Effect of Y-24180 on Ca2+ movement and proliferation in renal tubular cells.
In canine renal tubular cells, the effect of Y-24180, a presumed specific platelet activating factor (PAF) receptor antagonist, on intracellular Ca(2+) concentration ([Ca(2+)](i)) was measured by using fura-2 as a Ca(2+)-sensitive fluorescent probe. Y-24180 (0.1-10 microM) caused a rapid and sustained [Ca(2+)](i) rise in a concentration-dependent manner. The [Ca(2+)](i) rise was prevented by 30% by removal of extracellular Ca(2+), but was not changed by dihydropyridines, verapamil and diltiazem. Y-24180-induced Ca(2+) influx was confirmed by Mn(2+)-influx induced quench of fura-2 fluorescence. In Ca(2+)-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca(2+)-ATPase, caused a monophasic [Ca(2+)](i) rise, after which the increasing effect of 5 microM Y-24180 on [Ca(2+)](i) was abolished; conversely, depletion of Ca(2+) stores with 5 microM Y-24180 abolished thapsigargin-induced [Ca(2+)](i) rise. U73122, an inhibitor of phoispholipase C, inhibited ATP-, but not Y-24180-induced [Ca(2+)](i) rise. Overnight treatment with Y-24180 did not alter cell proliferation rate. Collectively, these results suggest that Y-24180 acts as a potent, but not cytotoxic, Ca(2+) mobilizer in renal tubular cells, by stimulating both extracellular Ca(2+) influx and intracellular Ca(2+) release. Since alterations in Ca(2+) movement may interfere many cellular signaling processes unrelated to modulation of PAF receptors, caution must be applied in using this chemical as a selective PAF receptor antagonist.
Chao
Yu-Ying
YY
School of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan.
Jan
Chung-Ren
CR
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D002118:Calcium / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D020013:Calcium Signaling; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D016257:Fura-2 / Q000494:pharmacology; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D001381:Azepines; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D004963:Estrenes; D011760:Pyrrolidinones; D014230:Triazoles; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C068035:4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-6,9-dimethyl-6H-thieno(3,2-f)(1,2,4)triazolo(4,3-a)(1,4)diazepine; D019284:Thapsigargin; D000255:Adenosine Triphosphate; D010738:Type C Phospholipases; D002118:Calcium; D016257:Fura-2