Calcium homeostasis in mouse fibroblast cells: affected by U-73122, a putative phospholipase C beta blocker, via multiple mechanisms.
1. The inhibitory effects of the putative phospholipase C beta inhibitor, U-73122, on ligand-induced and thapsigargin-induced [Ca2+]i transients were investigated in mouse fibroblast cells (the L line). 2. Ca2+ release from intracellular stores was stimulated either by ATP (and also by UTP or ADP) working through the activation of a P2U receptor, or by lysophosphatidic acid, which elicited a more pronounced response. 3. U-73122 inhibited the Ca2+ mobilization produced by all the agonists in a dose-dependent manner, consistent with a mode of action involving phospholipase C inhibition. 4. In addition, however, U-73122 slowed the kinetics of intracellular Ca2+ release induced by the Ca(2+)-ATPase inhibitor, thapsigargin, and reduced the influx of Ca2+ across the plasma membrane, following stimulation of store-dependent influx by the latter. 5. We conclude that U-73122 has multiple sites of action, all of which can lead to a change in Ca2+ homeostasis. Thus, particular caution is recommended when employing this agent and when interpreting the results obtained.
Grierson
J P
JP
Department of Pharmacology, DIBIT -S Raffaele Scientific Institute, Milan, Italy.
Meldolesi
J
J
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004963:Estrenes / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D007739:L Cells; D051379:Mice; D011760:Pyrrolidinones / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors*
D004963:Estrenes; D011760:Pyrrolidinones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D010738:Type C Phospholipases; D002118:Calcium