Signal transduction pathways involved in the acute potentiation of NMDA responses by 1S,3R-ACPD in rat hippocampal slices.
1. A grease-gap recording technique has been used to investigate the mechanisms underlying the acute potentiation of N-methyl-D-aspartate (NMDA) responses by aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD) in area CA1 of rat hippocampal slices. 2. 1S,3R-ACPD (10 microM), but not 1R,3S- ACPD (10 microM), potentiated submaximal responses to NMDA (dose-ratio of 0.81 +/- 0.02 (mean +/- s.e.mean); n = 55), but not to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), in a readily reversible manner. Potentiation also occurred in slices treated with 0.2 microM tetrodotoxin, and in slices perfused with Mg(2+)-free medium. 3. 1S,3R-ACPD-induced potentiation was unaffected by the protein kinase inhibitors K-252b (0.1 microM) and staurosporine (1 microM) and the intracellular Ca2+ store depletor, thapsigargin (10 microM). Coapplication of staurosporine and thapsigargin was also without effect. 4. 1S,3R-ACPD-induced potentiation was unaffected by inhibitors of arachidonic acid formation, bromophenacyl bromide (50 microM) and RG80267 (100 microM). Arachidonic acid (10-50 microM) depressed reversibly NMDA-induced responses. The potentiation was unaffected by 8-bromo cyclic AMP (500 microM) or the PKA inhibitor Rp-adenosine 3,5-cyclic monophosphothioate triethylamine (Rp-cAMPS; 50 microM). 5. 1S,3R-ACPD-induced potentiation was abolished in slices perfused with Ca(2+)-free medium. The potentiation was also blocked by phorbol-12,13-diacetate (1 microM), in a staurosporine-sensitive manner. 6. It is concluded that the potentiation of NMDA responses by 1S,3R-ACPD is not mediated by protein kinase A or C, by release of Ca2+ from intracellular stores or by arachidonic acid. It involves a Ca2+-sensitive process and is negatively regulated by protein kinase C.
Harvey
J
J
Department of Pharmacology, Medical School, University of Birmingham.
Collingridge
G L
GL
D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000502:physiology; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008274:Magnesium / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology*; D009473:Neuronal Plasticity / Q000187:drug effects; D009498:Neurotoxins / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017470:Receptors, Glutamate / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013237:Stereoisomerism; D013779:Tetrodotoxin / Q000494:pharmacology
D009498:Neurotoxins; D017470:Receptors, Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D016718:Arachidonic Acid; D013779:Tetrodotoxin; D016202:N-Methylaspartate; D000242:Cyclic AMP; D011493:Protein Kinase C; D008274:Magnesium; D002118:Calcium