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 journalArticlepeer-review

30 Scopus citations


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
Issue number6
StatePublished - Dec 2011


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

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine


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