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1 Pharmacology, Physiology & Neuroscience, University of South Carolina, Columbia, SC, USA
* To whom correspondence should be addressed. E-mail: walsh{at}med.sc.edu.
The volume-sensitive chloride current (ICl,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 ICl,swell regulation. Neonatal rat ventricular myocytes were cultured on collagen membranes and infected with adenovirus expressing 
-galactosidase (AdLacZ), FAK (AdFAK) or FAK-related non-kinase (AdFRNK). 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 ICl,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 (DNDS), 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) and tamoxifen, and was eliminated in hypertonic solution. In addition to activating ICl,swell, hypotonic swelling enhanced the tyrosine phosphorylation of multiple cardiac proteins including those in the range of 68-70 kDa and 120-130 kDa. Pretreatment of the cells with the drug PP2, an inhibitor of FAK and Src, diminished swelling-induced phosphorylation of these proteins, but paradoxically increased ICl,swell. Furthermore, over-expression of FRNK, but not FAK, caused a 2-fold augmentation in ICl,swell and increased the rate of current activation. Thus, the tyrosine kinases FAK and Src contribute to the regulation of ICl,swell.
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