Protective effects of SKF-96365, a non-specific inhibitor of SOCE, against MPP+-induced cytotoxicity in PC12 cells: potential role of Homer1.
Protective effects of SKF-96365, a non-specific inhibitor of SOCE, against MPP+-induced cytotoxicity in PC12 cells: potential role of Homer1.
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SOCE 非特异性抑制剂 SKF-96365 对 MPP 诱导的 PC12 细胞细胞毒性的保护作用：Homer1 的潜在作用
DOI：
10.1371/journal.pone.0055601
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Jiang XF
中科院分区：
文献类型：
--
作者：
Chen T;Zhu J;Zhang C;Huo K;Fei Z;Jiang XF
帕金森病（Parkinson's disease，PD）是最常见的神经退行性运动障碍，其特征是黑质背侧部（substantia nigra pars rectuata，SNpc）多巴胺能（dopominergic，DA）神经元的缺失。在这项研究中，我们研究了SKF-96365，一种SOCE（钙池操纵的钙离子进入）的非特异性抑制剂，对MPP+诱导的PC 12细胞毒性的潜在保护作用。我们发现，在损伤前30分钟用SKF-96365（10 µM和50 µM）预处理可显著增加MPP+应激PC 12细胞的细胞活力，减少LDH释放，防止核损伤，并抑制细胞凋亡。使用比率钙指示剂Fura-2-AM的钙成像结果也表明SKF-96365减少了MPP+在PC 12细胞中诱导的细胞内钙超载。此外，在PC 12细胞中给予MPP+后，SKF-96365降低了Homer 1的表达，Homer 1是一种最近发现的具有钙调节功能的突触后支架蛋白，而对内质网（ER）钙浓度没有统计学显着影响。此外，通过使用重组慢病毒过表达Homer 1部分逆转了SKF-96365对MPP+损伤的保护作用。MPP+损伤后，PC 12细胞中Homer 1的上调进一步放大了ER Ca 2+的释放，并延迟了ER Ca 2+的恢复。综上所述，这些数据表明SKF-96365可保护PC 12细胞免受MPP+诱导的细胞毒性，这种保护作用可能至少部分是通过抑制细胞内钙超载和抑制Homer 1介导的ER Ca 2+释放。
Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized by loss of dopominergic (DA) neurons in substantia nigra pars compacta (SNpc), and can be experimentally mimicked by the neurotoxin MPP+ in vitro models. In this study, we investigated the potential protective effect of SKF-96365, a non-specific inhibitor of SOCE (store-operated calcium entry), on MPP+ induced cytotoxicity in PC12 cells. We found that pretreatment with SKF-96365 (10 µM and 50 µM) 30 min before injury significantly increased cell viability, decreased LDH release, prevented nuclear damage, and inhibited apoptotic cell death in MPP+ stressed PC12 cells. The results of calcium image using the ratiometric calcium indicator Fura-2-AM also showed that SKF-96365 reduced the intracellular calcium overload induced by MPP+ in PC12 cells. In addition, SKF-96365 decreased the expression of Homer1, a more recently discovered postsynaptic scaffolding protein with calcium modulating function, following MPP+ administration in PC12 cells, while had no statistically significant effects on endoplasmic reticulum (ER) calcium concentration. Furthermore, overexpression of Homer1 by using recombinant lentivirus partly reversed protective effects of SKF-96365 against MPP+ injury. The ER Ca2+ release was further amplified and ER calcium recovery was delayed by Homer1 upregulation in PC12 cells following MPP+ insult. Taken together, these data suggest that SKF-96365 protects PC12 cells against MPP+ induced cytotoxicity, and this protection may be at least in part on the inhibition of intracellular calcium overload and suppression of Homer1-mediated ER Ca2+ release.
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DOI：
10.1073/pnas.0405313101
发表时间：
2004-12-14
影响因子：
11.1
作者：
Lo Bianco, C;Schneider, BL;Aebischer, P
通讯作者：
Aebischer, P
影响因子：
3.5
作者：
Ango, F;Robbe, D;Fagni, L
通讯作者：
Fagni, L
影响因子：
7.4
作者：
Gomez-Lazaro, Maria;Bonekamp, Nina A.;Schrader, Michael
通讯作者：
Schrader, Michael
影响因子：
120.7
作者：
Schapira, AHV;Olanow, CW
通讯作者：
Olanow, CW
影响因子：
9.9
作者：
Becker, Claudia;Jick, Susan S.;Meier, Christoph R.
通讯作者：
Meier, Christoph R.