NMDA receptor activation is associated with many critical physiological and pathophysiological processes in the brain. Consequently, several endogenous modulating agents tightly regulate NMDA receptor function. Studies that investigate the molecular mechanisms of NMDA receptor modulation are important for characterizing the structural and functional properties of this protein. These investigations can also lead to the development of novel drugs to treat neuronal disorders in which abnormal NMDA receptor activation has been implicated. In this proposal, we expand our studies of NMDA receptor modulation to a novel form of functional regulation of this ion channel. We have observed that brief focal pulses of light potentiate NMDA receptor-mediated physiological responses in cultured neurons. In order to characterize this phenomenon, we have designed a series of studies to address the following Specific Aims: (1) To define the properties of light modulation of NMDA receptor function; (2) To establish whether light alteration of NMDA receptor function is mediated via a novel modulatory site; (3) To determine the properties of light modulation in recombinant NMDA receptors; and (4) To assess whether light modulation of the NMDA receptor has physiological significance in retinal function. Experiments outlined here utilize well-defined culture systems of rat cerebral cortex and retinal ganglion cells. We will perform electrophysiological measurements in these preparations, as in well as in non-neuronal mammalian cell lines that transiently express recombinant NMDA receptors. Additional studies will be performed on retinal slices. The long-term goals of this research program are to characterize fully NMDA receptor function. Results from these studies could facilitate the design of new therapeutic strategies to block NMDA receptor-mediated excitotoxicity. In addition, the investigations proposed here will focus on a novel form of modulation of NMDA receptor function, which may be important in retinal physiology.
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