Abstract
The human defensins are recently discovered to inhibit potassium channels, which are classical targets of the animal toxins. Whether other vertebrate defensins are potassium channel inhibitors remains unknown. In this work, we reported that the mouse β-defensin 3 (mBD3) was a novel inhibitor of both endogenous and exogenous potassium channels. The structural analysis showed that mBD3 is the most identical to human Kv1.3 channel-sensitive human β-defensin 2 (hBD2). However, the pharmacological profiles indicated that the recombinant mBD3 (rmBD3) weakly inhibited the mouse and human Kv1.3 channels. Different from the pharmacological features of human β-defensins, mBD3 more selectively inhibited the mouse Kv1.6 and human KCNQ1/KCNE1 channels with IC50 values of 0.6 ± 0.4 μM and 1.2 ± 0.8 μM, respectively. The site directed mutagenesis experiments indicated that the extracellular pore region of mouse Kv1.6 channel was the interaction site of rmBD3. In addition, the minor effect on the channel conductance-voltage relationship curves implied that mBD3 might bind the extracellular transmembrane helices S1-S2 linker and/or S3-S4 linker of mouse Kv1.6 channel. Together, these findings not only revealed mBD3 as a novel inhibitor of both endogenous and exogenous potassium channels, but also provided a clue to investigate the role of mBD3-Kv1.6 channel interaction in the physiological and pathological field in the future.
Highlights
The defensins, which are widely produced by fungus, insects, invertebrates and vertebrate animals, are endogenous cationic peptides and effector molecules of the innate immune system because of their broad-spectrum antimicrobial activity [1,2,3]
Since the positively charged amino acid residues often play a critical role in mediating animal toxins to bind potassium channel pore region
In order to verify whether the mBD3 could be an inhibitor of potassium channels, we examined order topotassium verify whether the mBD3 could be an inhibitor potassium channels, we examined it on In different channels subtypes through the patchofclamp technique according to our it on different potassium channels subtypes through the were patchexpressed clamp technique according to our previously procedure
Summary
The defensins, which are widely produced by fungus, insects, invertebrates and vertebrate animals, are endogenous cationic peptides and effector molecules of the innate immune system because of their broad-spectrum antimicrobial activity [1,2,3]. Among the α-, β- and θ-defensin subfamilies, α- and β-defensins usually contain six or eight cysteine residues which intramolecularly form disulfide bonds [4] Such structural features resemble the typical toxin peptides acting on potassium channels, which have induced researchers to confirm defensins as novel potassium channel inhibitors in recent years [5,6,7]. The defensins, such as plectasin, AtPDF2.3 and BmKDfin were successively identified as potassium channel blockers from fungi, plant and invertebrate scorpion, respectively [8,9,10]. Different from HD5 and hBD1 as the blockers targeting the potassium channel pore region, HNP1 and hBD2 work as both modifiers and blockers binding the transmembrane helices S1-S2 linker and pore region of potassium channel, respectively [11,14]
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