Human beta-defensin 1, a new animal toxin-like blocker of potassium channel

Abstract

The discovery of human β-defensin 2 (hBD2), as a Kv1.3 channel inhibitor with the unique molecular mechanism and novel immune modulatory function, suggests that human β-defensins are a novel class of channel ligands. Here, the function and mechanism of the human β-defensin 1 (hBD1) binding to potassium channels was investigated. Based on the structural similarity between hBD1 and Kv1.3 channel-sensitive hBD2, hBD1 was found to selectively inhibit human and mouse Kv1.3 channels with IC50 values of 11.8 ± 3.1 μM and 13.2 ± 4.0 μM, respectively. Different from hBD2 modifying Kv1.3 channel activation and increasing activation time constant, hBD1 did not affect the activation feature of both human and mouse Kv1.3 channels. In comparison with hBD2 simultaneously interacting with the extracellular S1-S2 linker and pore region of Kv1.3 channel, the chimeric channel and mutagenesis experiments showed that hBD1 only bound to the extracellular pore region of Kv1.3 channel instead of extracellular S1-S2 linker or S3-S4 linker. Together, these findings enhance knowledge of hBD1 as a new immune-related Kv1.3 channel blocker and highlight the major functional differences between hBD1 and hBD2 to explore in future research.

Keywords: Endogenous blocker; Function and mechanism; Human β-defensin 1; Human β-defensin 2; Kv1.3 channel.