Methylmercury Inhibits Nitric Oxide Production Mediated by Ca super(2+) Overload and Protein Kinase A Activation

Neutrophils from male ICR mice were incubated with methylmercury (MeHg), and effects on nitric oxide production mediated by intracellular calcium (Cai) overload and protein kinase A activation were determined. The data showed that the presence of MeHg increased Cai markedly, reaching steady state after 300 s in a MeHg concentration-dependent manner. A MeHg concentration of 5 mu M inhibited lipopolysaccharide-induced NO generation. The Ca channel blocker, verapamil, antagonized the increase in Cai produced by MeHg in the presence of Ca, while an inhibitor of protein kinase A had an opposite effect on MeHg-inhibited NO production. The data suggested that MeHg activated protein kinase A through the Ca-activated adenylate cyclase cyclic AMP pathway, which inhibits NO synthase gene expression via raf protein-phosphorylation.