilize the whole-cell and outside-out variants of the patch-clamp technique. Additional studies will be performed in non-neuronal mammalian cell lines which have been induced to transiently or stably express recombinant NMDA receptors. The long-term goals of these studies are to assess the role of the redox site in modulating the NMDA receptor, as well as to identify the critical residues on the receptor that are responsible for this type of modulation. These investigations are ultimately aimed at evaluating the role of this site in influencing NMDA receptor function during stroke. Novel therapeutic approaches to this disorder may be developed as a result of this work.
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