IN-VITRO SELECTION OF PEPTIDES ACTING AT A NEW SITE OF NMDA GLUTAMATERECEPTORS

Oligomeric N-methyl D-aspartate receptor (NMDAR) in brain is a ligand- gated ion channel that becomes selectively permeable to ions upon bind ing to ligands. For NMDAR channel, the binding of glutamate and glycin e results in opening of the calcium permeable channel. Because the cal cium influx mediated by NMDAR is important for synaptic plasticity and excitotoxicity, the function of NMDA receptors has been implicated in both health and disease. Native NMDA receptors are thought to be hete romeric pentamers with a central ion conduction pathway, There are fiv e genes (NR1, 2A, 2B, 2C, and 2D) encoding various subunits that have been cloned, and NR1 is thought to be the essential subunit since it f orms a functional channel by itself. To study NMDAR structure and func tion, we have searched for peptide modulators of NR1 using random pept ide bacteriophage libraries. The peptides were identified based on the ir specific association with a purified receptor fusion protein that c ontains the putative ligand binding domain. We report the identificati on of one group of cyclic peptides (Mag-1) with a consensus sequence o f CDGLRHMWFC. Using biochemical binding analysis and patch clamp elect ro-physiological recording, we show that the synthetic Mag-1 peptides cause noncompetitive inhibition of the receptor channel activity.