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This Article Full Text Full Text (PDF) All Versions of this Article: 289/6/H2566    most recent 00292.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Walsh, K. B. Articles by Zhang, J. Search for Related Content PubMed PubMed Citation Articles by Walsh, K. B. Articles by Zhang, J.

Regulation of cardiac volume-sensitive chloride channel by focal adhesion kinase and Src kinase

Department of Pharmacology, Physiology, and Neuroscience, School of Medicine, University of South Carolina, Columbia, South Carolina

Submitted 24 March 2005 ; accepted in final form 18 July 2005

The volume-sensitive chloride current (I_Cl,swell) is found in the mammalian myocardium and is activated by osmotic swelling. The goal of this study was to examine the importance of the tyrosine kinases focal adhesion kinase (FAK) and Src kinase in cardiac I_Cl,swell regulation. Neonatal rat ventricular myocytes were cultured on collagen membranes and infected with adenovirus expressing -galactosidase (AdLacZ), FAK, or FAK-related nonkinase. FAK-related nonkinase (FRNK) is an endogenous cardiac protein, which functions as an inhibitor of FAK. Whole cell patch-clamp recordings demonstrated that osmotic swelling was associated with the activation of an outward rectifying current in uninfected and AdLacZ-infected cells. Consistent with the properties of I_Cl,swell, this current displayed a reversal potential close to the equilibrium potential for Cl^–; was inhibited by the Cl^– channel blockers 4,4'-dinitrostilbene-2,2'-disulfonic acid, 5-nitro-2-(3-phenylpropylamino)-benzoic acid, and tamoxifen; and was eliminated in hypertonic solution. In addition to activating I_Cl,swell, hypotonic swelling enhanced the tyrosine phosphorylation of multiple cardiac proteins including those in the range of 68–70 and 120–130 kDa. Pretreatment of the cells with the drug 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, an inhibitor of FAK and Src, diminished swelling-induced phosphorylation of these proteins but paradoxically increased I_Cl,swell. Furthermore, overexpression of FRNK but not FAK caused a twofold augmentation in I_Cl,swell and increased the rate of current activation. Thus the tyrosine kinases FAK and Src contribute to the regulation of I_Cl,swell.

cardiac myocytes

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