Signal transduction underlying carbachol-induced PGE2 generation and cox-1 mRNA expression of rat brain.
In this paper we have determined the different signal pathways involved in M(1) and M(3) muscarinic acetylcholine receptor (mAChR) dependent stimulation of cyclo-oxygenase 1 (cox-1) mRNA gene expression and PGE(2) production on rat cerebral frontal cortex. Carbachol stimulation of M(1) and M(3) mAChR exerts an increase in cox-1 mRNA gene expression without affecting cox-2 mRNA expression and increased PGE(2) generation. Besides, increased phosphoinositide (PI) turnover and stimulation of nitric oxide synthase (NOS) and cyclic GMP (cGMP) production. Inhibitors of phospholipase A(2) (PLA(2)), COX and phospholipase C (PLC), calcium/calmodulin (CaM), NOS and soluble guanylate cyclase prevent the carbachol effect. These results suggest that carbachol-activation of M(1) and M(3) mAChR increased PGE(2) release associated with an increased expression of cox-1 and NO-cGMP production. The mechanism appears to occur directly to PLC stimulation and indirectly to PLA(2) activation. These results may contribute to understand the effects and side effect of non-steroidal anti-inflammatory drugs in patients with cerebral degenerative diseases.
Orman
Betina
B
Pharmacology Unit, School of Dentistry, University of Buenos Aires, Argentina.
Reina
Silvia
S
Borda
Enri
E
Sterin-Borda
Leonor
L
D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D018679:Cholinergic Agonists / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D051545:Cyclooxygenase 1; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D008565:Membrane Proteins; D008954:Models, Biological; D018727:Muscarinic Antagonists / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects*
D018679:Cholinergic Agonists; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D018727:Muscarinic Antagonists; D010716:Phosphatidylinositols; D010880:Piperidines; D012333:RNA, Messenger; D010890:Pirenzepine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D002217:Carbachol; D019001:Nitric Oxide Synthase; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D006152:Cyclic GMP; D015232:Dinoprostone