INORGANIC MERCURY MODIFIES CA2+ SIGNALS, TRIGGERS APOPTOSIS AND POTENTIATES NMDA TOXICITY IN CEREBELLAR GRANULE NEURONS

Hg2+ (0.1 mu M - 0.5 mu M) modified the Ca2+ signals elicited by eithe r KCl or the glutamate-receptor agonist, N-methyl-D-aspartate (NMDA), in cerebellar granule cells (CGCs). Hg2+ enhanced the intracellular Ca 2+ transient elicited by high K+ and prevented a complete recovery of the resting intracellular Ca2+ concentration ([Ca2+](i)) after either KCl or NMDA stimulation. Higher Hg2+ concentrations (up to mu M) incre ased [Ca2+](i) directly, Following the short-term exposure to Hg2+, CG Cs underwent apoptosis, which was identified by the cleavage of DNA in to large (700-50 kbp) and oligonucleosomal DNA fragments, and by the a ppearance of typical apoptotic nuclei. Combined treatment with 0.1 - 0 .3 mu M Hg2+ and a sublethal NMDA concentration (50 mu M) potentiated DNA fragmentation and apoptotic cell death, When the exposure to Hg2was carried out in Ca2+-free media or in the presence of Ca2+ channel blockers (L-type or NMDA-R antagonists), the effects on signalling and apoptosis were prevented. Our results suggest that very low Hg2+ conc entrations can trigger apoptosis in CGCs by facilitating Ca2+ entry th rough membrane channels.