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Endogenous animal toxin-like human β-defensin 2 inhibits own K+ channels through interaction with channel extracellular pore region

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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.

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Acknowledgments

This work was supported by grants from the National Basic Research Program of China (No. 2010CB529800), the National Natural Sciences Foundation of China (Nos. 31170789 and 31200557), and Wuhan City Science and Technology Foundation of China (No. 2013070204020046).

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China

    Weishan Yang, Jing Feng, Fang Xiang, Zili Xie, Zhijian Cao, Wenxin Li, Zongyun Chen & Yingliang Wu

  2. Center for BioDrug Research, Wuhan University, Wuhan, 430072, China

    Zhijian Cao, Wenxin Li & Yingliang Wu

  3. Institute of Dermatology, Chinese Academy of Medicine Sciences, Nanjing, 210042, China

    Guoyi Zhang

  4. Laboratoire INSERM UMR 1097, Université d’Aix-Marseille, 163, Avenue de Luminy, Case 939, TPR2 INSERM, 13288, Marseille Cedex 09, France

    Jean-Marc Sabatier

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  1. Weishan Yang
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  2. Jing Feng
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  3. Fang Xiang
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  4. Zili Xie
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  7. Zhijian Cao
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  8. Wenxin Li
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  9. Zongyun Chen
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Corresponding authors

Correspondence to Zongyun Chen or Yingliang Wu.

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Weishan Yang and Jing Feng are contributed equally to the work.

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Yang, W., Feng, J., Xiang, F. et al. Endogenous animal toxin-like human β-defensin 2 inhibits own K+ channels through interaction with channel extracellular pore region. Cell. Mol. Life Sci. 72, 845–853 (2015). https://doi.org/10.1007/s00018-014-1715-z

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  • DOI: https://doi.org/10.1007/s00018-014-1715-z

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