Domesticated HERV-W env contributes to the activation of the small conductance Ca^(2+)-activated K^(+)type 2 channels via decreased 5-HT4 receptor in recent-onset schizophrenia  

作　　者：Xiulin Wua Qiujin Yan Lianzhong Liu Xing Xue Wei Yao Xuhang Li Wenshi Li Shuang Ding Yaru Xia Dongyan Zhang Fan Zhu 

机构地区：[1]State Key Laboratory of Virology and Department of Medical Microbiology,School of Basic Medical Sciences,Wuhan University,Wuhan,430071,China [2]Wuhan Mental Health Center,Wuhan,430071,China [3]Hubei Province Key Laboratory of Allergy&Immunology,Wuhan University,Wuhan,430071,China

出　　处：《Virologica Sinica》2023年第1期9-22,共14页中国病毒学（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.81971943,81772196,31470264,81271820,30870789,and 30300117);the Stanley Foundation from the Stanley Medical Research Institute(SMRI),United States(No.06R-1366);We acknowledge the Medicine Research Center for Structural Biology of Wuhan University for providing the confocal microscopy(Leica-LCS-SP8-STED).

摘　　要：The human endogenous retroviruses type W family envelope(HERV-W env)gene is located on chromosome 7q21-22.Our previous studies show that HERV-W env is elevated in schizophrenia and HERV-W env can increase cal-cium influx.Additionally,the 5-HTergie system and particularly 5-hydroxytryptamine(5-HT)receptors play a prominent role in the pathogenesis and treatment of schizophrenia.5-hydroxytryptamine receptor 4(5-HT4R)agonist can block calcium channels.However,the underlying relationship between HERV-W env and 5-HT4R in the etiology of schizophrenia has not been revealed.Here,we used enzyme-linked immunosorbent assay to detect the concentration of HERV-W env and 5-HT4R in the plasma of patients with schizophrenia and we found that there were decreased levels of 5-HT4R and a negative correlation between 5-HT4R and HERV-W env in schizophrenia.Overexpression of HERV-W env decreased the transcription and protein levels of 5-HT4R but increased small conductance Ca^(2+)-activated K^(+)type 2 channels(SK2)expression levels.Further studies revealed that HERV-w env could interact with 5-HT4R.Additionally,luciferase assay showed that an essential region(-364 to-176 from the transcription start site)in the SK2 promoter was required for HERV-W env-induced SK2 expression.Importantly,5-HT4R participated in the regulation of SK2 expression and promoter activity.Electrophysiological recordings suggested that HERV-Wenv could increase SK2 channel currents and the increase of SK2 currents was inhibited by 5-HT4R.In condusion,HERV-W env could activate SK2 channels via decreased 5-HT4R,which might exhibit a novel mechanism for HERV-Wenv to influence neuronal activity in schizophrenia.

关 键 词：Human endogenous retroviruses type W(HERV-W) ENV Small conductance Ca^(2+)-activated K^(+)type 2 channels(SK2) 5-Hydroxytryptamine receptor 4(5-HT4R) SCHIZOPHRENIA 

分 类 号：R392[医药卫生—免疫学]