Human ether-à-go-go-related gene (hERG or Kv11.1) encodes the rapidly activated 
delayed rectifier K(+) current (I(Kr)) in the human heart. Potential regulation 
of hERG channel by protein tyrosine kinases (PTKs) is not understood. The 
present study was designed to investigate whether this channel is modulated by 
PTKs using whole-cell patch clamp technique, and immunoprecipitation and Western 
blot analysis in HEK 293 cells stably expressing hERG gene. We found that the 
broad-spectrum PTK inhibitor genistein (30 microM), the selective EGFR 
(epidermal growth factor receptor) kinase inhibitor AG556 (10 microM) and the 
Src-family kinase inhibitor PP2 (10 microM) remarkably inhibited hERG channel 
current (I(hERG)), and the effects were significantly countered by the protein 
tyrosine phosphatase (PTP) inhibitor orthovanadate (1 mM). Immunoprecipitation 
and Western blot analysis demonstrated that membrane protein tyrosine 
phosphorylation of hERG channels was reduced by genistein, AG556, and PP2. The 
reduction of hERG channel phosphorylation level by genistein, AG556 or PP2 was 
antagonized by orthovanadate. Single point mutation(s) of Y475A and/or Y611A 
dramatically attenuated the inhibitory effect of I(hERG) by PP2 and/or AG556. 
Our results demonstrate the novel information that I(hERG) is modulated not only 
by Src-family kinases, but also by EGFR kinases. Y475 and/or Y611 are likely the 
preferred phosphorylation sites. Regulation of hERG channels by PTKs modifies 
the channel activity and thus likely alters electrophysiological properties 
including action potential duration and cell excitability in human heart and 
neurons.