Pb2+ reduces voltage- andN-methyl-d-aspartate (NMDA)-activated calcium channel currents

Abstract

1. While intracellular calcium concentrations are closely regulated, two types of ion channels in neurons allow calcium influx: both voltage-activated and NMDA-activated channels are significantly permeable to calcium. In this study we compare the effects of lead (Pb2+) on currents carried through voltage-activated calcium channels and NMDA-activated channels. 2. Pb2+ reduces voltage-activated calcium channel currents elicited by a voltage jump from -80 to 0 mV at 0.1 to 1 microM, with an IC50 of 0.64 microM and a Hill slope of 1.22. This effect was partially reversible and not voltage dependent. Sodium and potassium currents were relatively unaffected at Pb2+ concentrations sufficient to block calcium channel currents by more than 80%. Pb2+ is, thus, a potent, reversible and selective blocker of voltage-dependent calcium channel currents. 3. A fast reversible and slow irreversible blocking action of Pb2+ was found on NMDA-activated currents. When Pb2+ was applied simultaneously with aspartate and glycine (Asp/Gly), the inward currents were rapidly and reversibly reduced in a dose-dependent manner with a minimum effective concentration below 2 microM and a total blockade (> 80%) with 100 microM Pb2+. The IC50 was approximately 45 microM and the Hill coefficient 1.1. Preincubation with 50 microM Pb2+ resulted in a greater reduction in the response to Asp/Gly/Pb2+. This effect was reversed within 2 to 5 sec of wash. The lack of voltage dependence suggests that Pb2+ does not block the channel but rather alters the binding of agonists. Prolonged superfusion of a cell with the Asp/Gly/Pb(2+)-containing external solution resulted in a slow and irreversible decrease in the Asp/Gly activated current.(ABSTRACT TRUNCATED AT 250 WORDS)