Subcellular mechanisms of lead neurotoxicity.
The neurotoxic effects of inorganic lead (Pb) involve inhibition of calcium-dependent acetylcholine release and increases in calcium-dependent dopamine release. These apparently differential effects of Pb are associated with differing Pb-calcium (Ca) interactions: Pb blocks 45Ca binding to peripheral cholinergic ganglia and increases 45Ca binding to synaptosomes prepared from caudate nucleus (CN). Pb-induced increases in CN 45Ca binding did not result from nonspecific disruption of selective ion permeability of the membrane. Also, the Na-K ATPase-linked Ca extrusion system of synpatosomes was not affected by Pb. A Pb-sodium (Na) interaction was found such that elevation of intrasynaptosomal Na reversed effects of Pb on 45Ca binding. The intracellular localization of this effect appeared to be primarily at the mitochondrial level. Pb inhibited Na-induced release of 45Ca from preloaded mitochondria. This action may be translated into increased transmembrane flux of exogenous Ca, and thence into increased exocytotic events at the synapse. The apparently neurotransmitter-specific effects of Pb, cholinergic inhibition and dopaminergic augmentation, are hypothesized to result from different Pb-Ca interactions which are determined by the specific localization of Pb within nerve endings.
D000109:Acetylcholine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002421:Caudate Nucleus / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D007854:Lead / Q000494:pharmacology; D007855:Lead Poisoning / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009489:Neurosecretion / Q000187:drug effects; D010042:Ouabain / Q000494:pharmacology; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism; D012964:Sodium / Q000494:pharmacology; D013570:Synaptic Membranes / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism
D011954:Receptors, Dopamine; D007854:Lead; D010042:Ouabain; D000255:Adenosine Triphosphate; D012964:Sodium; D000109:Acetylcholine; D002118:Calcium; D004298:Dopamine