ReferenceID 3892
Acacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain
J Mol Cell Cardiol
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
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Record Fields
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- Reference Id
- 3892
- Evidence Id
- 20482
- Core Evidence Id
- 20482
- Source Reference Id
- 1070
- Herb2 Reference Id
- HBREF001802
- Subject Paper Key
- HBIN014294_21906601
- Pubmed Id
- 21906601
- Doi
- 10.1016/j.yjmcc.2011.08.022
- Paper Title
- Acacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain
- Paper 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.
- Journal
- J Mol Cell Cardiol
- Publish Year
- 2011
- Experiment Subject
- human atrial myocytes
- Experiment Type
- Cell Experiment
- Phenotype Related
- Atrial Fibrillation
- Paper Title Cn
- Paper Title En
- Acacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain
- Bilingual Status
- semi_complete