HERV-W env regulates calcium influx via activating TRPC3 channel together with depressing DISC1 in human neuroblastoma cells
HERV-W env regulates calcium influx via activating TRPC3 channel together with depressing DISC1 in human neuroblastoma cells
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HERV-W env 通过激活 TRPC3 通道并抑制人神经母细胞瘤细胞中的 DISC1 来调节钙内流
DOI：
10.1007/s13365-018-0692-7
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发表时间：
2019-02-01
影响因子：
3.2
通讯作者：
Zhu, Fan
中科院分区：
文献类型：
--
作者：
Chen, Yatang;Yan, Qiujin;Zhu, Fan
人类内源性逆转录病毒W家族包膜基因（HERV-W env，也称为ERVWE1）的激活和参与已被报道在几种神经精神疾病中，包括精神分裂症，以及多发性硬化症（MS）。细胞内钙含量的失调也参与了这些疾病的发病机制。我们之前的研究表明HERV-W env过表达导致小电导Ca2+激活的K+通道蛋白3 （SK3）的激活，SK3是精神分裂症的潜在危险因素。在本研究中，我们旨在阐明HERV-W env与精神分裂症钙信号传导之间的关系。我们的研究结果表明，HERV-W env可以诱导两种人神经母细胞瘤细胞系的Ca2+内流，并上调细胞中TRPC3的表达和激活。加入TRPC3通道阻滞剂pyr3可以抑制细胞内Ca2+浓度的异常升高，表明HERV-W env诱导的Ca2+内流是TRPC3依赖性的。进一步实验表明，HERV-W env过表达可下调DISC1，而DISC1敲低可促进TRPC3的激活，但不影响TRPC3的表达。综上所述，HERV-W env通过直接调节TRPC3通道的表达或下调DISC1激活TRPC3通道，诱导Ca2+内流进入人神经母细胞瘤细胞，也可以在不影响TRPC3表达的情况下增加TRPC3的激活。这些发现为HERV-W环境如何影响神经元活动和促进精神分裂症的发病机制提供了新的见解。
The activation and involvement of human endogenous retroviruses W family envelope gene (HERV-W env, also called ERVWE1) have been reported in several neuropsychiatric disorders, including schizophrenia, as well as in multiple sclerosis (MS). Dysregulation of intracellular calcium content is also involved in the pathogenesis of these diseases. Our previous studies showed that HERV-W env overexpression results in activation of small conductance Ca2+-activated K+channel protein 3 (SK3), a potential risk factor for schizophrenia. In the present study, we aimed to elucidate the relationship between HERV-W env and calcium signaling in schizophrenia. Our results showed that HERV-W env could induce Ca2+influx in two human neuroblastoma cell lines and upregulate the expression and activation of TRPC3 in cells. The abnormal increase in intracellular Ca2+concentration was inhibited by addition of the TRPC3 channel blocker pyr3, demonstrating that the Ca2+influx induced by HERV-W env was TRPC3-dependent. Further experiments showed that HERV-W env overexpression downregulated DISC1, while knockdown of DISC1 promoted activation of TRPC3 without affecting TRPC3 expression. In conclusion, HERV-W env induced Ca2+influx in human neuroblastoma cells by activating the TRPC3 channel through directly regulating its expression or downregulating DISC1, which could also increase TRPC3 activation without affecting TRPC3 expression. These findings provide new insights into how HERV-W env affects neuronal activity and contributes to the pathogenesis of schizophrenia.