N. Natsvlishvili, E. Juravliova, D. Dzneladze and D. Mikeladze
Department of Neurochemistry, I. Beritashvili Institute of Physiology, Georgian Academy of Sciences, 14 Gotua St., 380060 Tbilisi, Georgia
Haloperidol regulates the binding of guanine nucleotides to synaptic membranes through the NMDA receptor
The NMDA receptor is believed to be important in a wide range of nervous system functions including neuronal migration, synapse formation, learning and memory. In addition, it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders. Besides agonist/coagonist sites, other modulator sites, including the butyrophenone site, may regulate the NMDA receptor. It has been shown that many neuronal modulator mechanisms may be co-coordinated by a group of binding proteins that both clusters NMDA receptors and links them to signalling pathways within the cell. We have found that 5'-guanylylimidodiphosphate (Gpp(NH)p) inhibited the binding of [3H]haloperidol to both the cortical and hippocampal synaptic membranes with high affinity and, reciprocally, haloperidol reduced the binding of [3H]Gpp(NH)p to the membranes. Both effects are abolished by addition of anti-p21Ras. Affinity-purified preparations of the NMDA receptor, which were immunoprecipitated by anti-p21Ras contained only the e2 (NR2A/NR2B) subunits of NMDA receptors and nNOS. These data suggest that the possible proteins participating in the formation of the macromolecular signalling complexes in postsynaptic density may be nNOS and p21Ras.