Institute of Chemistry, University of Tartu, Ravila 14A, 50411 Tartu, Estonia.
Neurotoxicology. 2011 Jan;32(1):25-30. doi: 10.1016/j.neuro.2010.11.005. Epub 2010 Nov 30.
Manganese is an essential trace element but its overexposure causes poisoning (called manganism) that shares several symptoms with Parkinson's disease, but with a mechanism that is still not well understood: in addition to involvement of the dopaminergic system, both serotonergic and peptiergic systems have been implicated. In the present report we have studied the influence of Mn(2+) on 5-HT(1A) receptor signaling complexes in rat brain and found that Mn(2+) in millimolar concentration caused an increase of high-affinity agonist binding to rat hippocampal membranes in comparison with experiments in the presence of Mg(2+), but not in rat cortical membranes and in Sf9 cell membranes expressing 5-HT(1A) receptors and G(i1) heterotrimers. Activation of G proteins with 30μM GTPγS turned all 5-HT(1A) receptors in these preparations into a low-affinity state for agonist binding in the presence of 1mM Mg(2+), but not in the presence of 1mM Mn(2+) in rat hippocampal membranes. However, if 1μM GTPγS was used for G protein activation, a substantial amount of high affinity agonist binding was detected in the presence of Mn(2+) also in cortical membranes and Sf9 cells, but not with Mg(2+) or EDTA. Comparison of the abilities of GDP and GTPγS to modulate high affinity agonist binding to 5-HT(1A) receptors indicated that both nucleotides were almost 10-fold less potent in the presence of MnCl(2) compared to MgCl(2). This means that by inhibiting guanosine nucleotide binding to G proteins in complex with 5-HT(1A) receptors, Mn(2+) acts as an enhancer for agonist binding and signal transduction. As the influence of Mn(2+) resembles the hypersensitivity of dopaminergic system in Parkinsonial models, it can be proposed that at least some symptoms of manganism are connected with a change of signal transduction complex caused by manganese-nucleotide complexes.
锰是一种必需的微量元素，但过量暴露会导致中毒（称为锰中毒），其具有与帕金森病相似的几种症状，但机制尚不清楚：除了涉及多巴胺能系统外，5-羟色胺能和肽能系统也与锰中毒有关。在本报告中，我们研究了 Mn(2+)对大鼠脑内 5-HT(1A)受体信号复合物的影响，发现 Mn(2+)在毫摩尔浓度下可增加高亲和力激动剂与大鼠海马膜的结合，与镁存在时的实验相比，但在大鼠皮质膜和表达 5-HT(1A)受体和 G(i1)异三聚体的 Sf9 细胞膜中则没有。用 30μM GTPγS 激活 G 蛋白，在 1mM Mg(2+)存在的情况下，所有这些制剂中的 5-HT(1A)受体都变为低亲和力状态，对激动剂结合，但在 1mM Mn(2+)存在的情况下则没有。然而，如果用 1μM GTPγS 激活 G 蛋白，则在 Mn(2+)存在的情况下，皮质膜和 Sf9 细胞中也会检测到大量的高亲和力激动剂结合，但在 Mg(2+)或 EDTA 存在的情况下则没有。比较 GDP 和 GTPγS 调节 5-HT(1A)受体与高亲和力激动剂结合的能力表明，与 MgCl(2)相比，MnCl(2)存在时，两种核苷酸的效力降低了近 10 倍。这意味着 Mn(2+)通过抑制与 5-HT(1A)受体结合的 G 蛋白的鸟嘌呤核苷酸结合，作为激动剂结合和信号转导的增强剂。由于 Mn(2+)的影响类似于帕金森病模型中多巴胺能系统的过敏反应，因此可以提出，至少一些锰中毒的症状与锰-核苷酸复合物引起的信号转导复合物的变化有关。
