title: Involvement of large-conductance Ca2+-activated K+ channels in chloroquine-induced force alterations in pre-contracted airway smooth muscle.
abstract: The participation of large-conductance Ca2+ activated K+ channels (BKs) in chloroquine (chloro)-induced relaxation of precontracted airway smooth muscle (ASM) is currently undefined. In this study we found that iberiotoxin (IbTx, a selective inhibitor of BKs) and chloro both completely blocked spontaneous transient outward currents (STOCs) in single mouse tracheal smooth muscle cells, which suggests that chloro might block BKs. We further found that chloro inhibited Ca2+ sparks and caffeine-induced global Ca2+ increases. Moreover, chloro can directly block single BK currents completely from the intracellular side and partially from the extracellular side. All these data indicate that the chloro-induced inhibition of STOCs is due to the blockade of chloro on both BKs and ryanodine receptors (RyRs). We also found that low concentrations of chloro resulted in additional contractions in tracheal rings that were precontracted by acetylcholine (ACH). Increases in chloro concentration reversed the contractile actions to relaxations. In the presence of IbTx or paxilline (pax), BK blockers, chloro-induced contractions were inhibited, although the high concentrations of chloro-induced relaxations were not affected. Taken together, our results indicate that chloro blocks BKs and RyRs, resulting in abolishment of STOCs and occurrence of contraction, the latter will counteract the relaxations induced by high concentrations of chloro.
authors.affiliation: Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China.
authors.forename: Ming-Yu
authors.initials: MY
authors.lastname: Wei
authors.affiliation: Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Xue
authors.affiliation: Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China.
authors.forename: Li
authors.initials: L
authors.lastname: Tan
authors.affiliation: Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China.
authors.forename: Wen-Bo
authors.initials: WB
authors.lastname: Sai
authors.affiliation: Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China.
authors.forename: Xiao-Cao
authors.initials: XC
authors.lastname: Liu
authors.affiliation: Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China.
authors.forename: Qiu-Ju
authors.initials: QJ
authors.lastname: Jiang
authors.affiliation: Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Shen
authors.affiliation: Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China.
authors.forename: Yong-Bo
authors.initials: YB
authors.lastname: Peng
authors.affiliation: Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China.
authors.forename: Meng-Fei
authors.initials: MF
authors.lastname: Yu
authors.affiliation: Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China.
authors.forename: Li-Qun
authors.initials: LQ
authors.lastname: Ma
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Kui
authors.initials: K
authors.lastname: Zhai
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, United States of America.
authors.forename: Chunbin
authors.initials: C
authors.lastname: Zou
authors.affiliation: Lankenau Institute for Medical Research & Main Line Health Heart Center, 100 Lancaster Avenue, Wynnewood, PA 19096, United States of America.
authors.forename: Donglin
authors.initials: D
authors.lastname: Guo
authors.affiliation: Department of Medicine-Cardiology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States of America.
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208, United States of America.
authors.forename: Yun-Min
authors.initials: YM
authors.lastname: Zheng
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208, United States of America.
authors.forename: Yong-Xiao
authors.initials: YX
authors.lastname: Wang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Guangju
authors.initials: G
authors.lastname: Ji
authors.affiliation: Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan 430074, China.
authors.forename: Qing-Hua
authors.initials: QH
authors.lastname: Liu
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D066298:In Vitro Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D014132:Trachea / Q000166:cytology / Q000502:physiology
chemical_list: D002121:Calcium Channel Blockers; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D019837:Ryanodine Receptor Calcium Release Channel; C064719:iberiotoxin; D002738:Chloroquine
references.citation: Nat Med. 2010 Nov;16(11):1299-304
references.pmid: 20972434
references.citation: Science. 1995 Oct 27;270(5236):633-7
references.pmid: 7570021
references.citation: PLoS One. 2014;9(7):e101578
references.pmid: 24992312
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11418-23
references.pmid: 19549818
references.citation: Am J Physiol. 1993 Oct;265(4 Pt 1):C976-85
references.pmid: 8238323
references.citation: Pflugers Arch. 2013 Jul;465(7):965-75
references.pmid: 23344746
references.citation: PLoS One. 2010;5(8):e12304
references.pmid: 20808839
references.citation: PLoS Biol. 2013;11(3):e1001501
references.pmid: 23472053
references.citation: J Biol Chem. 2008 Jul 25;283(30):21036-44
references.pmid: 18524769
references.citation: Nat Med. 2012 May 04;18(5):650-1
references.pmid: 22561815
references.citation: Sci Rep. 2013;3:1995
references.pmid: 23771282
references.citation: Biochem Biophys Res Commun. 2013 May 10;434(3):498-502
references.pmid: 23583396
references.citation: Nature. 2000 Oct 19;407(6806):870-6
references.pmid: 11057658
references.citation: Clin Exp Pharmacol Physiol. 2014 Apr;41(4):301-8
references.pmid: 24552423
references.citation: Br J Pharmacol. 2014 Feb;171(3):646-62
references.pmid: 24117140
references.citation: J Gen Physiol. 2011 Aug;138(2):195-209
references.pmid: 21746845
references.citation: Nat Med. 2012 May;18(5):648-50; author reply 650-1
references.pmid: 22561814
references.citation: Nat Rev Neurosci. 2006 Dec;7(12):921-31
references.pmid: 17115074
references.citation: Sci Rep. 2013;3:1666
references.pmid: 23588888
references.citation: J Physiol. 2011 Apr 1;589(Pt 7):1803-17
references.pmid: 21300746