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Human α‐defensins are immune‐related Kv1.3 channel inhibitors: new support for their roles in adaptive immunity
Author(s) -
Xie Zili,
Feng Jing,
Yang Weishan,
Xiang Fang,
Yang Fan,
Zhao Yonghui,
Cao Zhijian,
Li Wenxin,
Chen Zongyun,
Wu Yingliang
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.15-274787
Subject(s) - chemistry , potassium channel , subfamily , defensin , peptide , linker , ion channel , biophysics , immune system , beta defensin , acquired immune system , voltage gated potassium channel , microbiology and biotechnology , biochemistry , biology , receptor , gene , immunology , computer science , operating system
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.—Xie, Z., Feng, J., Yang, W., Xiang, F., Yang, F., Zhao, Y., Cao, Z., Li, W., Chen, Z., Wu, Y. Human α‐defensins are immune‐related Kv1.3 channel inhibitors: new support for their roles in adaptive immunity. FASEB J. 29, 4324‐4333 (2015). www.fasebj.org