Abstract
Effects of the neurotoxic heavy metals Cd 2+, Pb 2+ and CH 3Hg + on current carried by Ca 2+ ions ( I Ca) through high-voltage activated Ca 2+ channels in nerve growth factor (NGF)-differentiated pheochromocytoma (PC12) cells were examined to characterize possible differences in the mechanism of action of these metals on Ca 2+ channel function. Specifically, the potency and reversibility of effect on I Ca by each metal was examined, as well as the relationship between extracellular [Ca 2+] and potency of block of I Ca by Cd 2+ and Pb 2+. In addition, the effect of each of these metals on Ca 2+ channels when applied to the intracellular side of the membrane was also examined. When extracellular solution contained 20, 10 or 5 mM Ca 2+, the estimated IC 50 values (total metal concentration) for block of I Ca were 15, 10, and 6.5 μM for Cd 2+ and 7.5, 2.0 and 1.1 μM for Pb 2+, respectively. CH 3Hg + (1–10 μM) blocked I Ca (20 mM Ca 2+) in a time- and concentration-dependent manner. When cells were washed with metal-free solutions, block of I Ca by Cd 2+ was reversed rapidly, whereas block by Pb 2+ was reversed only partially, and block of I Ca by CH 3Hg + was not reversed. When Pb 2+ and CH 3Hg + treated cells were washed in metal-free solutions containing 50 μM d-penicillamine (DPEN), block of I Ca by 10 μM Pb 2+ was rapidly and completely reversed, whereas, block of I Ca by 5 μM CH 3Hg + was not reversed. Higher concentrations (500 μM) of 2,3-dimercapto-1-propane sulfonic acid (DMPS) did reverse partially the block of I Ca by 5 and 10 μM CH 3Hg +. When Cd 2+, Pb 2+ or CH 3Hg + was present in the intracellular solution, Ca 2+ channel currents were significantly reduced. These results characterize effects of Cd 2+ on Ca 2+ channels and demonstrate that Cd 2+, Pb 2+ and CH 3Hg + differ in their actions on Ca 2+ channels.
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