Prostacyclin receptor-mediated activation of extracellular signal-regulated kinases 1 and 2.
The prostacyclin mimetic cicaprost increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in Chinese hamster ovary cells transiently expressing human (hIP-CHO) or mouse prostacyclin (mIP-CHO) receptors, but not in human neuroblastoma SK-N-SH cells or rat/mouse neuroblastoma-glioma NG108-15 cells which endogenously express IP receptors. Cicaprost stimulated ERK1/2 activity in hIP-CHO and mIP-CHO cells with EC50 values of 60 and 83 nM, respectively, and this response was significantly inhibited by protein kinase C inhibitors and agents which elevate cyclic AMP. A poor correlation was discovered between the level of ERK1/2 activity and the ability of agents to increase or decrease cyclic AMP production. The potent inhibitory effect of 3-isobutyl-1-methyl xanthine on cicaprost-stimulated phospho-ERK1/2 may be due to inhibition of phosphoinositide 3-kinase. Therefore, IP receptor-mediated activation of ERK1/2 in CHO cells occurs through a Gq/11/protein kinase C-dependent and a phosphoinoside 3-kinase-dependent process which is insensitive to IP receptor-generated cyclic AMP.
Chu
Kit Man
KM
Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong S.A.R, China.
Chow
Kevin B S
KB
Wong
Yung H
YH
Wise
Helen
H
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D044006:Receptors, Epoprostenol / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D044006:Receptors, Epoprostenol; D011464:Epoprostenol; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C043867:cicaprost; D015056:1-Methyl-3-isobutylxanthine