Article: Acacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain
| Title | Acacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Authors | Wu, HJ1 Wu, W1 Sun, HY1 Qin, GW2 Wang, HB3 Wang, P1 Yalamanchili, HK1 Wang, J1 Tse, HF1 Lau, CP1 Vanhoutte, PM1 Li, GR1 | ||||||||
| Keywords | Acacetin HKv1.5 Open channel blockade Rate-dependent blockade Tonic blockade | ||||||||
| Issue Date | 2011 | ||||||||
| Publisher | Academic 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?] DOI: http://dx.doi.org/10.1016/j.yjmcc.2011.08.022 | ||||||||
| 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 1.7μM, 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. | ||||||||
| ISSN | 0022-2828 2011 Impact Factor: 5.166 2011 SCImago Journal Rankings: 0.585 | ||||||||
| DOI | http://dx.doi.org/10.1016/j.yjmcc.2011.08.022 | ||||||||
| ISI Accession Number ID | WOS:000296943800012
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 | References in Scopus | ||||||||
| Grants | Study on the Natural Anti-Atrial Fibrillation Compound Acacetin and Its Analogues/Derivatives |
| dc.contributor.author | Wu, HJ | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| dc.contributor.author | Wu, W | ||||||||
| dc.contributor.author | Sun, HY | ||||||||
| dc.contributor.author | Qin, GW | ||||||||
| dc.contributor.author | Wang, HB | ||||||||
| dc.contributor.author | Wang, P | ||||||||
| dc.contributor.author | Yalamanchili, HK | ||||||||
| dc.contributor.author | Wang, J | ||||||||
| dc.contributor.author | Tse, HF | ||||||||
| dc.contributor.author | Lau, CP | ||||||||
| dc.contributor.author | Vanhoutte, PM | ||||||||
| dc.contributor.author | Li, GR | ||||||||
| dc.date.accessioned | 2011-10-28T02:42:28Z | ||||||||
| dc.date.available | 2011-10-28T02:42:28Z | ||||||||
| dc.date.issued | 2011 | ||||||||
| dc.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 1.7μM, 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.grant | Study on the Natural Anti-Atrial Fibrillation Compound Acacetin and Its Analogues/Derivatives | ||||||||
| dc.description.grantcode | 102461 | ||||||||
| dc.description.nature | Link_to_subscribed_fulltext | ||||||||
| dc.identifier.citation | Journal 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.doi | http://dx.doi.org/10.1016/j.yjmcc.2011.08.022 | ||||||||
| dc.identifier.epage | 973 | ||||||||
| dc.identifier.hkuros | 197232 | ||||||||
| dc.identifier.isi | WOS:000296943800012
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.issn | 0022-2828 2011 Impact Factor: 5.166 2011 SCImago Journal Rankings: 0.585 | ||||||||
| dc.identifier.issue | 6 | ||||||||
| dc.identifier.pmid | 21906601 | ||||||||
| dc.identifier.scopus | eid_2-s2.0-80055122349 | ||||||||
| dc.identifier.spage | 966 | ||||||||
| dc.identifier.uri | http://hdl.handle.net/10722/142306 | ||||||||
| dc.identifier.volume | 51 | ||||||||
| dc.language | eng | ||||||||
| dc.publisher | Academic Press. The Journal's web site is located at http://www.elsevier.com/locate/yjmcc | ||||||||
| dc.publisher.place | United Kingdom | ||||||||
| dc.relation.ispartof | Journal of Molecular and Cellular Cardiology | ||||||||
| dc.relation.references | References in Scopus | ||||||||
| dc.subject.mesh | Amino Acid Substitution | ||||||||
| dc.subject.mesh | Flavones - metabolism - pharmacology | ||||||||
| dc.subject.mesh | HEK293 Cells | ||||||||
| dc.subject.mesh | Kv1.5 Potassium Channel - antagonists and inhibitors - chemistry - genetics | ||||||||
| dc.subject.mesh | Potassium Channel Blockers - metabolism - pharmacology | ||||||||
| dc.subject | Acacetin | ||||||||
| dc.subject | HKv1.5 | ||||||||
| dc.subject | Open channel blockade | ||||||||
| dc.subject | Rate-dependent blockade | ||||||||
| dc.subject | Tonic blockade | ||||||||
| dc.title | Acacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain | ||||||||
| dc.type | Article |
Author Affiliations
- The University of Hong Kong Li Ka Shing Faculty of Medicine
- Chinese Academy of Sciences
- Tongji University