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

Hui Jun Wu, Wei Wu, Hai Ying Sun, Guo Wei Qin, Hong Bing Wang, Panwen Wang, Hari Krishna Yalamanchili, Junwen Wang, Hung Fat Tse, Chu Pak Lau, Paul M. Vanhoutte, Gui Rong Li

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)966-973
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume51
Issue number6
DOIs
StatePublished - Dec 2011
Externally publishedYes

Fingerprint

S 6
flavone
Patch-Clamp Techniques
acacetin
HEK293 Cells
Site-Directed Mutagenesis
Ion Channels
Mutagenesis
Atrial Fibrillation
Muscle Cells
Genes
Potassium
Membranes

Keywords

  • Acacetin
  • HKv1.5
  • Open channel blockade
  • Rate-dependent blockade
  • Tonic blockade

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Acacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain. / Wu, Hui Jun; Wu, Wei; Sun, Hai Ying; Qin, Guo Wei; Wang, Hong Bing; Wang, Panwen; Yalamanchili, Hari Krishna; Wang, Junwen; Tse, Hung Fat; Lau, Chu Pak; Vanhoutte, Paul M.; Li, Gui Rong.

In: Journal of Molecular and Cellular Cardiology, Vol. 51, No. 6, 12.2011, p. 966-973.

Research output: Contribution to journalArticle

Wu, HJ, Wu, W, Sun, HY, Qin, GW, Wang, HB, Wang, P, Yalamanchili, HK, Wang, J, Tse, HF, Lau, CP, Vanhoutte, PM & Li, GR 2011, 'Acacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain', Journal of Molecular and Cellular Cardiology, vol. 51, no. 6, pp. 966-973. https://doi.org/10.1016/j.yjmcc.2011.08.022
Wu, Hui Jun ; Wu, Wei ; Sun, Hai Ying ; Qin, Guo Wei ; Wang, Hong Bing ; Wang, Panwen ; Yalamanchili, Hari Krishna ; Wang, Junwen ; Tse, Hung Fat ; Lau, Chu Pak ; Vanhoutte, Paul M. ; Li, Gui Rong. / Acacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain. In: Journal of Molecular and Cellular Cardiology. 2011 ; Vol. 51, No. 6. pp. 966-973.
@article{64c7a085566f415ea474a2ed7f657aa5,
title = "Acacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain",
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.",
keywords = "Acacetin, HKv1.5, Open channel blockade, Rate-dependent blockade, Tonic blockade",
author = "Wu, {Hui Jun} and Wei Wu and Sun, {Hai Ying} and Qin, {Guo Wei} and Wang, {Hong Bing} and Panwen Wang and Yalamanchili, {Hari Krishna} and Junwen Wang and Tse, {Hung Fat} and Lau, {Chu Pak} and Vanhoutte, {Paul M.} and Li, {Gui Rong}",
year = "2011",
month = "12",
doi = "10.1016/j.yjmcc.2011.08.022",
language = "English (US)",
volume = "51",
pages = "966--973",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Academic Press Inc.",
number = "6",

}

TY - JOUR

T1 - Acacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain

AU - Wu, Hui Jun

AU - Wu, Wei

AU - Sun, Hai Ying

AU - Qin, Guo Wei

AU - Wang, Hong Bing

AU - Wang, Panwen

AU - Yalamanchili, Hari Krishna

AU - Wang, Junwen

AU - Tse, Hung Fat

AU - Lau, Chu Pak

AU - Vanhoutte, Paul M.

AU - Li, Gui Rong

PY - 2011/12

Y1 - 2011/12

N2 - 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.

AB - 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.

KW - Acacetin

KW - HKv1.5

KW - Open channel blockade

KW - Rate-dependent blockade

KW - Tonic blockade

UR - http://www.scopus.com/inward/record.url?scp=80055122349&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80055122349&partnerID=8YFLogxK

U2 - 10.1016/j.yjmcc.2011.08.022

DO - 10.1016/j.yjmcc.2011.08.022

M3 - Article

VL - 51

SP - 966

EP - 973

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

SN - 0022-2828

IS - 6

ER -