Localization of metals: Issues of importance to neurotoxicology of lead

Several hypotheses have been advanced for the molecular mechanisms of neurotoxic action of lead. Some of its effects are associated with lead itself. In these cases, the issue of intracellular localization is of obvious importance in determining mechanism. In lead neurotoxicology, an important issue relates to how lead interferes with chemical neurotransmission. Two hypotheses have been proposed. The first one implies that lead associates with the external neuronal membrane and blocks depolarization-coupled entry of calcium through voltage-sensitive channels or other components. Reduced calcium influx is associated with reduced exocytotic events and with decreases in stimulated transmitter release. Intraterminal mitochondrial calcium fluxes are unaffected. The second one states that, lead is taken up by calcium-relasing sites within neuronal mitochondria and reduces lability of this pool (specifically, calcium release in response to influxes of sodium). Calcium fluxes at the active zones are unaffected, and may increase as a consequence of the reduced contribution of intra-mitochondrial calcium to the free cytosolic compartment. Increased flux is associated with increases in calcium-dependent transmitter release.