NMDA receptor-mediated stimulation of rat cerebellar nitric oxide formation is modulated by cyclic AMP.
The effect of intracellular cyclic AMP (cAMP) on N-methyl-D-aspartate (NMDA) receptor-mediated stimulation of nitric oxide (NO) formation was investigated in rat cerebellar slices. Forskolin (30-120 microM), while lacking any direct effect on NO production, elicited a concentration-dependent enhancement of the response to 10 microM NMDA. Dideoxyforskolin, which does not activate adenylyl cyclase did not influence the NMDA response. Increasing intracellular cAMP directly by incubation with the membrane-permeant analogue of cAMP, 2'-o-dibutyryladenosine 3'5'-cyclic monophosphate (dibutyryl cAMP) (1 mM), similarly enhanced NO formation, as did prevention of cAMP degradation with the phosphodiesterase inhibitor theophylline. The enhancement of NMDA activity appeared to involve protein phosphorylation (possibly of the receptor itself) since the protein kinase A inhibitor H-89, abolished the enhancements with both forskolin and dibutyryl cAMP. Thus cAMP may have a physiological role in the modulation of NMDA receptor-stimulated synthesis of NO.
Toms
N J
NJ
Department of Pharmacology, University of Bristol, UK.
Roberts
P J
PJ
D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D005576:Colforsin / Q000031:analogs & derivatives / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D013449:Sulfonamides
D007546:Isoquinolines; D016194:Receptors, N-Methyl-D-Aspartate; D013449:Sulfonamides; D005576:Colforsin; D009569:Nitric Oxide; D016202:N-Methylaspartate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C047983:1,9-dideoxyforskolin