MOLECULAR MECHANISMS OF LEAD NEUROTOXICITY

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DESCRIPTION: The long-term goal of this project is to understand fundamental molecular mechanisms by which lead mediates increased neurotransmitter release. Several lines of evidence support the thesis that lead interferes with the coordinated regulation of synaptic loading, vesicular movement, docking and fusion with presynaptic membranes. Recent biochemical data, employing in the vivo and in the vitro models, provides compelling evidence implicating lead-mediated perturbation of normal vesicular trafficking processes resulting in the inappropriate release of neurotransmitters in the neuromuscular in the inappropriate release of neurotransmitters in the neuromuscular junction, synaptosomes and in the permeabilized cell cultures. Preliminary data obtained in the response to previous review further strengthens the principal investigator's assertion that the effects of lead on ephaptic synaptic release of neurotransmitters may be mediated by binding to the regulatory protein synaptotagmin. However, the exact mechanism(s) of lead-induced spontaneous neurotransmitter release remain to be determined. The hypothesis that lead binds to synaptotagmin and, therefore, stimulates unscheduled release of neurotransmitters is addressed by three specific aims. Proposed experiments are aimed at understanding (1) the pharmacology of lead- binding to the calcium-dependent regulatory protein, synaptotagmin; (2) the role of lead-synaptotagmin complexes in the unscheduled neurotransmitter release; and (3) the alteration of lead-effects on proposed in the this revised submission may provide new insights into the role of lead in the perturbation of normal synaptic vesicular function.