Lack of interaction between prostaglandin E2 receptor subtypes in regulating adenylyl cyclase activity in cultured rat dorsal root ganglion cells.
The hyperalgesic response to prostaglandin E2 (PGE2) is thought to be mediated by activation of the cAMP/protein kinase A pathway in primary sensory neurones. The aim of this study was to investigate the relative contribution of different PGE2 (EP) receptor subtypes to the overall activity of adenylyl cyclase in adult rat isolated dorsal root ganglion (DRG) cells, in vitro. PGE2 and the prostanoid EP4 receptor agonist ONO-AE1-329 increased [3H]cAMP production with EC50 values of 500 nM and 70 nM, respectively, and showed similar efficacies. No combination of prostanoid EP1, EP2, EP3 or EP4 receptor selective agonists produced synergistic increases in [3H]cAMP. The prostacyclin mimetic cicaprost increased [3H]cAMP production with an EC50 value of 42 nM and produced a significantly greater maximal response compared with PGE2. No evidence for prostanoid EP3 receptor-dependent inhibition of adenylyl cyclase activity could be obtained to account for the relatively weak effect of PGE2 compared with prostacyclin receptor agonists. Interestingly, sulprostone (prostanoid EP3/EP1 receptor agonist) caused a Rho-kinase-dependent retraction of neurites, suggesting an alternative role for prostanoid EP3 receptors in DRG cells. In conclusion, PGE2 mediated increases in adenylyl cyclase activity in primary sensory neurones is likely to be mediated by activation of prostanoid EP4 receptors, and is not under inhibitory control by prostanoid EP3 receptors.
Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong S.A.R., China. helenwise@cuhk.edu.hk
Helen
H
Wise
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D015230:Prostaglandin D2 / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013997:Time Factors; D014316:Tritium; D054460:rho-Associated Kinases
C499423:9-deoxy-9-chloro-15-deoxy-16-hydroxy-17,17-trimethylene-19,20-didehydroprostaglandin E2; D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008738:Methyl Ethers; C121546:ONO AE 248; C461399:ONO-AE1-329; C500045:ONO-DI-004; C545635:PTGER1 protein, human; C545644:PTGER2 protein, human; C545647:PTGER3 protein, human; C545650:PTGER4 protein, human; C545637:Ptger1 protein, rat; C545646:Ptger2 protein, rat; C545649:Ptger3 protein, rat; C545652:Ptger4 protein, rat; D011725:Pyridines; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014316:Tritium; C108830:Y 27632; C016767:sulprostone; D011464:Epoprostenol; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D000262:Adenylyl Cyclases; D000527:Alprostadil; D015232:Dinoprostone; C043867:cicaprost; D015230:Prostaglandin D2