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 language | English (US) |
|---|---|
| Pages (from-to) | 966-973 |
| Number of pages | 8 |
| Journal | Journal of Molecular and Cellular Cardiology |
| Volume | 51 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 2011 |
| Externally published | Yes |
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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 journal › Article
}
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 -