title: Human α-defensins are immune-related Kv1.3 channel inhibitors: new support for their roles in adaptive immunity.
abstract: Defensins form a major family of antimicrobial peptides. Recently, human β-defensin 2 and fungal plectasin were shown to be immune-related potassium voltage-gated channel subfamily A member 3 (Kv1.3) channel inhibitors. This work continued to show that the human α-defensins human neutrophil peptide (HNP) 1 and human defensin (HD) 5 are selective Kv1.3 channel inhibitors with 50% inhibition concentration values of 102.0 ± 30.3 nM and 2.2 ± 0.2 μM, respectively. Furthermore, HNP1 was found to inhibit Kv1.3 currents and IL-2 secretion in human CD3(+) T cells. Despite the structural similarity between HNP1 and HD5, HNP1 could simultaneously bind to the S1-S2 linker and the pore region of the Kv1.3 channel as both a toxinlike blocker and a novel modifier, whereas HD5 could only bind to the channel pore region as a toxinlike blocker. As a channel modifier, HNP1 could shift the conductance-voltage relationship curve of the Kv1.3 channel by ∼9.5 mV in the positive direction and could increase the time constant for channel activation through the electrostatic repulsion between the cationic HNP1 anchored in the S1-S2 linker and the positively charged S4 domain of the Kv1.3 channel. Together, these findings reveal that human α-defensins are novel endogenous inhibitors of Kv1.3 channels with distinct interaction mechanisms, which facilitates future research into their adaptive immune functions.
authors.affiliation: *State Key Laboratory of Virology, College of Life Sciences, and Center for BioDrug Research, Wuhan University, Wuhan, China.
authors.forename: Zili
authors.initials: Z
authors.lastname: Xie
authors.affiliation: *State Key Laboratory of Virology, College of Life Sciences, and Center for BioDrug Research, Wuhan University, Wuhan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Feng
authors.affiliation: *State Key Laboratory of Virology, College of Life Sciences, and Center for BioDrug Research, Wuhan University, Wuhan, China.
authors.forename: Weishan
authors.initials: W
authors.lastname: Yang
authors.affiliation: *State Key Laboratory of Virology, College of Life Sciences, and Center for BioDrug Research, Wuhan University, Wuhan, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Xiang
authors.affiliation: *State Key Laboratory of Virology, College of Life Sciences, and Center for BioDrug Research, Wuhan University, Wuhan, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: *State Key Laboratory of Virology, College of Life Sciences, and Center for BioDrug Research, Wuhan University, Wuhan, China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: *State Key Laboratory of Virology, College of Life Sciences, and Center for BioDrug Research, Wuhan University, Wuhan, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Cao
authors.affiliation: *State Key Laboratory of Virology, College of Life Sciences, and Center for BioDrug Research, Wuhan University, Wuhan, China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Li
authors.affiliation: *State Key Laboratory of Virology, College of Life Sciences, and Center for BioDrug Research, Wuhan University, Wuhan, China chenzy2005@126.com ylwu@whu.edu.cn.
authors.forename: Zongyun
authors.initials: Z
authors.lastname: Chen
authors.affiliation: *State Key Laboratory of Virology, College of Life Sciences, and Center for BioDrug Research, Wuhan University, Wuhan, China chenzy2005@126.com ylwu@whu.edu.cn.
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects / Q000502:physiology; D000595:Amino Acid Sequence; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D007700:Kinetics; D051664:Kv1.3 Potassium Channel / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D008969:Molecular Sequence Data; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D023084:alpha-Defensins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C500225:DEFA5 protein, human; D051664:Kv1.3 Potassium Channel; D023084:alpha-Defensins; C406413:human neutrophil peptide 1
keywords: HD5; HNP1; immune modulation; interaction mechanism; potassium channel modifier