Regulation of voltage-gated cardiac sodium current by epidermal growth factor receptor kinase in guinea pig ventricular myocytes.
Voltage-gated cardiac fast sodium channel current (I(Na)) plays a critical role in the initiation and propagation of the myocardial action potential, and regulation of cardiac I(Na) by protein tyrosine kinases (PTKs) is not well documented, though it is known that ion channels are among the targets of PTKs. The present study was therefore designed to investigate whether/how cardiac I(Na) was modulated by PTKs in guinea pig ventricular myocytes using whole-cell patch clamp and immunoprecipitation and Western blotting approaches. It was found that cardiac I(Na) was enhanced by epidermal growth factor (EGF), and the effect was antagonized by the selective epidermal growth factor receptor (EGFR) kinase inhibitor tyrphostin AG556 while potentiated by orthovanadate (a protein tyrosine phosphatase (PTP) inhibitor). In addition, AG556 inhibited, while orthovanadate increased I(Na), and the inhibition of I(Na) by AG556 was antagonized by orthovanadate. Immunoprecipitation and Western blotting analysis demonstrated that tyrosine phosphorylation level of cardiac sodium channels was enhanced by EGF or orthovanadate, and reduced by AG556. The AG556-induced reduction of phosphorylation level was significantly reversed by orthovanadate. Our results demonstrate the novel information that EGFR kinase enhances, and PTPs reduce native cardiac I(Na) in guinea pig ventricular myocytes.
Liu
Hui
H
Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
Sun
Hai-Ying
HY
Lau
Chu-Pak
CP
Li
Gui-Rong
GR
D000818:Animals; D022062:Electrophysiologic Techniques, Cardiac; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D015222:Sodium Channels; D014443:Tyrosine; D012964:Sodium; D066246:ErbB Receptors