Acidic amino acids likely constitute the principal excitatory neurotransmitters in the mammalian central nervous system. Of the receptor subtypes mediating excitatory amino acid neurotransmission the N-methyl-D-aspartate (NMDA) receptor has been uniquely implicated in a wide range of neuronal processes. Physiologic neuronal processes in which the NMDA receptor has been implicated include spatial learning and neuronal arrangement during development. Pathologic neuronal processes in which NMDA receptor mediated neurotransmission is involved include generation of seizure activity and epileptogenesis. NMDA receptor mediated neurotransmission regulates neuronal activity, at least in part, by activation of a voltage dependent cation channel. Recent findings indicate that NMDA activation of the channel is regulated by a glycine receptor and by divalent cations including zinc and magnesium. The mechanism of glycine and ionic regulation of the NMDA receptor coupled channel is unknown. However, results from electrophysiologic and biochemical studies suggest that they may act through specific recognition sites in and on the receptor/channel complex. We propose to characterize the ionic and amino acid regulation of the NMDA receptor coupled channel in brain tissue derived from normal animals and then to determine whether alterations in this receptor/channel complex may underlie the pathophysiology of an experimental epilepsy (kindling). In contrast to the traditional, electrophysiologic, methods of examining channel function we will use a biochemical marker of channel activation. This approach will permit quantitative analysis of the interactions of NMDA receptor ligands, glycine agonists and divalent ions on channel activation. The biochemical approach, proposed here, will give insight into the mechanisms regulating the NMDA receptor/channel complex not readily obtainable by other means. This information will help in understanding the role of NMDA receptor mediated neurotrans- mission in physiological neuronal processes and may eventually lead to the development effective treatments for disorders such as epilepsy.
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