Investigation of microcystin congener-dependent uptake into primary murine neurons.
Investigation of microcystin congener-dependent uptake into primary murine neurons.
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DOI：
10.1289/ehp.0901289
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发表时间：
2010-10
影响因子：
10.4
通讯作者：
Dietrich DR
中科院分区：
文献类型：
--
作者：
Feurstein D;Kleinteich J;Heussner AH;Stemmer K;Dietrich DR
有毒蓝藻对自然沃茨水域的污染是世界范围内日益严重的问题，导致严重的水污染和人类健康危害。微囊藻毒素（MC）代表一组> 80个环七肽，在等摩尔浓度下通过特异性蛋白磷酸酶（PP）抑制介导细胞毒性（毒性动力学相当）。由于MC的结构和大小，通过有机阴离子转运多肽（OATP/Oatp）主动摄取到细胞中，如肝脏特异性人OATP 1B 1和OATP 1B 3、小鼠Oatp 1b 2（mOatp 1b 2）、旱冰鞋Oatp 1d 1和更广泛分布的OATP 1A 2（例如，在血脑屏障表达）所证实。因此，OATP/Oatp转运蛋白的组织特异性和细胞类型特异性表达以及MC同源物的特异性转运（毒代动力学）似乎是MC暴露后报告的人类和其他物种毒性效应的先决条件。除了MC-LR同源物诱导的肝毒性外，其他MC同源物的影响，特别是神经元摄取和毒性，尚不清楚。在这项研究中，我们研究了原代小鼠神经元中mOatps的表达和同源物MC-LR、MC-LW和MC-LF的摄取。通过摄取抑制实验间接指示细胞内MC积累，并通过蛋白质印迹分析和PP抑制测定直接证实。在mRNA和蛋白水平上验证神经元mOatp表达。MC可以穿过神经元细胞膜，随后PP活性降低。在15个mOatps中，12个在mRNA水平上表达，但我们发现只有两个可检测的蛋白水平：mOatp 1a 5（Slco 1a 5）和已知的MC-LR转运蛋白mOatp 1b 2（Slco 1b 2）。这些数据表明mOatp介导的MC同源物摄取进入神经元，从而证实了早期的假设的神经毒性潜力的MC。
Contamination of natural waters by toxic cyanobacteria is a growing problem worldwide, resulting in serious water pollution and human health hazards. Microcystins (MCs) represent a group of > 80 cyclic heptapeptides, mediating cytotoxicity via specific protein phosphatase (PP) inhibition at equimolar concentrations (comparable toxicodynamics). Because of the structure and size of MCs, active uptake into cells occurs via organic anion-transporting polypeptides (OATP/Oatp), as confirmed for liver-specific human OATP1B1 and OATP1B3, mouse Oatp1b2 (mOatp1b2), skate Oatp1d1, and the more widely distributed OATP1A2 expressed, for example, at the blood–brain barrier. Tissue-specific and cell-type–specific expression of OATP/Oatp transporters and specific transport of MC congeners (toxicokinetics) therefore appear prerequisite for the reported toxic effects in humans and other species upon MC exposure. Beyond hepatotoxicity induced by the MC-LR congener, the effects of other MC congeners, especially neuronal uptake and toxicity, are unknown. In this study we examined the expression of mOatps and the uptake of congeners MC-LR, MC-LW, and MC-LF in primary murine neurons. Intracellular MC accumulation was indicated indirectly via uptake inhibition experiments and directly confirmed by Western blot analysis and a PP inhibition assay. Neuronal mOatp expression was verified at the mRNA and protein level. MCs can cross neuronal cell membranes, with a subsequent decrease of PP activity. Of 15 mOatps, 12 were expressed at the mRNA level, but we found detectable protein levels for only two: mOatp1a5 (Slco1a5) and the known MC-LR transporter mOatp1b2 (Slco1b2). These data suggest mOatp-mediated uptake of MC congeners into neurons, thus corroborating earlier assumptions of the neurotoxic potential of MCs.
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影响因子：
4.5
作者：
Batista, T;de Sousa, G;Suput, DA
通讯作者：
Suput, DA
影响因子：
4.5
作者：
Hagenbuch, B;Meier, PJ
通讯作者：
Meier, PJ
DOI：
10.1016/j.beem.2007.03.004
发表时间：
2007-06-01
影响因子：
7.4
作者：
Hagenbuch, Bruno
通讯作者：
Hagenbuch, Bruno
影响因子：
5.1
作者：
FALCONER, IR;YEUNG, DSK
通讯作者：
YEUNG, DSK
影响因子：
5.7
作者：
Monks, Noel R.;Liu, Shuqian;Moscow, Jeffrey A.
通讯作者：
Moscow, Jeffrey A.