Human α-defensins are immune-related Kv1.3 channel inhibitors: New support for their roles in adaptive immunity

Defensins form a major family of antimicrobial peptides. Recently, humanb-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 a-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 ± 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 timeconstant 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.