Methylmercury inhibits nitric oxide production mediated by Ca(2+) overload and protein kinase A activation.
The importance of cytosolic free calcium level intracellular Ca(2+), [Ca(2+)]i, in neutrophil activation prompted us to investigate changes in [Ca(2+)]i of neutrophils caused by methylmercury (MeHg), which has been shown to have immunomodulatory properties. We have shown in this paper that MeHg increased [Ca(2+)]i in the mouse peritoneal neutrophil. The L-type calcium channel blocker verapamil can decrease the elevated [Ca(2+)]i caused by 10 microM MeHg, suggesting that Ca(2+)-influx through L-type Ca(2+) channel mediates the effect of MeHg. Moreover, MeHg potently decreased nitric oxide (NO) production but also the protein and mRNA level of NO synthase induced by lipopolysaccharide. Both verapamil (1 microM) and H-89 (10 microM) can antagonize the inhibitory effect of MeHg (10 microM) on NO production. These findings lead us to conclude that MeHg inhibits NO production mediated at least in part by Ca(2+)-activated adenylate cyclase-cAMP-protein kinase A pathway.
Kuo
Tsun-Cheng
TC
Institute of Toxicology, College of Medicine, National Taiwan University, No. 1, Jen Ai road, 1st Section, Taipei, Taiwan.
Huang
Chin -ien
C-
Lin-Shiau
Shoei-Yn
SY
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007546:Isoquinolines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008767:Methylmercury Compounds / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010529:Peritoneal Cavity / Q000166:cytology; D010533:Peritoneal Lavage; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides; D014700:Verapamil / Q000494:pharmacology
D007546:Isoquinolines; D008070:Lipopolysaccharides; D008767:Methylmercury Compounds; D012333:RNA, Messenger; D013449:Sulfonamides; D009569:Nitric Oxide; D014700:Verapamil; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002118:Calcium