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Cellular mechanisms underlying the increase in cytosolic free calcium concentration induced by methylmercury in cerebrocortical synaptosomes from guinea pig.

Risto A. Kauppinen,H. Komulainen,Hannu T. Taipale

Published 1989 in Journal of Pharmacology and Experimental Therapeutics

ABSTRACT

Neurotoxic mechanisms of methylmercury (Met-Hg) on presynaptic nerve terminals were studied using the synaptosomes from the cerebral cortex of guinea pig as a model. Cytosolic free calcium [Ca++)c was determined using intrasynaptically trapped fluorescence indicator, fura-2; the plasma membrane potential (delta Up) by measuring the diffusion potential of 86Rb+ and the mitochondrial membrane potential was monitored using the safranine method. Synaptosomal respiration, glycolysis and concentrations of ATP and ADP in the presence and absence of Met-Hg also were quantified. Met-Hg increased synaptosomal [Ca++]c by two distinctive mechanisms. Moderate elevation of [Ca++]c by 127 nM was observed at 30 microM Met-Hg, at which concentration synaptosomal respiration was inhibited completely, leading to partial depolarization of mitochondria. A 3-fold activation of anaerobic glycolysis upon inhibition of respiration was insufficient to sustain terminal energy levels. The delta Up did not depolarize significantly from the resting potential of--67 mV. Thus, the rise in [Ca++]c was due to the energy failure of the synaptosomes, which has been caused by Met-Hg. With 100 microM Met-Hg, [Ca++]c increased extensively by 882 nM. Upon addition of 100 microM Met-Hg the delta Up depolarized instantly dropping 36 mV within 1 min. Synaptosomes were severely energy-deprived, because anaerobic glycolysis was inhibited by 90% from the aerobic level and mitochondrial membrane potential dropped below the limit that could be detected by the safranine method. The proportion of fura-2 signal quenching by Mn++ also increased, indicating that the plasma membrane had become leaky. Thus, at high concentrations of Met-Hg, the rise in [Ca++]c was ascribed to increased ionic permeability of the plasma membrane. The contribution of presynaptic energy failure by Met-Hg is discussed as a possible biochemical mechanism underlying the neurotoxicity of organic mercury.

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