Factors affecting prostacyclin receptor agonist efficacy in different cell types

• Published in: Cellular signalling Vol. 13; no. 11; pp. 841 - 847
• Main Authors: Kam, Yiu-Wing, Chow, Kevin B.S., Wise, Helen
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.11.2001
• Subjects: Acetates - pharmacology; Adenylate Cyclase Toxin; Animals; CHO Cells; Cricetinae; Cyclic AMP - biosynthesis; Dose-Response Relationship, Drug; Epoprostenol - analogs & derivatives; Epoprostenol - pharmacology; Heterotrimeric GTP-Binding Proteins - metabolism; Humans; Imidazoles - pharmacology; IP receptor; Neuroblastoma cells; Oxazoles - pharmacology; Partial agonists; Pertussis Toxin; Phenoxyacetates - pharmacology; Prostacyclin; Receptor coupling; Receptors, Epoprostenol; Receptors, Prostaglandin - agonists; Receptors, Prostaglandin - metabolism; Signal Transduction; Tumor Cells, Cultured; Type C Phospholipases - metabolism; Virulence Factors, Bordetella - pharmacology; Octimibate (BMY 22389); BMY 42393; mIP-CHO; PLC; PKA; [ 3H]IP; PKC; Prostacyclin; Partial agonists; Neuroblastoma cells; DPDPE; IP receptor; mIP; PTx; Receptor coupling; GPCR; BMY 45778
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/S0898-6568(01)00210-8

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.