title: Regulation of TRPM7 Function by IL-6 through the JAK2-STAT3 Signaling Pathway.
abstract: OBJECTIVE
  Previous studies have demonstrated that expression of the TRPM7 channel, which may induce delayed cell death by mediating calcium influx, is precisely regulated. However, functional regulation of TRPM7 channels by endogenous molecules has not been elucidated. The proinflammatory cytokine IL-6 contributes to regulation of Ca2+ influx in cerebral ischemia, but the role of IL-6 in regulating TRPM7 functioning is unknown. Thus, we here investigated the interaction between IL-6 and TRPM7 channels and the relevant mechanisms.
  
  
  METHODS
  Using whole-cell patch-clamping, we first investigated the effect of IL-6 on TRPM7-like currents in primary cultured cortical neurons. Next, TRPM7-overexpressing HEK293 cells were used to confirm the effect of IL-6/sIL-6R on TRPM7. Finally, we used specific signaling pathway inhibitors to investigate the signaling pathways involved.
  
  
  RESULTS
  IL-6 or IL-6/sIL-6R dose-dependently inhibited inward TRPM7 currents, in both primary cultured neurons and HEK293 cells overexpressing TRPM7. In intracellular Mg2+-free conditions, extracellular Ca2+ or the α-kinase domain of TRPM7 did not participate in this regulation. The inhibitory effect of IL-6 on TRPM7 could be blocked by specific inhibitors of the JAK2-STAT3 pathway, but not of the PI3K, ERK1/2, or PLC pathways.
  
  
  CONCLUSIONS
  IL-6 inhibits the inward TRPM7 current via the JAK2-STAT3 signaling pathway.
authors.affiliation: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.|Basic Medical Research Centre, Medical College of Nantong University, Nantong, Jiangsu, P.R. China.
authors.forename: Aifen
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.|Basic Medical Research Centre, Medical College of Nantong University, Nantong, Jiangsu, P.R. China.
authors.forename: Fengbo
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
authors.forename: Zhenzhao
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005260:Female; D015850:Interleukin-6 / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D050053:TRPM Cation Channels / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D050053:TRPM Cation Channels; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; C486584:Trpm7 protein, rat