Dopamine D(2) receptor-induced COX-2-mediated production of prostaglandin E(2) in D(2)-transfected Chinese hamster ovary cells without simultaneous administration of a Ca(2+)-mobilizing agent.
We have earlier demonstrated that dopamine stimulates the liberation of the prostaglandin E(2) (PGE(2)) precursor, arachidonic acid, in Chinese hamster ovary cells transfected with the rat dopamine D(2) receptor (long isoform), also without concomitant administration of a Ca(2+)-releasing agent [Nilsson et al., Br J Pharmacol 1998;124:1651-8]. In the present report, we show that dopamine, under the same conditions, also induces a concentration-dependent increase in the production of PGE(2), with a maximal effect of 235% at approximately 100 microM, and with an EC(50) of 794 nM. The effect was counteracted by the D(2) antagonist eticlopride, pertussis toxin, the inhibitor of intracellular Ca(2+) release TMB-8, incubation in Ca(2+)-free experimental medium, and PKC desensitization obtained by chronic pretreatment with the phorbol ester TPA. It was also antagonized by the non-specific cyclooxygenase (COX) inhibitor, indomethacin, and by the selective COX-2 inhibitor, NS-398, but not by the specific COX-1 inhibitor, valeryl salicylate. Both the non-specific phospholipase A(2) inhibitor, quinacrine, and an inhibitor of cPLA(2) and iPLA(2), AACOF3, counteracted the effect; in contrast, a selective iPLA(2) inhibitor, BEL, and a selective sPLA(2) inhibitor, TAPC, were ineffective. No effects of dopamine were obtained in control cells mock-transfected with the p3C vector only. The results reinforce previous assumptions that dopamine may interact with eicosanoid metabolism by means of D(2) receptor activation, and implicate an involvement of cPLA(2) and COX-2 in this effect. It is suggested that measurement of dopamine-induced PGE(2) production may serve as a convenient way to study D(2) receptor function in vitro.
Department of Pharmacology, Institute of Physiology and Pharmacology, Göteborg University, Box 431, SE 405 30 Göteborg, Sweden. monika.hellstrand@pharm.gu.se
Monika
M
Hellstrand
Elias
E
Eriksson
Christer L
CL
Nilsson
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D006224:Cricetinae; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis*; D004298:Dopamine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D009578:Nitrobenzenes / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology; D011796:Quinacrine / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D012457:Salicylamides / Q000494:pharmacology; D012459:Salicylates / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009281:Naphthalenes; D009578:Nitrobenzenes; D010713:Phosphatidylcholines; D011753:Pyrones; D017448:Receptors, Dopamine D2; D012457:Salicylamides; D012459:Salicylates; D013449:Sulfonamides; C401835:valerylsalicylate; C081565:arachidonyltrifluoromethane; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C081346:1-(hexylthio)-2-(hexanoylamino)-1,2-dideoxy-sn-glycero-3-phosphocholine; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D005707:Gallic Acid; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011796:Quinacrine; C045989:eticlopride; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D004298:Dopamine; D007213:Indomethacin