Factors affecting prostacyclin receptor agonist efficacy in different cell types.
Octimibate and related nonprostanoid prostacyclin mimetics are partial agonists displaying highly tissue-specific responses. Octimibate demonstrated considerably greater efficacy for stimulation of adenylyl cyclase activity in Chinese hamster ovary cells transiently expressing mouse prostacyclin receptors (mIP-CHO cells) when compared to human SK-N-SH neuroblastoma cells, which endogenously express prostacyclin (IP) receptors. Pretreatment of both cell types with pertussis toxin (PTx) failed to influence IP agonist efficacy or potency, indicating a lack of involvement of an agonist-stimulated inhibitory G(i)-coupled pathway. Although stimulation of mIP-CHO cells with the full agonist cicaprost increased both [3H]cyclic AMP and [3H]inositol phosphate ([3H]IP) accumulation (pEC(50) values of 8.35 and 6.82, respectively), IP receptor signalling through G(q) in SK-N-SH cells was absent. Inhibition of protein kinase C (PKC) in mIP-CHO cells increased [3H]IP accumulation but had no effect on [3H]cyclic AMP accumulation. Therefore, the poor coupling of the IP receptor in SK-N-SH cells to G(q) is unlikely to explain the relatively low efficacy of octimibate for stimulating adenylyl cyclase in these cells. Furthermore, protein kinase A (PKA) inhibition appears to enhance IP receptor signalling through both G(s) and G(q) in mIP-CHO cells.
Kam
Y
Y
Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, SAR, Hong Kong, China.
Chow
K B
KB
Wise
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H
D000085:Acetates / Q000494:pharmacology; D037361:Adenylate Cyclase Toxin; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D037342:Pertussis Toxin; D010642:Phenoxyacetates / Q000494:pharmacology; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000085:Acetates; D037361:Adenylate Cyclase Toxin; D007093:Imidazoles; D010080:Oxazoles; D010642:Phenoxyacetates; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D010566:Virulence Factors, Bordetella; C080116:BMY 42393; C084677:BMY 45778; D011464:Epoprostenol; D000242:Cyclic AMP; D037342:Pertussis Toxin; D010738:Type C Phospholipases; D020962:Heterotrimeric GTP-Binding Proteins; C043867:cicaprost; C054659:octimibate