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Journal of NeuroVirology

, Volume 25, Issue 1, pp 101–113 | Cite as

HERV-W env regulates calcium influx via activating TRPC3 channel together with depressing DISC1 in human neuroblastoma cells

  • Yatang Chen
  • Qiujin Yan
  • Ping Zhou
  • Shan Li
  • Fan ZhuEmail author
Article
  • 96 Downloads

Abstract

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.

Keywords

HERV-W env Intracellular Ca2+ concentration TRPC3 DISC1 Schizophrenia 

Notes

Author contributions

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.

Funding information

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).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

13365_2018_692_Fig12_ESM.png (437 kb)
Supplementary Fig. S1

HERV-W env was overexpressed in neuroblastoma cell lines after transfection with pCMV-env. (a, c, d) In SH-SY5Y cells, the mRNA and protein expression levels of HERV-W env were increased by 117.2% and 143.5%. (b, e, f) In IMR-32 cells, the mRNA and protein expression levels of HERV-W env were increased by 151.9% and 90.7%. *p < 0.05, **p < 0.01. (PNG 436 kb)

13365_2018_692_MOESM1_ESM.tif (5.4 mb)
High Resolution Image (TIF 5478 kb)
13365_2018_692_Fig13_ESM.png (360 kb)
Supplementary Fig. S2

The expression of TRPC3 could be silenced by shTRPC3. (a, c, d) In SH-SY5Y cells, shTRPC3 decreased the mRNA expression of TRPC3 to 2.7% of the level in control cells. TRPC3 protein level was decreased to 24.8% of that in control cells. (b, e, f) In IMR-32 cells, shTRPC3 decreased the mRNA expression of TRPC3 to 2.9% of that in control cells. TRPC3 protein level was decreased to 41.0% of that in control cells. *p < 0.05, ***p < 0.001, ****p < 0.0001. (PNG 360 kb)

13365_2018_692_MOESM2_ESM.tif (3 mb)
High Resolution Image (TIF 3044 kb)
13365_2018_692_Fig14_ESM.png (335 kb)
Supplementary Fig. S3

The expression of DISC1 could be silenced by shDISC1. (a, c, d) In SH-SY5Y cells, shDISC1 decreased the mRNA expression of DISC1 to 47.2% of that in control cells, and the DISC1 protein level was decreased to 25.9% of that in control cells. (b, e, f) In IMR-32 cells, shDISC1 decreased the mRNA expression of DISC1 to 36.2% of that in control cells, and the DISC1 protein level was decreased to 11.2% of that in control cells. *p < 0.05, **p < 0.01, ****p < 0.0001. (PNG 334 kb)

13365_2018_692_MOESM3_ESM.tif (2.8 mb)
High Resolution Image (TIF 2887 kb)

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Copyright information

© Journal of NeuroVirology, Inc. 2018

Authors and Affiliations

  1. 1.Department of Medical Microbiology, School of MedicineWuhan UniversityWuhanPeople’s Republic of China
  2. 2.Department of Integrated Medicine, Dongfeng HospitalHubei University of MedicineHubeiPeople’s Republic of China
  3. 3.Hubei Province Key Laboratory of Allergy and ImmunologyWuhan UniversityWuhanPeople’s Republic of China

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