Regulation of N-methyl-D-aspartate receptor-mediated calcium transport and norepinephrine release in rat hippocampus synaptosomes by polyamines.
The role of polyamines (PA) synthesis in NMDA receptor-mediated 45Ca2+ fluxes and norepinephrine release was studied in rat hippocampal synaptosomes. NMDA (50 microM) caused a sharp (> 2-fold) transient increase in PA synthesis regulating enzyme, ornithine decarboxylase (ODC) activity with concomitant elevation in PA levels in the order putrescine > spermidine > spermine. ODC inhibitor, alpha-difluoromethylornithine (DFMO), and NMDA antagonist, 2-amino-5-phosphonovaleric acid (D-AP5), both blocked increases in ODC activity and PA levels. Activation of NMDA receptors induced a sharp (3 to 4-fold) and quick (15 seconds) increase in 45Ca2+ uptake by synaptosomes within 15 seconds of exposure at 37 degrees C. The efflux of 45Ca2+ and 3H-norepinephrine (NE) release at 22 degrees C from pre-loaded synaptosomes was also significantly (2 to 4-fold) enhanced by NMDA within 15 seconds. These NMDA receptor-mediated effects on calcium fluxes and NE release were blocked by NMDA receptor-antagonists (DAP-5 and MK-801) and PA synthesis inhibitor, DFMO and the DFMO inhibition nullified by exogenous putrescine. These observations establish that ODC/PA cascade play an important role in transduction of excitatory amino acid mediated signals at NMDA receptors.
Siddiqui
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F
Department of Neurology, Northwestern University Medical School, Illinois 60611-3008.
Iqbal
Z
Z
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D000518:Eflornithine / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D007700:Kinetics; D016202:N-Methylaspartate / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism*; D011700:Putrescine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; D013096:Spermine; D004533:Egtazic Acid; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D009955:Ornithine Decarboxylase; D002118:Calcium; D013095:Spermidine; D011700:Putrescine; D009638:Norepinephrine; D000518:Eflornithine