Factors affecting prostacyclin receptor agonist efficacy in different cell types.

Abstract

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.

• Authors: Y Kam, K B Chow, H Wise
• Journal: Cellular signalling (Cell Signal) Vol. 13 Issue 11 Pg. 841-7 (Nov 2001) ISSN: 0898-6568 [Print] England
• PMID: 11583920 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetates
• Adenylate Cyclase Toxin
• Imidazoles
• Oxazoles
• Phenoxyacetates
• Receptors, Epoprostenol
• Receptors, Prostaglandin
• Virulence Factors, Bordetella
• BMY 42393
• BMY 45778
• Epoprostenol
• Cyclic AMP
• Pertussis Toxin
• Type C Phospholipases
• Heterotrimeric GTP-Binding Proteins
• cicaprost
• octimibate

Topics

• Acetates (pharmacology)
• Adenylate Cyclase Toxin
• Animals
• CHO Cells
• Cricetinae
• Cyclic AMP (biosynthesis)
• Dose-Response Relationship, Drug
• Epoprostenol (analogs & derivatives, pharmacology)
• Heterotrimeric GTP-Binding Proteins (metabolism)
• Humans
• Imidazoles (pharmacology)
• Oxazoles (pharmacology)
• Pertussis Toxin
• Phenoxyacetates (pharmacology)
• Receptors, Epoprostenol
• Receptors, Prostaglandin (agonists, metabolism)
• Signal Transduction
• Tumor Cells, Cultured
• Type C Phospholipases (metabolism)
• Virulence Factors, Bordetella (pharmacology)