Vesicular distribution of Secretory Pathway Ca²+-ATPase isoform 1 and a role in manganese detoxification in liver-derived polarized cells.
Vesicular distribution of Secretory Pathway Ca²+-ATPase isoform 1 and a role in manganese detoxification in liver-derived polarized cells.
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DOI：
10.1007/s10534-010-9384-3
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发表时间：
2011-02
期刊：
影响因子：
3.5
通讯作者：
Rao, Rajini
中科院分区：
文献类型：
--
作者：
Leitch, Sharon;Feng, Mingye;Muend, Sabina;Braiterman, Lelita T.;Hubbard, Ann L.;Rao, Rajini
锰是一种微量元素，是多种生物途径关键酶的重要辅助因子。然而，过量的Mn 2+导致神经毒性，精神和运动功能障碍类似帕金森症。肝脏是Mn ~（2+）解毒的主要器官，通过排泄进入胆汁。虽然已经建立了许多细胞Mn 2+摄取的途径，外排机制仍然基本上不确定。在这项研究中，我们评估了在Mn 2+解毒的潜在作用，通过分泌途径Ca 2+，Mn 2 +-ATP酶在大鼠肝脏和肝源性细胞模型WIF-B，极化到不同的胆小管和窦域的文化。在已知的两种亚型中，只有分泌途径Ca 2 +-ATP酶亚型1（SPCA 1）在肝脏和WIF-B细胞中表达。如先前在非极化细胞中观察到的，SPCA 1显示与TGN 38重叠的分布，与高尔基体/TGN定位一致。然而，一个突出的新的本地化的SPCA 1的内体人口接近，但不是在基底外侧膜上也观察到。这一点通过大鼠肝匀浆的分级分离得到证实，该分级分离揭示了SPCA 1向高尔基体/TGN的双重分布和包括早期内体标记物EEA 1的级分。我们认为，这种新的池的内体可能有助于螯合Mn 2+，因为它进入从窦/基底外侧域。同种型特异性部分敲低SPCA 1延迟细胞生长和小管结构域的形成约30%，并在暴露于Mn 2+后降低活力。相反，SPCA 1在HEK 293 T细胞中的过表达赋予了对Mn 2+毒性的耐受性。综上所述，我们的研究结果表明SPCA 1在肝脏Mn 2+解毒中的作用。
Manganese is a trace element that is an essential co-factor in many enzymes critical to diverse biological pathways. However, excess Mn2+ leads to neurotoxicity, with psychiatric and motor dysfunction resembling parkinsonism. The liver is the main organ for Mn2+ detoxification by excretion into bile. Although many pathways of cellular Mn2+ uptake have been established, efflux mechanisms remain essentially undefined. In this study, we evaluated a potential role in Mn2+ detoxification by the Secretory Pathway Ca2+, Mn2+-ATPase in rat liver and a liver-derived cell model WIF-B that polarizes to distinct bile canalicular and sinusoidal domains in culture. Of two known isoforms, only secretory pathway Ca2+-ATPase isoform 1 (SPCA1) was expressed in liver and WIF-B cells. As previously observed in non-polarized cells, SPCA1 showed overlapping distribution with TGN38, consistent with Golgi/TGN localization. However, a prominent novel localization of SPCA1 to an endosomal population close to, but not on the basolateral membrane was also observed. This was confirmed by fractionation of rat liver homogenates which revealed dual distribution of SPCA1 to the Golgi/TGN and a fraction that included the early endosomal marker, EEA1. We suggest that this novel pool of endosomes may serve to sequester Mn2+ as it enters from the sinusoidal/basolateral domains. Isoform-specific partial knockdown of SPCA1 delayed cell growth and formation of canalicular domain by about 30% and diminished viability upon exposure to Mn2+. Conversely, overexpression of SPCA1 in HEK 293T cells conferred tolerance to Mn2+ toxicity. Taken together, our findings suggest a role for SPCA1 in Mn2+ detoxification in liver.
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影响因子：
3.7
作者：
Au C;Benedetto A;Anderson J;Labrousse A;Erikson K;Ewbank JJ;Aschner M
通讯作者：
Aschner M
影响因子：
64.5
作者：
Feng M;Grice DM;Faddy HM;Nguyen N;Leitch S;Wang Y;Muend S;Kenny PA;Sukumar S;Roberts-Thomson SJ;Monteith GR;Rao R
通讯作者：
Rao R
影响因子：
2.9
作者：
BECKMAN, RA;MILDVAN, AS;LOEB, LA
通讯作者：
LOEB, LA
DOI：
10.1016/j.bbrc.2008.03.003
发表时间：
2008-05-09
影响因子：
3.1
作者：
Faddy, Helen M.;Smart, Chanel E.;Monteith, Gregory R.
通讯作者：
Monteith, Gregory R.
影响因子：
2.1
作者：
Maeda, T;Sugiura, R;Kuno, T
通讯作者：
Kuno, T