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Article: Acacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain

TitleAcacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain
Authors
KeywordsAcacetin
HKv1.5
Open channel blockade
Rate-dependent blockade
Tonic blockade
Issue Date2011
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/yjmcc
Citation
Journal Of Molecular And Cellular Cardiology, 2011, v. 51 n. 6, p. 966-973 How to Cite?
AbstractWe have demonstrated that the natural flavone acacetin selectively inhibits ultra-rapid delayed rectifier potassium current (I Kur) in human atria. However, molecular determinants of this ion channel blocker are unknown. The present study was designed to investigate the molecular determinants underlying the ability of acacetin to block hKv1.5 channels (coding I Kur) in human atrial myocytes using the whole-cell patch voltage-clamp technique to record membrane current in HEK 293 cells stably expressing the hKv1.5 gene or transiently expressing mutant hKv1.5 genes generated by site-directed mutagenesis. It was found that acacetin blocked hKv1.5 channels by binding to both closed and open channels. The blockade of hKv1.5 channels by acacetin was use- and frequency-dependent, and the IC 50 of acacetin for inhibiting hKv1.5 was 3.5, 3.1, 2.9, 2.1, and 1.7μM, respectively, at 0.2, 0.5, 1, 3, and 4Hz. The mutagenesis study showed that the hKv1.5 mutants V505A, I508A, and V512A in the S6-segment remarkably reduced the channel blocking properties by acacetin (IC 50, 29.5μM for V505A, 19.1μM for I508A, and 6.9μM for V512A). These results demonstrate the novel information that acacetin mainly blocks open hKv1.5 channels by binding to their S6 domain. The use- and rate-dependent blocking of hKv1.5 by acacetin is beneficial for anti-atrial fibrillation. © 2011 Elsevier Ltd.
Persistent Identifierhttp://hdl.handle.net/10722/142306
ISSN
2014 Impact Factor: 4.655
ISI Accession Number ID
Funding AgencyGrant Number
Sun Cheh Yeh Heart Foundation of Hong Kong
Innovation and Technology Commission of the Hong Kong SAR GovernmentITS/339/09
University of Hong Kong
Funding Information:

