R. R. Bosch, A. Patel, S. E. van Emst-de Vries
Apr 10, 1998
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Influential Citations
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Journal
European journal of pharmacology
Abstract
The aminosteroid 1-(6-¿[17beta-3-methoxyestra- 1,3,5(10)-trien- 17-yl]-amino¿hexyl)- 1H-pyrrole-2,5-dione (U73122) and its inactive analogue 1-(6-¿[17beta-3-methoxyestra-1,3,5(10)-trien- 17-yl]-amino¿hexyl-2,5-pyrrolidine-dione (U73343) are widely used to study the involvement of G protein-coupled 1-phosphatidylinositol-phosphodiesterase, or phospholipase C, in receptor-mediated cell activation. The present work shows that both aminosteroids inhibit cholecystokinin-(26-33)-peptide amide (CCK-8)-induced phospholipase D activation equipotently in Chinese hamster ovary cells expressing the cholecystokinin-A receptor (CHO-CCK(A) cells). In addition, the two aminosteroids virtually completely inhibited thapsigargin- and 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced phospholipase D activation. Since the latter two drugs mimic inositol 1,4,5-trisphosphate-mediated Ca2+ mobilisation and 1,2-diacylglycerol-mediated protein kinase C activation. respectively, this suggests that both U73122 and U73343 act downstream of phospholipase C to inhibit receptor-mediated phospholipase D activation. U73122, but not U73343. effectively inhibited both TPA/Ca2+-stimulated phospholipase D activation and TPA/phosphatidylserine-stimulated protein kinase C activation in a homogenate of CHO-CCK(A) cells. The data presented suggest that U73122 may act at the level of protein kinase C to inhibit activation of phospholipase D. The exact site of action of U73343 is presently unknown.