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Article: The 5-HT 2 antagonist ketanserin is an open channel blocker of human cardiac ether-à-go-go-related gene (hERG) potassium channels

TitleThe 5-HT 2 antagonist ketanserin is an open channel blocker of human cardiac ether-à-go-go-related gene (hERG) potassium channels
Authors
KeywordsHuman Ether-À-Go-Go-Related Gene (Herg) Potassium Channels
Ketanserin
Long Qts
Open Channel Block
Issue Date2008
PublisherJohn Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0007-1188&site=1
Citation
British Journal Of Pharmacology, 2008, v. 155 n. 3, p. 365-373 How to Cite?
AbstractBackground and purpose: Ketanserin, a selective 5-HT receptor antagonist, prolongs the QT interval of ECG in patients. The purpose of the present study was to determine whether ketanserin would block human cardiac ether-à-go-go-related gene (hERG) potassium channels. Experimental approach: Whole-cell patch voltage-clamp technique was used to record membrane currents in HEK 293 cells expressing wild type or mutant hERG channel genes. Key results: Ketanserin blocked hERG current (I hERG) in a concentration-dependent manner (IC 50=0.11 μM). The drug showed an open channel blocking property, the block increasing significantly at depolarizing voltages between +10 to +60 mV. Voltage-dependence for inactivation of hERG channels was negatively shifted by 0.3 μM ketanserin. A 2.8 fold attenuation of inhibition by elevation of external K + concentration (from 5.0 to 20 mM) was observed, whereas the inactivation-deficient mutants S620T and S631A had the IC 50s of 0.84±0.2 and 1.7±0.4 μM (7.6 and 15.4 fold attenuation of block). In addition, the hERG mutants in pore helix and S6 also significantly reduced the channel block (2-59 fold) by ketanserin. Conclusions and implications: These results suggest that ketanserin binds to and blocks the open hERG channels in the pore helix and the S6 domain; channel inactivation is also involved in the blockade of hERG channels. Blockade of hERG channels most likely contributes to the prolongation of QT intervals in ECG observed clinically at therapeutic concentrations of ketanserin. © 2008 Macmillan Publishers Limited All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/163204
ISSN
2015 Impact Factor: 5.259
2015 SCImago Journal Rankings: 2.368
ISI Accession Number ID
Funding AgencyGrant Number
Sun Chieh Yeh Heart Foundation of Hong Kong
Funding Information:

This study was supported by a grant from Sun Chieh Yeh Heart Foundation of Hong Kong. We thank Dr G Robertson (University of Wisconsin-Madison, WI, USA) for providing the vector of hERG/pcDNA3.

References

 

DC FieldValueLanguage
dc.contributor.authorTang, Qen_US
dc.contributor.authorLi, ZQen_US
dc.contributor.authorLi, Wen_US
dc.contributor.authorGuo, Jen_US
dc.contributor.authorSun, HYen_US
dc.contributor.authorZhang, XHen_US
dc.contributor.authorLau, CPen_US
dc.contributor.authorTse, HFen_US
dc.contributor.authorZhang, Sen_US
dc.contributor.authorLi, GRen_US
dc.date.accessioned2012-09-05T05:28:44Z-
dc.date.available2012-09-05T05:28:44Z-
dc.date.issued2008en_US
dc.identifier.citationBritish Journal Of Pharmacology, 2008, v. 155 n. 3, p. 365-373en_US
dc.identifier.issn0007-1188en_US
dc.identifier.urihttp://hdl.handle.net/10722/163204-
dc.description.abstractBackground and purpose: Ketanserin, a selective 5-HT receptor antagonist, prolongs the QT interval of ECG in patients. The purpose of the present study was to determine whether ketanserin would block human cardiac ether-à-go-go-related gene (hERG) potassium channels. Experimental approach: Whole-cell patch voltage-clamp technique was used to record membrane currents in HEK 293 cells expressing wild type or mutant hERG channel genes. Key results: Ketanserin blocked hERG current (I hERG) in a concentration-dependent manner (IC 50=0.11 μM). The drug showed an open channel blocking property, the block increasing significantly at depolarizing voltages between +10 to +60 mV. Voltage-dependence for inactivation of hERG channels was negatively shifted by 0.3 μM ketanserin. A 2.8 fold attenuation of inhibition by elevation of external K + concentration (from 5.0 to 20 mM) was observed, whereas the inactivation-deficient mutants S620T and S631A had the IC 50s of 0.84±0.2 and 1.7±0.4 μM (7.6 and 15.4 fold attenuation of block). In addition, the hERG mutants in pore helix and S6 also significantly reduced the channel block (2-59 fold) by ketanserin. Conclusions and implications: These results suggest that ketanserin binds to and blocks the open hERG channels in the pore helix and the S6 domain; channel inactivation is also involved in the blockade of hERG channels. Blockade of hERG channels most likely contributes to the prolongation of QT intervals in ECG observed clinically at therapeutic concentrations of ketanserin. © 2008 Macmillan Publishers Limited All rights reserved.en_US
dc.languageengen_US
dc.publisherJohn Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0007-1188&site=1en_US
dc.relation.ispartofBritish Journal of Pharmacologyen_US
dc.subjectHuman Ether-À-Go-Go-Related Gene (Herg) Potassium Channelsen_US
dc.subjectKetanserinen_US
dc.subjectLong Qtsen_US
dc.subjectOpen Channel Blocken_US
dc.titleThe 5-HT 2 antagonist ketanserin is an open channel blocker of human cardiac ether-à-go-go-related gene (hERG) potassium channelsen_US
dc.typeArticleen_US
dc.identifier.emailTse, HF:hftse@hkucc.hku.hken_US
dc.identifier.emailLi, GR:grli@hkucc.hku.hken_US
dc.identifier.authorityTse, HF=rp00428en_US
dc.identifier.authorityLi, GR=rp00476en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1038/bjp.2008.261en_US
dc.identifier.pmid18574455-
dc.identifier.scopuseid_2-s2.0-52949095382en_US
dc.identifier.hkuros146210-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-52949095382&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume155en_US
dc.identifier.issue3en_US
dc.identifier.spage365en_US
dc.identifier.epage373en_US
dc.identifier.isiWOS:000259655900011-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridTang, Q=40861778800en_US
dc.identifier.scopusauthoridLi, ZQ=37078698100en_US
dc.identifier.scopusauthoridLi, W=36514933400en_US
dc.identifier.scopusauthoridGuo, J=23012290600en_US
dc.identifier.scopusauthoridSun, HY=35723049200en_US
dc.identifier.scopusauthoridZhang, XH=37092287700en_US
dc.identifier.scopusauthoridLau, CP=7401968501en_US
dc.identifier.scopusauthoridTse, HF=7006070805en_US
dc.identifier.scopusauthoridZhang, S=8610688300en_US
dc.identifier.scopusauthoridLi, GR=7408462932en_US

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