Properties and regulation of hippocampal NMDA receptors

Informations projet

N° de convention de subvention: INTAS-94-4072

Projet clôturé

Date de début 1 Octobre 1995

Date de fin 31 Mars 1997

Financé au titre de

• International Association for the promotion of cooperation with scientists from the independent states of the former Soviet Union (INTAS), 1993-

Coût total € 0,00

Contribution de l’UE € 45 000,00

Coordonné par

Universität des Saarlandes
Germany

Résultats exploitables

Properties and regulation of hippocampal NMDA receptors

This study intended to make an extensive study of the different properties of NMDA receptor channels. We used electrophysiological, biochemical, pharmacological and fluorometric approaches to elucidate properties of hippocampal NMDA receptors in situ and to provide new drugs interacting with the NMDA receptors. We established the fractional Ca2+ current through somatic ( been 10.69± 2.13% (mean± S.D.)) and dendritic (10.70± 1.96%) NMDA receptor channels in CA1 pyramidal neurones. We characterized the expression pattern of NMDA receptor subunits encoding messenger ribonucleic acids and found the NMDA-receptor subunits NR2A, NR2B been abundantly expressed in all CA1 pyramidal neurones tested. We synthesized and tested electrophysiologically two new analogues of 3N-oxalyl-L-2,3- diaminopropionic acid and three new analogues of N-phthalamoyl-L-glutamic acid (PhGA). Among these drugs we identified two new low-affinity selective agonists of the NMDA-receptors isoPhGA and terePhGA with IC50 values of 1.77± 0.46 mM and 1.15 ± 0.28 mM respectively. We examined the effect of photolytically released nitric oxide on NMDA receptor function in the CA1 region of hippocampal slices and in dissociated CA1 neurones. In slices, NO (1-4.5 mM) induced a dose-dependent reduction in the slope of NMDA receptor-mediated field potentials (64 ± 12% reduction at 3 mM NO, n=6). In the contrary, NO released to isolated CA1 pyramidal cells had no effect on NMDA-activated currents (1.4± 15% block after 1-3 min, n=17), at estimated concentrations as high as 160 mM. Our results raise doubt about the postulated direct mode of action for NO at the postsynaptic NMDA receptor-ionophore complex and suggest that the presence of either some intracellular factor missing in the whole-cell experiments or intact presynaptic cells/synaptic structures may account for the blocking effect of NO in slices. All together our data will contribute to the understanding of the NMDA receptor function in central nervous system and provide clues for the design of new drugs.