Presynaptic Disruption of Transmitter Release by Lead

Abstract

Low concentrations of inorganic lead ions (Pb 2+) disrupt transmitter release by causing aberrant augmentation of spontaneous and suppression of evoked release. These effects result from high affinity interactions of Pb 2+ with the voltage-gated calcium channels (VGCC) as well as Ca 2+ binding proteins which regulate the synaptic vesicle mobilization, docking, and exocytosis processes. Augmentation of spontaneous release may involve stimulation of vesicle mobilization consequent to Pb 2+ activation of CaMKII-dependent phosphorylation of synapsin I and/or stimulation of asynchronous exocytosis via direct Pb 2+ activation of the putative exocytotic Ca 2+-sensor protein synaptotagmin I. In addition, synergistic stimulation of PLC and DAG/Pb 2+-dependent activation of PKC may enhance the secretagogue effects of Pb 2+ by increasing metal sensitivity of exocytosis and/or modulating calcium channel activity. In contrast to intracellularly-mediated actions of Pb 2+ resulting in augmentation of spontaneous release, the inhibition of evoked transmitter release by Pb 2+ is largely attributable to extracellular block of the voltage-gated calcium channels.