Can blocking calcium channels protect cells from cadmium?

Details

The cellular uptake mechanism for cadmium, a highly toxic metal ion, was unknown. Researchers studied cadmium uptake and toxicity in the established GH4C1 secretory cell line, whose calcium channels are well characterized.

Nimodipine, a voltage-sensitive calcium channel antagonist, protected cells against cadmium toxicity, increasing the LD50 for CdCl2 from 15 to 45 µM, while the calcium channel agonist BAY K8644 decreased the LD50. Organic calcium channel blockers from three classes protected cells at concentrations previously shown to block high K+-induced 45Ca2+ influx and secretion. Half-maximal protection occurred at 20 nM nifedipine, 4 µM verapamil, and 7 µM diltiazem. Increasing extracellular calcium from 20 µM to 10 mM also protected cells, producing a 5-fold increase in the LD50 for CdCl2.

Neither nimodipine nor BAY K8644 changed intracellular metallothionein concentrations, whereas cadmium increased metallothionein 9–20-fold over 18 hours. Cadmium strongly blocked depolarization-stimulated 45Ca2+ uptake (IC50 = 4 µM), and net cadmium uptake measured using 109Cd2+ was less than 0.3% of calcium uptake. Despite the low cadmium uptake rate relative to calcium, entry through voltage-sensitive calcium channels appeared to account for a significant portion: high K+/BAY K8644, which facilitates entry through channels, increased 109Cd2+ uptake at 30 minutes by 57%. Blocking calcium channels with 100 nM nimodipine reduced total cellular 109Cd2+ accumulation after 24 hours by 63%.

The researchers concluded that cadmium flux through dihydropyridine-sensitive, voltage-sensitive calcium channels is a major uptake mechanism in GH4C1 cells and that pharmacological channel blockade can provide dramatic protection against cadmium toxicity.