MERCURIAL-INDUCED ALTERATIONS IN NEURONAL DIVALENT-CATION HOMEOSTASIS

Mercurials such as Hg2+ and methylmercury (MeHg) are environmental con taminants. Both are neurotoxic upon chronic and acute exposure, howeve r, these toxic manifestations are distinct The mechanisms underlying t his cytotoxicity remain unknown, but may be related to a disruption in divalent cation homeostasis because both disrupt Ca2+-dependent proce sses 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 decr ease Ca2+ influx following nerve stimulation, and increase intracellul ar Ca2+ concentration [(Ca2+](i)) in the nerve terminal. Although thes e 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, si nce Hg2+ and MeHg are competitive and noncompetitive inhibitors of Ca2 + influx respectively. The functional consequence in both instances re mains decreased Ca2+ influx into the nerve terminal following the inva sion of an action potential leading to decreased nerve-evoked release of neurotransmitter. The effects of mercurials on voltage-activated Ca 2+ channels are distinct from those which mediate the increases in spo ntaneous transmitter release. Reducing extracellular Ca2+ concentratio n ([Ca2+](e)) decreased, but did not prevent, the mercurial-induced in creases in spontaneous transmitter release, suggesting that both intra - and extracellular sources of Ca2+ contribute to mercurial-induced el evations in [Ca2+](i) in a nerve terminals. The effects of MeHg on div alent cation homeostasis have been studied using isolated nerve termin als from the rat brain (synaptosomes) and cells in culture (NG108-15 a nd isolated cerebellar granule cells) loaded with the Ca2+-selective f luorescent indicator fura-a. In synaptosomes, MeHg caused an Ca-e(2+)- independent elevation in intrasynaptosomal Zn2+ concentration ([Zn2+]( i)) as well as an Ca-e(2+)-dependent elevation in [Ca2+](i). The eleva tions in [Zn2+](i) and [Ca2+](i) were mediated by release of Zn2+ from soluble synaptosomal proteins and increased plasma membrane permeabil ity, respectively. In NG108-15 cells, the effects of MeHg on divalent cation concentrations were more complex. First, MeHg mobilized Ca2+ fr om an intracellular store sensitive to inositol-1,4,5-tris-phosphate ( IP3) which was independent of IP3 generation. Second, MeHg increased t he intracellular concentration of an endogenous polyvalent cation, pos sibly Zn2+. Finally, MeHg caused an increase in the plasma membrane pe rmeability to Ca2+ which was attenuated by high concentrations of the voltage-activated Ca2+ channel blocker nifedipine or by the voltage-ac tivated Na+ channel blocker tetrodotoxin (TTX). While these studies de monstrate mercurials interfere with divalent cation regulation in neur onal systems, the consequences of these effects are not yet known. (C) 1996 Inter Press, Inc.