Calmodulin-stimulated plasma membrane (Ca2+ + Mg2+)-ATPase: inhibition by calcium channel entry blockers.
Calcium channel entry blockers representing different structural classes were studied for their effects on human erythrocyte basal and calmodulin-stimulated (Ca2+ + Mg2+)-ATPase. Effects on the activity of (Mg2+)-ATPase and (Na+ + K+)-ATPase were also assessed. Of the four Ca2+ entry blockers tested, only verapamil and diltiazem specifically inhibited the calmodulin-stimulated (Ca2+ + Mg2+)-ATPase activity, the basal enzyme activity being unaltered by these drugs. Other membrane-associated ATPases were not affected. Calmodulin concentration effect curves showed the inhibition by verapamil (10(-3) M) and diltiazem (10(-3) M) to be non-competitive. This concentration inhibited the calmodulin-dependent increment (5.1 nM calmodulin) of the ATPase activity by 35 and 36% respectively. Similarly, both drugs inhibited the Ca2+-activation process of calmodulin-stimulated activity in a non-competitive manner, decreasing Vmax by 23 and 17% respectively. Basal (Ca2+ + Mg2+)-ATPase activity was not affected by verapamil or diltiazem at any calcium concentration. In contrast, cinnarizine non-specifically inhibited all four membrane ATPases including calmodulin-stimulated (Ca2+ + Mg2+)-ATPase activity at concentrations above 3 X 10(-6) M. Nifedipine was without effect on any of the four membrane ATPases. From this we conclude that certain calcium channel entry blockers can inhibit calmodulin-regulated plasma membrane Ca2+-pump ATPase. Therefore, this identifies an additional functional low affinity receptor in the plasma membrane for some of the calcium channel entry blockers.
D017301:Ca(2+) Mg(2+)-ATPase / Q000037:antagonists & inhibitors / Q000097:blood*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000097:blood*; D002147:Calmodulin / Q000378:metabolism*; D002936:Cinnarizine / Q000494:pharmacology; D004110:Diltiazem / Q000494:pharmacology; D004910:Erythrocyte Membrane / Q000201:enzymology*; D006801:Humans; D007700:Kinetics; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D002147:Calmodulin; D002936:Cinnarizine; D014700:Verapamil; D017301:Ca(2+) Mg(2+)-ATPase; D000252:Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D004110:Diltiazem