HERV-W env regulates calcium influx via activating TRPC3 channel together with depressing DISC1 in human neuroblastoma cells
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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.
KeywordsHERV-W env Intracellular Ca2+ concentration TRPC3 DISC1 Schizophrenia
Mr. Chen conducted the overall study and drafted the manuscript; Miss Yan performed the cytological experiments; Mr. Zhou conducted data analysis; Dr. Li carried out electrophysiology experiments; Dr. Zhu served on the scientific advisory board for the School of Medicine, Wuhan University, conceived and designed the experiments, drafted the manuscript, and paid bills for this procedure.
This work was financially supported by grants from the National Natural Sciences Foundation of China (No. 81772196, No.31470264, No. 81271820, No. 30870789, and No. 30300117), the Key Program of Natural Science Foundation of Hubei Province of China (No. 2014CFA078), Stanley Foundation from the Stanley Medical Research Institute (SMRI), USA (No. 06R-1366) for Dr. F Zhu and the Scientific Innovation Team Project of Hubei Province of China (No. 2015CFA009).
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Conflict of interest
The authors declare that they have no conflict of interest.
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