Guanosine-5'-monophosphate induces cell death in rat hippocampal slices via ionotropic glutamate receptors activation and glutamate uptake inhibition.
Guanine derivatives modulate the glutamatergic system through displacement of binding of glutamate to its receptors acting as antagonist of glutamate receptors in moderate to high micromolar concentrations. Guanosine-5'-monophosphate (GMP) is shown to be neuroprotective against glutamate- or oxygen/glucose deprivation-induced neurotoxicity and also against NMDA-induced apoptosis in hippocampal slices. However, in this study we are showing that high extracellular GMP concentrations (5mM) reduced cell viability in hippocampal brain slices. The toxic effect of GMP was not blocked by dipyridamole, a nucleoside transport inhibitor, nor mimicked by guanosine, suggesting an extracellular mode of action to GMP which does not involve its hydrolysis to guanosine. GMP-dependent cell damage was not blocked by P1 purinergic receptor antagonists, neither altered by adenosine A(1) or A(2A) receptor agonists. The blockage of the ionotropic glutamate receptors AMPA or NMDA, but not KA or metabotropic glutamate receptors, reversed the toxicity induced by GMP. GMP (5mM) induced a decrease in glutamate uptake into hippocampal slices, which was reversed by dl-TBOA. Therefore, GMP-induced hippocampal cell damage involves activation of ionotropic glutamate receptors and inhibition of glutamate transporters activity.
Molz
Simone
S
Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, Brazil.
Dal-Cim
Tharine
T
Tasca
Carla I
CI
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D004176:Dipyridamole / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D006157:Guanosine Monophosphate / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D007202:Indicators and Reagents; D008297:Male; D009924:Organ Culture Techniques; D011419:Propidium / Q000378:metabolism; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000187:drug effects*; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles
D004396:Coloring Agents; D018690:Excitatory Amino Acid Agonists; D007202:Indicators and Reagents; D058915:Purinergic P1 Receptor Antagonists; D017470:Receptors, Glutamate; D018047:Receptors, Purinergic P1; D013778:Tetrazolium Salts; D013844:Thiazoles; D011419:Propidium; D018698:Glutamic Acid; D004176:Dipyridamole; D006157:Guanosine Monophosphate; C022616:thiazolyl blue