title: Genistein and tyrphostin AG556 decrease ultra-rapidly activating delayed rectifier K+current of human atria by inhibiting EGF receptor tyrosine kinase.
abstract: The ultra-rapidly activating delayed rectifier K+current IKur(encoded by Kv1.5 or KCNA5) plays an important role in human atrial repolarization. The present study investigates the regulation of this current by protein tyrosine kinases (PTKs).
  
  
  
  Whole-cell patch voltage clamp technique and immunoprecipitation and Western blotting analysis were used to investigate whether the PTK inhibitors genistein, tyrphostin AG556 (AG556) and PP2 regulate human atrial IKurand hKv1.5 channels stably expressed in HEK 293 cells.
  
  
  
  Human atrial IKurwas decreased by genistein (a broad-spectrum PTK inhibitor) and AG556 (a highly selective EGFR TK inhibitor) in a concentration-dependent manner. Inhibition of IKurinduced by 30 μM genistein or 10 μM AG556 was significantly reversed by 1 mM orthovanadate (a protein tyrosine phosphatase inhibitor). Similar results were observed in HEK 293 cells stably expressing hKv1.5 channels. On the other hand, the Src family kinase inhibitor PP2 (1 μM) slightly enhanced IKurand hKv1.5 current, and the current increase was also reversed by orthovanadate. Immunoprecipitation and Western blotting analysis showed that genistein, AG556, and PP2 decreased tyrosine phosphorylation of hKv1.5 channels and that the decrease was countered by orthovanadate.
  
  
  
  The PTK inhibitors genistein and AG556 decrease human atrial IKurand cloned hKv1.5 channels by inhibiting EGFR TK, whereas the Src kinase inhibitor PP2 increases IKurand hKv1.5 current. These results imply that EGFR TK and the soluble Src kinases may have opposite effects on human atrial IKur.
authors.affiliation: Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, Fujian, China.
authors.forename: Guo-Sheng
authors.initials: GS
authors.lastname: Xiao
authors.affiliation: Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, Fujian, China.|Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Yan-Hui
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Sun
authors.affiliation: Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, Fujian, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, Fujian, China.|Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Gui-Rong
authors.identifier: 0000-0002-9437-2280
authors.initials: GR
authors.lastname: Li
mesh_terms: D002478:Cells, Cultured; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019833:Genistein / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D020032:Tyrphostins / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C412373:AG 1879; D051668:Delayed Rectifier Potassium Channels; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D020032:Tyrphostins; C098981:AG 556; D019833:Genistein; C512478:EGFR protein, human; D066246:ErbB Receptors