Membrane transport of toxic metals by ionic mimicry in mammalian cells: where do calcium channels fit in?

Cellular membranes are basically impermeable to ions and have developed specific pathways (transporters, channels or pumps) to facilitate metal translocation. These physiological carriers are not ideally selective and their specificity spectrum may include xenobiotic species, such as toxic metals whose availability in the environment has increased enormously with the onset of the industrial era. Competition between divalent endogenous and noxious metal ions at specific sites on membrane transport proteins and enzymes is referred to as "ionic mimicry". In the chapter I will present some studies on the permeation mechanisms through mammalian cell plasma membranes of lead (Pb) and cadmium (Cd), two metals whose toxicity has been linked to their putative ability to mimic calcium (Ca) and zinc (Zn) at specific binding sites. Both metals can permeate through neuronal membrane taking advantage of different Ca channels, but, while Cd appears to pass through the cell membrane mainly by the same pathways as Ca, Pb is also rapidly taken up in different cell types by passive transport systems that are distinct from Ca channels and independent of specific stimuli. To further elucidate the role of voltage-dependent Ca channels (VDCC) in Cd uptake, we compared the effect of this metals in two Chinese hamster ovary (CHO) cell lines, a wild type and modified cell line, which was permanently transfected with an L-type VDCC. Both cultures were subjected to brief (30-60 min) exposure to 50-100 µM Cd in serum-free culture medium. Cell death was evident after 18-24 h with comparable features in both cell lines. Although VDCC represent a pathway of Cd entry and participate in Cd-induced toxicity, as demonstrate by the effect of DHP modifiers, expression of L-type Ca channels is not sufficient to modify Cd accumulation and sensitivity to a toxicological significant extent. This study confirmed that both Cd and Pb can take advantage of VDCC to permeate the membrane, but these transport proteins are not the only, and frequently not the most important, pathways of permeation.