TY - JOUR
T1 - Pharmacological characterization of human beta-defensins 3 and 4 on potassium channels
T2 - Evidence of diversity in beta-defensin-potassium channel interactions
AU - Zhao, Yonghui
AU - Xie, Zili
AU - Feng, Jing
AU - Li, Wenxin
AU - Cao, Zhijian
AU - Wu, Yingliang
N1 - Funding Information:
This work was supported by grants from the National Natural Sciences Foundation of China (Nos. 81630091 and 31670840). The State Key Project of Research and Development Plan (No. 2016YFE0122800) and the Hubei Natural Sciences Foundation (No. 2016CFA018).
Funding Information:
This work was supported by grants from the National Natural Sciences Foundation of China (Nos. 81630091 and 31670840 ). The State Key Project of Research and Development Plan (No. 2016YFE0122800 ) and the Hubei Natural Sciences Foundation (No. 2016CFA018 ).
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/10
Y1 - 2018/10
N2 - Recent reports have identified defensins as a new type of potassium channel inhibitors; differential binding mechanisms of human β-defensins hBD1 and hBD2 point to complex interactions between human β-defensins and potassium channels. We investigated the inhibitory effects of human defensins hBD3 and hBD4 on potassium channels. The data indicate that hBD3 is a voltage-gated channel subfamily A member 3 (Kv1.3) inhibitor with an IC 50 value of 187.6 ± 25.7 nM; 1 μM hBD4 inhibited 34.0 ± 0.2% of Kv1.3 channel currents. Moreover, 1 μM hBD3 inhibited 50.6 ± 3.6% of Kv1.2 channel currents and had smaller effects on Kv1.1, SKCa3, and IKCa channel currents; these effects differed from the Kv1.3 channel-specific inhibitors hBD1 and hBD2. Similar to the pharmacological profiles of hBD1 and hBD2, hBD4 had lower inhibitory effects on Kv1.1, Kv1.2, SKCa3, and IKCa channels. Subsequent mutagenesis and channel activation experiments confirmed that hBD3 binds in a manner similar to that of hBD1, interacting with the outer pore region of the Kv1.3 channel without affecting Kv1.3 channel activation. Thus, the data indicate that the human β-defensin family is a novel group of potassium channel inhibitors with diverse types of human β-defensin-potassium channel interactions.
AB - Recent reports have identified defensins as a new type of potassium channel inhibitors; differential binding mechanisms of human β-defensins hBD1 and hBD2 point to complex interactions between human β-defensins and potassium channels. We investigated the inhibitory effects of human defensins hBD3 and hBD4 on potassium channels. The data indicate that hBD3 is a voltage-gated channel subfamily A member 3 (Kv1.3) inhibitor with an IC 50 value of 187.6 ± 25.7 nM; 1 μM hBD4 inhibited 34.0 ± 0.2% of Kv1.3 channel currents. Moreover, 1 μM hBD3 inhibited 50.6 ± 3.6% of Kv1.2 channel currents and had smaller effects on Kv1.1, SKCa3, and IKCa channel currents; these effects differed from the Kv1.3 channel-specific inhibitors hBD1 and hBD2. Similar to the pharmacological profiles of hBD1 and hBD2, hBD4 had lower inhibitory effects on Kv1.1, Kv1.2, SKCa3, and IKCa channels. Subsequent mutagenesis and channel activation experiments confirmed that hBD3 binds in a manner similar to that of hBD1, interacting with the outer pore region of the Kv1.3 channel without affecting Kv1.3 channel activation. Thus, the data indicate that the human β-defensin family is a novel group of potassium channel inhibitors with diverse types of human β-defensin-potassium channel interactions.
KW - Interaction mechanism
KW - Interaction mode
KW - Kv1.3 channel
KW - Pore-blocking
KW - Potassium channel
KW - β-Defensin
UR - http://www.scopus.com/inward/record.url?scp=85052865012&partnerID=8YFLogxK
U2 - 10.1016/j.peptides.2018.08.005
DO - 10.1016/j.peptides.2018.08.005
M3 - Article
C2 - 30121363
AN - SCOPUS:85052865012
VL - 108
SP - 14
EP - 18
JO - Peptides
JF - Peptides
SN - 0196-9781
ER -