Increased free intrasynaptosomal Ca2+ by neurotoxic organometals: Distinctive mechanisms

Abstract

Increased Free Intrasynaptosomal CaH by Neurotoxic Organometals: Distinetive Mechanisms. KOMULAINEN, H., AND BONDY. S. c. (1987). Toxico/. Appl. Pharmacol. 88,[77][78][79][80][81][82][83][84][85][86] Effects of several alkylmetals on free intrasynaptosomal Ca 2 + concentration, [Ca2+],, were studied in vitro using the fluorescent Ca 2 + indicator fura-2. Neurotoxic alkylmetals methylmercury than TET while dimethyltin and methyl tin were inactive. These results indicate that neurotoxic derivatives of alkylmetals studied increase [Caz+];. This occurs mainly either by nonspecific increase (Met-Hg, TET) ofCa 2 + leakage through the plasma membrane and/or specific interference with the mechanisms regulating Ca 2 + fluxes through the plasma membrane (TEL). '9 1987 Academic Press, Inc.The organometals methylmercury (Met-Hg), triethyllead (TEL) (Seawright et al.. 1984; Walsh and Tilson, 1984), triethyltin (TET), and trimethyltin (TMT) (Reuhl and Cranmer, l 984;Reiter and Ruppert, 1984) are neurotoxic but the underlying biochemical mechanisms causing impaired cell function and neuronal death are not as yet fully established. Trialkyltin and trialkyllead are thought to affect primarily mitochondria and thus energy metabolism of the cell (Aldridge, 1984;Bierkamper and Bassett, 1984). They

Disruption of the potential across the synaptosomal plasma membrane and mitochondria by neurotoxic agents

“…Exposure to methyl mercury has been found to effect reduction of ATP-generating capacity [26,27]. The elevation of cytosolic calcium, [Ca 2 +];, reported to be effected by both methyl mercury and toluene [19,24,27], may in part be due to the collapse of the mitochondrial potential, leading to release of calcium sequestered within mitochondrial binding sites.…”

“…where Fis fluorescence ofrhodamine when synaptosomes are in HEPES buffer, Fk is that fluorescence in the presence of 100 mM KCl, and R, T and F have the usual thermodynamic significance [11 calculated potentials is minimal [17,19]. This may be due to the deleterious effect of low potassium in the preparative medium on free mitochondria.…”

Intracellular calcium and neurotoxic events

“…When used in a synaptosomal preparation, such dyes do not significantly modulate some key parameters such as ATP content and membrane potential BONDY of the synaptosome. Furthermore, the physiological properties of the dye-loaded synaptosome, such as neurotransmitter release and other responses to pharmacological agents, appear to be appropriate (30,31). Limitations of the use of these dyes include:…”

“…Anestheticinduced elevations of [Ca 2 +]; may have their origins in modulation of the overall microviscosity of the plasma membrane (14). However, the toxicity of organochlorine insecticides or organometals may involve damage to both mitochondria and the plasma membrane (6,31,32). These chemicals with a relatively high LD 50 are likely to be less specific than pharmacological agents or biological toxins, both of which have a relatively precise effect due to man-made or evolutionary design, respectively.…”

“…This suggests that mitochondria are not the major site of damage caused by these neurotoxic agents. It also implies that calcium-removing processes have a priority for available energy when ATP levels are abnormally depressed (31). A promising aspect of the use synaptosomes in this type of study is the finding that the effect upon [Ca 2 +]; of toxic agents within a given class is directly related to their known neurotoxicity in vivo.…”