Inhibition of ATPase activity in rat synaptic plasma membranes by simultaneous exposure to metals.
Inhibition of Na+/K+-ATPase and Mg2+-ATPase activities by in vitro exposure to Cd2+, Pb2+ and Mn2+ was investigated in rat brain synaptic plasma membranes (SPMs). Cd2+ and Pb2+ produced a larger maximal inhibition of Na+/K+-ATPase than of Mg2+-ATPase activity. Metal concentrations causing 50% inhibition of Na+/K+-ATPase activity (IC50 values) were Cd2+ (0.6 microM) < Pb2+ (2.1 microM) < Mn2+ (approximately 3 mM), and the former two metals were substantially more potent in inhibiting SPM versus synaptosomal Na+/K+-ATPase. Dixon plots of SPM data indicated that equilibrium binding of metals occurs at sites causing enzyme inhibition. In addition, IC50 values for SPM K+-dependent p-nitrophenylphosphatase inhibition followed the same order and were Cd2+ (0.4 microM) < Pb2+ (1.2 microM) < Mn2+ (300 microM). Simultaneous exposure to the combinations Cd2+/Mn2+ or Pb2+/Mn2+ inhibited SPM Na+/K+-ATPase activity synergistically (i.e., greater than the sum of the metal-induced inhibitions assayed separately), while Cd2+/Pb2+ caused additive inhibition. Simultaneous exposure to Cd2+/Pb2+ antagonistically inhibited Mg2+-ATPase activity while Cd2+/Mn2+ or Pb2+/Mn2+ additively inhibited Mg2+-ATPase activity at low Mn2+ concentrations, but inhibited antagonistically at higher concentrations. The similar IC50 values for Cd2+ and Pb2+ versus Mn2+ inhibition of Na+/K+-ATPase and the pattern of inhibition/activation upon exposure to two metals simultaneously support similar modes of interaction of Cd2+ and Pb2+ with this enzyme, in agreement with their chemical reactivities.
Carfagna
M A
MA
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, 46202 USA.
Ponsler
G D
GD
Muhoberac
B B
BB
D009597:4-Nitrophenylphosphatase / Q000378:metabolism; D000818:Animals; D017301:Ca(2+) Mg(2+)-ATPase / Q000037:antagonists & inhibitors*; D002104:Cadmium / Q000008:administration & dosage; D002462:Cell Membrane / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007854:Lead / Q000008:administration & dosage; D008297:Male; D008345:Manganese / Q000008:administration & dosage; D008670:Metals / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013569:Synapses / Q000201:enzymology*
D004791:Enzyme Inhibitors; D008670:Metals; D002104:Cadmium; D007854:Lead; D008345:Manganese; D009597:4-Nitrophenylphosphatase; D017301:Ca(2+) Mg(2+)-ATPase; D000254:Sodium-Potassium-Exchanging ATPase