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Activation of cardiac chloride conductance by the tyrosine kinase inhibitor, genistein
Author(s) -
Shuba Lesya M.,
Asai Tatsuya,
Pelzer Siegried,
McDonald Terence F.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15991.x
Subject(s) - genistein , forskolin , chemistry , cystic fibrosis transmembrane conductance regulator , chloride channel , protein tyrosine phosphatase , dids , endocrinology , medicine , phosphorylation , biochemistry , biophysics , biology , receptor , membrane , gene
1 Genistein (GST), an inhibitor of protein tyrosine kinase (PTK), Na 3 VO 4 (VO 4 ), an inhibitor of phosphotyrosine phosphatase (PTPase), and forskolin (FSK), an activator of the cyclic AMP‐dependent, cystic fibrosis transmembrane conductance regulator (CFTR) Cl − channel, were applied to guinea‐pig ventricular myocytes to probe for a possible role of tyrosine phosphorylation in the regulation of cardiac Cl − channels. 2 Myocytes in the standard whole‐cell configuration were pulsed to various potentials and Cl − current ( I C1 ) measured as the difference from control background current. GST (1–500 μ m ) activated a current that had similar biophysical properties (time‐ and voltage‐independent; Cl − ‐dependent reversal potential and outward rectification) as I C1 activated by 5 μ m FSK. The EC 50 for activation of Cl − conductance (g C1 ) by GST was approximately 100 μ m , and g C1 activated by GST (500 μ m ) was as large as g C1 activated by maximally‐effective FSK (5 μ m ). Daidzein, a GST analogue with little effect on PTK, was at least one order less effective than GST. 3 GST responses were rapidly and reversibly inhibited by 0.1‐1 mM VO 4 treatments that had little effect on FSK‐activated I C1 . 4 Niflumic acid (100–200 μ m ) reversibly depressed GST (100 μ m )‐activated g C1 by 55%. 5 GST (50 μ m ) strongly incremented current in myocytes with cyclic AMP‐dependent CFTR I C1 already activated by maximally‐effective FSK 5 μ m . 6 Based on these results, and on evidence of a synergistic interaction between GST and FSK, we conclude that inhibition of tyrosine phosphorylation by GST causes an activation of cardiac CFTR that is not mediated by an elevation of cyclic AMP.