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Identification of WP1066, an inhibitor of JAK2 and STAT3, as a K V 1.3 potassium channel blocker
Author(s) -
Li Min,
Yu Haibo
Publication year - 2021
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15441
Subject(s) - potassium channel , blockade , pharmacology , microbiology and biotechnology , chemistry , biophysics , ion channel , potassium channel blocker , channel blocker , patch clamp , ic50 , in vitro , biology , biochemistry , receptor , calcium , organic chemistry
Background and Purpose K V 1.3 potassium channels play a predominant role in regulating calcium signalling that is essential for the activation and proliferation of effector memory T (T EM ) cells. This ion channel has been recognized as a promising therapeutic target against various autoimmune diseases. Experimental Approach In a high‐throughput screening programme, WP1066 was identified as a K V 1.3 channel inhibitor. Using molecular biology and electrophysiological methods, the mechanism(s) underlying WP1066 blockade of Kv1.3 channels was investigated. Using T EM cell proliferation assay and mouse delayed‐type hypersensitivity (DTH) model, the effects of WP1066 were examined. Key Results WP1066 blocked K V 1.3 channels in a dose‐dependent manner with an IC 50 of 3.2 μM and induced a hyperpolarizing shift of the steady‐state inactivation curve. This blockade was use‐dependent, as WP1066 interacted preferentially with channels in their open state, rather than the closed state or inactivated state. When the residues located in the S6 domain scaffolding the inner vestibule, were sequentially mutated, the potency of WP1066 was significantly impaired, especially by mutations A413C and I420C, indicating a higher affinity of interacting sites for WP1066. Moreover, WP1066 effectively suppressed mouse T EM cell proliferation in vitro and mouse DTH reaction in vivo. Conclusions and Implications The results presented here have identified WP1066 as a K V 1.3 channel blocker with an open‐state‐dependent property, providing fundamental evidence for the application of WP1066 in further immunomodulatory studies targeting K V 1.3 channels.