Effects of Hg2+ and CH3Hg+ on Ca2+ fluxes in rat brain microsomes.
A permanent increase in cytosolic Ca2+ levels seems to be associated with various pathological situations which may result in cell death. Hg2+ and CH3Hg+ are potent neurotoxic agents, but the precise molecular mechanism(s) underlying their effects are not sufficiently understood. In the present study we investigated the potential role of Ca(2+)-ATPase located in the endoplasmic reticulum as a molecular target for mercury. Hg2+ and CH3Hg+ inhibited Ca(2+)-ATPase and Ca2+ uptake by brain microsomes with similar potencies. However, the inhibitory potency of Hg2+ was higher than that of CH3Hg+, probably reflecting differences in the affinity for the sulfhydryl groups of these compounds. Passive or unidirectional Ca2+ efflux (measured in the absences of Ca(2+)-ATPase ligands) was increased significantly by CH3Hg+ and Hg2+. Again, the potency of Hg2+ was higher than that of CH3Hg+. Blockers of Ca2+ channels (ruthenium red, procaine, heparin) did not affect the increase in passive Ca2+ efflux induced by mercury compounds, possibly indicating that Ca2+ release occurs through Ca(2+)-ATPase. Addition of physiological concentrations of glutathione (GSH) simultaneously with mercury abolished the inhibitory effects of both forms of Hg on ca(2+)-transport. However, if the enzyme was first inhibited with Hg2+ or CH3Hg+ and subsequently treated with GSH, the reversal of inhibition was about 50%, suggesting that part of the cysteinyl residues involved in the inhibitory actions of mercury in Ca(2+)-transport bind to mercury with an extremely high affinity.
Freitas
A J
AJ
Departamento de Quimica, Universidade Federal de Santa Maria, RS, Brazil.
Rocha
J B
JB
Wolosker
H
H
Souza
D O
DO
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D017301:Ca(2+) Mg(2+)-ATPase / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000187:drug effects / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D008628:Mercury / Q000494:pharmacology*; D008767:Methylmercury Compounds / Q000494:pharmacology*; D008861:Microsomes / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D013439:Sulfhydryl Reagents / Q000494:pharmacology*
D008767:Methylmercury Compounds; D013439:Sulfhydryl Reagents; D017301:Ca(2+) Mg(2+)-ATPase; D000252:Calcium-Transporting ATPases; D008628:Mercury; D005978:Glutathione; D002118:Calcium; D004229:Dithiothreitol