Volume 3, Number 1, p. 18-22
K. Natchkebia, N. Natsvlishvili and D. Mikeladze
Institute of Physiology, Georgian Academy of Sciences, Tbilisi,
Georgia
Effect of phencyclidine, MK-801 and dextrorphan on the viability of neuronal/glial cells and expression of NMDA-receptor subunits, PSD-95, nNOS and Ras-GRF1
The NMDA subtype of the glutamate receptor (NMDAR) is an abundant constituent of the postsynaptic density (PSD), they are anchored in the PSD by interactions between the cytoplasmic C-terminal tails of their NR2(e) subunits. Having multiple domains that bind to a variety of cytoplasmic proteins, PSD-95 functions as a scaffold to assemble a specific set of signalling proteins around the NMDAR. These proteins, such as neuronal nitric oxide synthase (nNOS) and SynGAP, may participate in downstream signalling by NMDARs. Administration of noncompetitive NMDA-glutamate receptor antagonists to humans induces a broad range of schizophrenia-like symptomatology. We found that treatment of neuronal/glial primary culture cells by noncompetitive NMDA antagonists—phencyclidine (PCP) and MK-801—decreases the viability of mixed neuronal/glial cells in the presence of NMDA, while dextrorphan does not change the effect of NMDA. Western blots performed with antibodies against NR2A(e)and NR2B(e) revealed that PCP and MK-801 induced an increase in the level of NR2B(e) and a decrease in the level of NR2A(e), while dextrorphan reduced the level of both NR2A(e) and NR2B(e) subunits. In addition, PCP-treated cells exhibited a marked decrease of PSD-95, nNOS and Ras-GRF1. Our results suggest that a decrease in the level of PSD-95 and regulatory proteins such as Ras-GRF and nNOS can change the NMDAR signalling pathway, and may lead to memory impairment in patients with schizophrenia.