title: Endogenous animal toxin-like human β-defensin 2 inhibits own K(+) channels through interaction with channel extracellular pore region.
abstract: Human potassium channels are widely inhibited by peptide toxins from venomous animals. However, no human endogenous peptide inhibitor has been discovered so far. In this study, we demonstrate for the first time using electrophysiological techniques, that endogenous human β-defensin 2 (hBD2) is able to selectively and dose-dependently inhibit the human voltage-gated Kv1.3 channel at picomolar peptide concentration. The co-immunoprecipitation assays further supported the selective binding of hBD2 to Kv1.3 channel. Using mutagenesis experiments, we found that the outer pore domain of Kv1.3 channel was the binding site of hBD2, which is similar to the interacting site of Kv1.3 channel recognized by animal toxin inhibitors. The hBD2 was able to suppress IL-2 production through inhibition of Kv1.3 channel currents in human Jurkat cells, which was further confirmed by the lack of hBD2 activity on IL-2 production after Kv1.3 knockdown in these cells. More interestingly, hBD2 was also found to efficiently inhibit Kv1.3 channel currents and suppress IL-2 production in both human primary CD3(+) T cells and peripheral mononuclear cells from either healthy donors or psoriasis patients. Our findings not only evidenced hBD2 as the first characterized endogenous peptide inhibitor of human potassium channels, but also paved a promising avenue to investigate newly discovered function of hBD2 as Kv1.3 channel inhibitor in the immune system and other fields.
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
authors.forename: Weishan
authors.initials: W
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Feng
authors.forename: Fang
authors.initials: F
authors.lastname: Xiang
authors.forename: Zili
authors.initials: Z
authors.lastname: Xie
authors.forename: Guoyi
authors.initials: G
authors.lastname: Zhang
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Sabatier
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Cao
authors.forename: Wenxin
authors.initials: W
authors.lastname: Li
authors.forename: Zongyun
authors.initials: Z
authors.lastname: Chen
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D008969:Molecular Sequence Data; D016296:Mutagenesis; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D014118:Toxins, Biological / Q000494:pharmacology; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism*
chemical_list: C106641:DEFB4A protein, human; D007376:Interleukin-2; D051664:Kv1.3 Potassium Channel; D034741:RNA, Small Interfering; D014118:Toxins, Biological; D023083:beta-Defensins