Mercurial-induced alterations in neuronal divalent cation homeostasis.

Mercurials such as Hg2+ and methylmercury (MeHg) are environmental contaminants. Both are neurotoxic upon chronic and acute exposure, however, these toxic manifestations are distinct. The mechanisms underlying this cytotoxicity remain unknown, but may be related to a disruption in divalent cation homeostasis because both disrupt Ca(2+)-dependent processes in several model systems. These effects include a block in nerve-evoked neurotransmitter release as well as an increase in spontaneous transmitter release. This suggests that mercurials simultaneously decrease Ca2+ influx following nerve stimulation, and increase intracellular Ca2+ concentration ([Ca2+]i) in the nerve terminal. Although these effects appear to be at odds, they can be justified mechanistically. Both Hg2+ and MeHg block voltage-activated Ca2+ channels in the nerve terminal. The mechanism of block by these mercurials is different, since Hg2+ and MeHg are competitive and noncompetitive inhibitors of Ca2+ influx, respectively. The functional consequence in both instances remains decreased Ca2+ influx into the nerve terminal following the invasion of an action potential leading to decreased nerve-evoked release of neurotransmitter. The effects of mercurials on voltage-activated Ca2+ channels are distinct from those which mediate the increases in spontaneous transmitter release. Reducing extracellular Ca2+ concentration ([Ca2+]e) decreased, but did not prevent, the mercurial-induced increases in spontaneous transmitter release, suggesting that both intra- and extracellular sources of Ca2+ contribute to mercurial-induced elevations in [Ca2+]i in a nerve terminals. The effects of MeHg on divalent cation homeostasis have been studied using isolated nerve terminals from the rat brain (synaptosomes) and cells in culture (NG108-15 and isolated cerebellar granule cells) loaded with the Ca(2+)-selective fluorescent indicator fura-2. In synaptosomes, MeHg caused an Ca(2+)e-independent elevation in intrasynaptosomal Zn2+ concentration ([Zn2+]i) as well as an Ca(2+)e-dependent elevation in [Ca2+]i. The elevations in [Zn2+]i and [Ca2+]i were mediated by release of Zn2+ from soluble synaptosomal proteins and increased plasma membrane permeability, respectively. In NG108-15 cells, the effects of MeHg on divalent cation concentrations were more complex. First, MeHg mobilized Ca2+ from an intracellular store sensitive to inositol-1,4,5-tris-phosphate (IP3) which was independent of IP3 generation. Second, MeHg increased the intracellular concentration of an endogenous polyvalent cation, possibly Zn2+. Finally, MeHg caused an increase in the plasma membrane permeability to Ca2+ which was attenuated by high concentrations of the voltage-activated Ca2+ channel blocker nifedipine or by the voltage-activated Na+ channel blocker tetrodotoxin (TTX). While these studies demonstrate mercurials interfere with divalent cation regulation in neuronal systems, the consequences of these effects are not yet known.