Bouton C M, Frelin L P, Forde C E, Arnold Godwin H, Pevsner J
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
J Neurochem. 2001 Mar;76(6):1724-35. doi: 10.1046/j.1471-4159.2001.00168.x.
Lead poisoning can cause a wide range of symptoms with particularly severe clinical effects on the CNS. Lead can increase spontaneous neurotransmitter release but decrease evoked neurotransmitter release. These effects may be caused by an interaction of lead with specific molecular targets involved in neurotransmitter release. We demonstrate here that the normally calcium-dependent binding characteristics of the synaptic vesicle protein synaptotagmin I are altered by lead. Nanomolar concentrations of lead induce the interaction of synaptotagmin I with phospholipid liposomes. The C2A domain of synaptotagmin I is required for lead-mediated phospholipid binding. Lead protects both recombinant and endogenous rat brain synaptotagmin I from proteolytic cleavage in a manner similar to calcium. However, lead is unable to promote the interaction of either recombinant or endogenous synaptotagmin I and syntaxin. Finally, nanomolar concentrations of lead are able to directly compete with and inhibit the ability of micromolar concentrations of calcium to induce the interaction of synaptotagmin I and syntaxin. Based on these findings, we conclude that synaptotagmin I may be an important, physiologically relevant target of lead.
铅中毒可引发一系列症状，对中枢神经系统具有尤为严重的临床影响。铅可增加神经递质的自发释放，但会减少诱发的神经递质释放。这些效应可能是由铅与参与神经递质释放的特定分子靶点相互作用所致。我们在此证明，突触囊泡蛋白突触结合蛋白I通常依赖钙的结合特性会被铅改变。纳摩尔浓度的铅可诱导突触结合蛋白I与磷脂脂质体相互作用。突触结合蛋白I的C2A结构域是铅介导的磷脂结合所必需的。铅以类似于钙的方式保护重组和内源性大鼠脑突触结合蛋白I不被蛋白水解。然而，铅无法促进重组或内源性突触结合蛋白I与 syntaxin 的相互作用。最后，纳摩尔浓度的铅能够直接竞争并抑制微摩尔浓度的钙诱导突触结合蛋白I与 syntaxin 相互作用的能力。基于这些发现，我们得出结论，突触结合蛋白I可能是铅的一个重要的、具有生理相关性的靶点。
