We propose to investigate the NMDA receptor (one of the major types of excitatory amino acid receptors) using Conus peptides, in particular the conantokins. The conantokins are the only peptide ligands known which affect the function of the NMDA receptor. These peptides are small (~20 amino acids), have been chemically synthesized and contain an unusual amino acid, gamma-carboxyglutamate. The conantokins were discovered because they induce a sleep-like state in young mice, but paradoxically, in mature mice, a hyperactive state characterized by climbing a rapid running syndrome is observed instead. A long-range goal of the project is to elucidate at the molecular level how conantokins interact with their receptor targets to produce these behavioral effects. Preliminary data from our laboratories indicate that the conantokins interact with a receptor complex composed of several subunits with differing MWs. One of the putative subunits is not inconsistent with the MW range expected from recent expression cloning data for the NMDA receptor. This receptor complex will be purified and characterized. In addition, because of the striking developmental symptomatology induced by these peptides, the possibility of developmental switching in receptor subtypes will be explored.
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