Synergistic effects of acetylcholine and glutamate on the release of arachidonic acid from cultured striatal neurons.
The activation of muscarinic and NMDA receptors by carbachol and NMDA, respectively, stimulated the release of [3H]arachidonic acid ([3H]AA) from cultured striatal neurons. Striking synergistic effects were observed when both agonists were coapplied. This synergistic response was suppressed by atropine or (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-im ine hydrogen maleate and inhibited by magnesium. It was markedly reduced in the absence of external calcium and suppressed by mepacrine. NMDA strongly elevated the intracellular calcium concentration ([Ca2+]i), but carbachol was ineffective. Ionomycin, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate, or potassium depolarization, which increased [Ca2+]i but was ineffective on [3H]AA release, also potentiated the carbachol response. Sphingosine and Ro 31-8220 suppressed the responses evoked by carbachol, NMDA, or both agonists. However, no synergistic responses could be observed when phorbol 12-myristate 13-acetate was associated with either carbachol or NMDA. Together, these results suggest that both the massive influx of calcium induced by NMDA and the coupling of muscarinic receptors with a putative phospholipase A2 are required for the strong synergistic effects of carbachol and NMDA on [3H]AA release. Synergistic effects were also observed with acetylcholine and glutamate in the presence of magnesium, further revealing the physiological relevance of this process.
Tencé
M
M
Chaire de Neuropharmacologie, INSERM U114, Collège de France, Paris, France.
Murphy
N
N
Cordier
J
J
Prémont
J
J
Glowinski
J
J
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002118:Calcium / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D004357:Drug Synergism; D018698:Glutamic Acid / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology
D016718:Arachidonic Acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; D002217:Carbachol; D011493:Protein Kinase C; D000109:Acetylcholine; D002118:Calcium