NMDA type receptors play an essential role in the central nervous system (CNS) by responding to glutamate, the major excitatory transmitter in the brain. These receptors play essential roles such in diverse processes as long term potentiation (LTP), excitotoxicity, phencyclidine (PCP) induced psychosis and also in the causes of neurologic disorders such as Parkinson's disease, epilepsy and Huntington's chorea. Although much is known about the pharmacology of NMDA receptors, biochemical characterization of receptor proteins is still lacking. These receptors are currently believed to exist as multimeric combinations of at least five known subunits. This proposal is designed to determine the subunit stoichiometries of native NMDA receptors, using subunit-specific antibodies. A developmental correlate of subunit expression will also be studied. By constructing mutant NMDA receptors, we will also further define pharmacologic binding regions responsible for the modulatory effects of agents such as PCP. Coupling biochemical and pharmacologic characterization of NMDA receptors will hopefully lead to development of useful therapeutic agents to combat neurological disease.
