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Facilitation of Ca2+-activated K+ channels (IKCa1) by mibefradil in B lymphocytes

Cited 10 time in Web of Science Cited 11 time in Scopus
Authors
Yoo, Hae Young; Zheng, Haifeng; Nam, Joo Hyun; Nguyen, Yen Hoang; Kang, Tong Mook; Earm, Yung E; Kim, Sung Joon
Issue Date
2008-01-12
Publisher
Springer Verlag
Citation
Pflugers Arch. 456(3):549-560
Keywords
AnimalsB-Lymphocytes/*drug effects/metabolismCalcium/metabolismCalcium Channel Blockers/pharmacologyCell LineCharybdotoxin/pharmacologyDose-Response Relationship, DrugHumansIntermediate-Conductance Calcium-Activated PotassiumChannels/*agonists/genetics/metabolismLymphocyte Activation/*drug effectsMembrane PotentialsMembrane Transport Modulators/*pharmacologyMibefradil/*pharmacologyMicePatch-Clamp TechniquesPotassium Channel Blockers/pharmacologyPotassium Channels, Voltage-Gated/antagonists & inhibitors/metabolismTransfection
Abstract
K+ channels play critical roles in the proliferation and activation of lymphocytes. Mouse B cells express large-conductance background K+ channel (LK bg) in addition to the voltage-gated K+ channel (Kv) and Ca2+-activated K+ channel current (IKCa1). Mibefradil, a blocker of T-type Ca2+ channels, has been reported to affect the proliferation of immune cells. In this study, we investigated the effects of mibefradil on the membrane potential and ion channels in murine B cell lines, WEHI-231 and Bal-17. In the whole-cell patch clamp experiments, mibefradil blocked Kv and LK bg current with half inhibitory concentration (IC50), 1.9 and 2.3 microM, respectively. Interestingly, IKCa1 current was increased by mibefradil. In the inside-out patch clamp study with cloned murine IKCa1 (mIKCa1) in HEK-293, mibefradil increased both Ca2+ sensitivity and maximum activity of mIKCa1. At high concentrations (>10 microM), mibefradil inhibited mIKCa1 in a voltage-dependent manner. Application of anti-IgM antibody to stimulate B cell receptors (BCR-ligation) induced transient hyperpolarization of Bal-17 and WEHI-231 cells, which became persistent with 1 microM mibefradil. The hyperpolarizing response was abolished by charybdotoxin, a selective blocker for SK4/IKCa1. In summary, our study firstly reports the ion channel-activating effects of mibefradil. The selective potent activation of IKCa1 suggests that mibefradil-derived drugs might be useful in the control of cell responses related with IKCa1.
ISSN
0031-6768 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18188587

http://www.springerlink.com/content/n6w14j76k5701782/fulltext.pdf

http://hdl.handle.net/10371/68466
DOI
https://doi.org/10.1007/s00424-007-0438-5
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Physiology (생리학교실)Journal Papers (저널논문_생리학교실)
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