The study was supported in part by Sun Cheh Yeh Heart Foundation of Hong Kong and a grant (ITS/339/09) from Innovation and Technology Commission of the Hong Kong SAR Government. Miss Hui-Jun Wu and Mr. Wei Wu are supported by a postgraduate studentship from the University of Hong Kong. The authors thank Dr. M Tamkun (Colorado State University, CO, USA) for provide us with hKv1.5/pBK<INF>CMV</INF> plasmid.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorWu, HJen_HK
dc.contributor.authorWu, Wen_HK
dc.contributor.authorSun, HYen_HK
dc.contributor.authorQin, GWen_HK
dc.contributor.authorWang, HBen_HK
dc.contributor.authorWang, Pen_HK
dc.contributor.authorYalamanchili, HKen_HK
dc.contributor.authorWang, Jen_HK
dc.contributor.authorTse, HFen_HK
dc.contributor.authorLau, CPen_HK
dc.contributor.authorVanhoutte, PMen_HK
dc.contributor.authorLi, GRen_HK
dc.date.accessioned2011-10-28T02:42:28Z-
dc.date.available2011-10-28T02:42:28Z-
dc.date.issued2011en_HK
dc.identifier.citationJournal Of Molecular And Cellular Cardiology, 2011, v. 51 n. 6, p. 966-973en_HK
dc.identifier.issn0022-2828en_HK
dc.identifier.urihttp://hdl.handle.net/10722/142306-
dc.description.abstractWe have demonstrated that the natural flavone acacetin selectively inhibits ultra-rapid delayed rectifier potassium current (I Kur) in human atria. However, molecular determinants of this ion channel blocker are unknown. The present study was designed to investigate the molecular determinants underlying the ability of acacetin to block hKv1.5 channels (coding I Kur) in human atrial myocytes using the whole-cell patch voltage-clamp technique to record membrane current in HEK 293 cells stably expressing the hKv1.5 gene or transiently expressing mutant hKv1.5 genes generated by site-directed mutagenesis. It was found that acacetin blocked hKv1.5 channels by binding to both closed and open channels. The blockade of hKv1.5 channels by acacetin was use- and frequency-dependent, and the IC 50 of acacetin for inhibiting hKv1.5 was 3.5, 3.1, 2.9, 2.1, and 1.7μM, respectively, at 0.2, 0.5, 1, 3, and 4Hz. The mutagenesis study showed that the hKv1.5 mutants V505A, I508A, and V512A in the S6-segment remarkably reduced the channel blocking properties by acacetin (IC 50, 29.5μM for V505A, 19.1μM for I508A, and 6.9μM for V512A). These results demonstrate the novel information that acacetin mainly blocks open hKv1.5 channels by binding to their S6 domain. The use- and rate-dependent blocking of hKv1.5 by acacetin is beneficial for anti-atrial fibrillation. © 2011 Elsevier Ltd.en_HK
dc.languageengen_US
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/yjmccen_HK
dc.relation.ispartofJournal of Molecular and Cellular Cardiologyen_HK
dc.subjectAcacetinen_HK
dc.subjectHKv1.5en_HK
dc.subjectOpen channel blockadeen_HK
dc.subjectRate-dependent blockadeen_HK
dc.subjectTonic blockadeen_HK
dc.subject.meshAmino Acid Substitution-
dc.subject.meshFlavones - metabolism - pharmacology-
dc.subject.meshHEK293 Cells-
dc.subject.meshKv1.5 Potassium Channel - antagonists and inhibitors - chemistry - genetics-
dc.subject.meshPotassium Channel Blockers - metabolism - pharmacology-
dc.titleAcacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domainen_HK
dc.typeArticleen_HK
dc.identifier.emailWang, J: junwen@hkucc.hku.hken_HK
dc.identifier.emailTse, HF: hftse@hkucc.hku.hken_HK
dc.identifier.emailVanhoutte, PM: vanhoutt@hku.hken_HK
dc.identifier.emailLi, GR: grli@hkucc.hku.hken_HK
dc.identifier.authorityWang, J=rp00280en_HK
dc.identifier.authorityTse, HF=rp00428en_HK
dc.identifier.authorityVanhoutte, PM=rp00238en_HK
dc.identifier.authorityLi, GR=rp00476en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.yjmcc.2011.08.022en_HK
dc.identifier.pmid21906601en_HK
dc.identifier.scopuseid_2-s2.0-80055122349en_HK
dc.identifier.hkuros197232en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80055122349&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume51en_HK
dc.identifier.issue6en_HK
dc.identifier.spage966en_HK
dc.identifier.epage973en_HK
dc.identifier.isiWOS:000296943800012-
dc.publisher.placeUnited Kingdomen_HK
dc.relation.projectStudy on the Natural Anti-Atrial Fibrillation Compound Acacetin and Its Analogues/Derivatives-
dc.identifier.scopusauthoridWu, HJ=53880675900en_HK
dc.identifier.scopusauthoridWu, W=43161580300en_HK
dc.identifier.scopusauthoridSun, HY=53265070800en_HK
dc.identifier.scopusauthoridQin, GW=7202860696en_HK
dc.identifier.scopusauthoridWang, HB=54405232700en_HK
dc.identifier.scopusauthoridWang, P=54397871300en_HK
dc.identifier.scopusauthoridYalamanchili, HK=35182263500en_HK
dc.identifier.scopusauthoridWang, J=8950599500en_HK
dc.identifier.scopusauthoridTse, HF=7006070805en_HK
dc.identifier.scopusauthoridLau, CP=7401968501en_HK
dc.identifier.scopusauthoridVanhoutte, PM=7202304247en_HK
dc.identifier.scopusauthoridLi, GR=7408462932en_HK

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