Presynaptic disruption of transmitter release by lead.
Low concentrations of inorganic lead ions (Pb2+) disrupt transmitter release by causing aberrant augmentation of spontaneous and suppression of evoked release. These effects result from high affinity interactions of Pb2+ with the voltage-gated calcium channels (VGCC) as well as Ca2+ binding proteins which regulate the synaptic vesicle mobilization, docking, and exocytosis processes. Augmentation of spontaneous release may involve stimulation of vesicle mobilization consequent to Pb2+ activation of CaMKII-dependent phosphorylation of synapsin I and/or stimulation of asynchronous exocytosis via direct Pb2+ activation of the putative exocytotic Ca2+-sensor protein synaptotagmin I. In addition, synergistic stimulation of PLC and DAG/Pb2+-dependent activation of PKC may enhance the secretagogue effects of Pb2+ by increasing metal sensitivity of exocytosis and/or modulating calcium channel activity. In contrast to intracellularly-mediated actions of Pb2+ resulting in augmentation of spontaneous release, the inhibition of evoked transmitter release by Pb2+ is largely attributable to extracellular block of the voltage-gated calcium channels.
Suszkiw
Janusz B
JB
Department of Cellular and Molecular Physiology, College of Medicine, University of Cincinnati, P.O. Box 670576, Cincinnati, OH 45267-0576, USA. j.suszkiw@uc.edu
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D006801:Humans; D007854:Lead / Q000633:toxicity*; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism*
D015220:Calcium Channels; D018377:Neurotransmitter Agents; D007854:Lead