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Article: Acacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain
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TitleAcacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain
 
AuthorsWu, HJ1
Wu, W1
Sun, HY1
Qin, GW2
Wang, HB3
Wang, P1
Yalamanchili, HK1
Wang, J1
Tse, HF1
Lau, CP1
Vanhoutte, PM1
Li, GR1
 
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
 
CitationJournal Of Molecular And Cellular Cardiology, 2011, v. 51 n. 6, p. 966-973 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.yjmcc.2011.08.022
 
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.
 
ISSN0022-2828
2012 Impact Factor: 5.148
2012 SCImago Journal Rankings: 1.991
 
DOIhttp://dx.doi.org/10.1016/j.yjmcc.2011.08.022
 
ISI Accession Number IDWOS:000296943800012
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.

 
ReferencesReferences in Scopus
 
GrantsStudy on the Natural Anti-Atrial Fibrillation Compound Acacetin and Its Analogues/Derivatives
 
DC FieldValue
dc.contributor.authorWu, HJ
 
dc.contributor.authorWu, W
 
dc.contributor.authorSun, HY
 
dc.contributor.authorQin, GW
 
dc.contributor.authorWang, HB
 
dc.contributor.authorWang, P
 
dc.contributor.authorYalamanchili, HK
 
dc.contributor.authorWang, J
 
dc.contributor.authorTse, HF
 
dc.contributor.authorLau, CP
 
dc.contributor.authorVanhoutte, PM
 
dc.contributor.authorLi, GR
 
dc.date.accessioned2011-10-28T02:42:28Z
 
dc.date.available2011-10-28T02:42:28Z
 
dc.date.issued2011
 
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.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationJournal Of Molecular And Cellular Cardiology, 2011, v. 51 n. 6, p. 966-973 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.yjmcc.2011.08.022
 
dc.identifier.doihttp://dx.doi.org/10.1016/j.yjmcc.2011.08.022
 
dc.identifier.epage973
 
dc.identifier.hkuros197232
 
dc.identifier.isiWOS:000296943800012
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.

 
dc.identifier.issn0022-2828
2012 Impact Factor: 5.148
2012 SCImago Journal Rankings: 1.991
 
dc.identifier.issue6
 
dc.identifier.pmid21906601
 
dc.identifier.scopuseid_2-s2.0-80055122349
 
dc.identifier.spage966
 
dc.identifier.urihttp://hdl.handle.net/10722/142306
 
dc.identifier.volume51
 
dc.languageeng
 
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/yjmcc
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofJournal of Molecular and Cellular Cardiology
 
dc.relation.projectStudy on the Natural Anti-Atrial Fibrillation Compound Acacetin and Its Analogues/Derivatives
 
dc.relation.referencesReferences in Scopus
 
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.subjectAcacetin
 
dc.subjectHKv1.5
 
dc.subjectOpen channel blockade
 
dc.subjectRate-dependent blockade
 
dc.subjectTonic blockade
 
dc.titleAcacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain
 
dc.typeArticle
 
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<description.abstract>We 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 1.7&#956;M, 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, 29.5&#956;M for V505A, 19.1&#956;M for I508A, and 6.9&#956;M 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. &#169; 2011 Elsevier Ltd.</description.abstract>
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. Shanghai Institute of Materia Medica, Chinese Academy of Sciences
  3. Tongji University