Effects of three different Ca(2+)-ATPase inhibitors on Ca2+ response and leukotriene release in RBL-2H3 cells.
The effects of three Ca(2+)-ATPase inhibitors, thapsigargin (TG), cyclopiazonic acid (CPA), and 2,5-di(tert-butyl)-1,4-hydroquinone (DTBHQ), on the Ca2+ response, degranulation, and leukotriene C4 (LTC4) release in RBL-2H3 cells were investigated. All three compounds elevated the intracellular free Ca2+ concentration ([Ca2+]i), and caused degranulation in the presence of 12-O-tetradecanoylphorbol-13-acetate (TPA), a protein kinase C activator. The dose-dependency of each compound in the Ca2+ response was in good agreement with that in degranulation. TG and CPA also caused the release of LTC4 in a dose-dependent manner, and this effect was unaffected by TPA or calphostin C, a selective PKC inhibitor. DTBHQ, however, did not induce LTC4 release, and rather inhibited the antigen-induced release of LTC4. These results suggest [1] that both degranulation and LTC4 release caused by these compounds are dependent on their [Ca2+]i increasing effect, [2] that degranulation and LTC4 release are mediated via independent pathways following the Ca2+ response, and [3] that DTBHQ additionally prevents the synthesis of LTC4 possibly by inhibition of 5-lipoxygenase.
Akasaka
R
R
Division of Biochemistry and Immunochemistry, National Institute of Health Sciences, Tokyo, Japan.
Teshima
R
R
Ikebuchi
H
H
Sawada
J
J
D000818:Animals; D001491:Basophils / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D015550:Cell Degranulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006873:Hydroquinones / Q000633:toxicity; D007211:Indoles / Q000633:toxicity; D015471:Leukemia, Basophilic, Acute / Q000473:pathology; D017997:Leukotriene C4 / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000633:toxicity; D051379:Mice; D009281:Naphthalenes / Q000633:toxicity; D013050:Spectrometry, Fluorescence; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D019284:Thapsigargin / Q000633:toxicity; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D006873:Hydroquinones; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D009281:Naphthalenes; C019359:2,5-di-tert-butylhydroquinone; D017997:Leukotriene C4; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases; C058819:calphostin C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; C000543:cyclopiazonic acid