Involvement of Tyrosine Kinase in the Hyposmotic Stimulation of I Ks in Guinea-pig Ventricular Myocytes
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The objective of this study was to investigate the involvement of tyrosine phosphorylation in the hyposmotic stimulation of cardiac I Ks, a slowly activating delayed-rectifier K+ current that promotes repolarization of the action potential. The current was recorded from whole-cell-configured guinea-pig ventricular myocytes before, during, and after their exposure to solution whose osmolarity was 0.75 times normal. Exposure to hyposmotic solution caused a near-doubling of the amplitude of I Ks, with little change in the voltage dependence of current activation. Stable, hyposmotically stimulated I Ks (I Ks,Hypo) was decreased by broadspectrum tyrosine kinase (TK) inhibitors tyrphostin A23 (IC50 approximately 5 microM) and tyrphostin A25 (IC50 15.8 +/- 1.6 microM) but not by TK-inactive tyrphostin analogs, suggesting that tyrosine phosphorylation is important for maintenance of the current. In agreement with that view, we found that the TK-inhibitor action on I Ks,Hypo was strongly antagonized by vanadate compounds known to inhibit phosphotyrosyl phosphatase. When myocytes were pretreated with TK inhibitors, the stimulation of I Ks was attenuated in a concentration-dependent manner. The attenuation was not due to concomitant attenuation of a stimulation of tyrosine phosphorylation because neither the stimulation of I Ks nor its rate of decay following removal of hyposmotic solution was affected by pretreatment with vanadates. We suggest that the stimulation of I Ks by hyposmotic solution is dependent on a basal tyrosine phosphorylation that modulates a swelling-induced I Ks-stimulatory signal and/or the receptivity of Ks channels to that signal.
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Moench I, Meekhof K, Cheng L, Lopatin A Exp Physiol. 2013; 98(7):1164-77.
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Piron J, Choveau F, Amarouch M, Rodriguez N, Charpentier F, Merot J J Physiol. 2010; 588(Pt 18):3471-83.
PMID: 20660559 PMC: 2988512. DOI: 10.1113/jphysiol.2010.195313.
Zankov D, Toyoda F, Omatsu-Kanbe M, Matsuura H, Horie M Pflugers Arch. 2009; 458(5):837-49.
PMID: 19404674 DOI: 10.1007/s00424-009-0669-8.