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Am J Physiol Heart Circ Physiol (January 28, 2005). doi:10.1152/ajpheart.00992.2004
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Submitted on September 27, 2004
Accepted on January 24, 2005

Antagonistic Regulation of Swelling-Activated Chloride Current in Rabbit Ventricle by Src and EGFR Protein Tyrosine Kinases

Zuojun Ren1 and Clive M Baumgarten2*

1 Cardiology, China Medical University, Shenyang, Liaoning, China; Physiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA
2 Physiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA; Internal Medecine and Biomedical Engineering, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA

* To whom correspondence should be addressed. E-mail: baumgart{at}hsc.vcu.edu.

Regulation of swelling-activated Cl- current (ICl,swell) is complex and multiple signaling cascades are implicated. To determine whether protein tyrosine kinase (PTK) modulates ICl,swell and identify the PTK involved, we studied the effects of a broad-spectrum PTK inhibitor (genistein), selective inhibitors of Src (PP2) and epidermal growth factor receptor (EGFR) kinase (PD153035), and a protein tyrosine phosphatase (PTP) inhibitor (orthovanadate). ICl,swell evoked by hypoosmotic swelling was increased 181 ± 17% by 100 µM genistein, and the genistein-induced current was blocked by tamoxifen (10 µM), a selective ICl,swell blocker. Block of Src with PP2 (10 µM) stimulated tamoxifen-sensitive ICl,swell by 234 ± 27%, mimicking genistein, whereas PP3 (10 µM), its inactive analogue, had no effect. Moreover, block of PTP by orthovanadate (1 mM) inhibited ICl,swell and prevented its stimulation by PP2. In contrast to block of Src, block of EGFR kinase with PD153035 (20 nM) inhibited ICl,swell. Several lines of evidence argue that PP2-stimulated current was ICl,swell: stimulation was volume dependent and the current was blocked by tamoxifen, outwardly rectified with both symmetrical and physiological Cl- gradients, and reversed near ECl. To rule out contributions of other currents, Cd2+ (0.2 mM) and Ba2+ (1 mM) were added to the bath. Surprisingly, Cd2+ suppressed the decay of ICl,swell, and Cd2+ plus Ba2+ eliminated time-dependent currents between -100 and +100 mV. Nevertheless, these divalents did not eliminate ICl,swell nor prevent its stimulation by PP2. The results indicate that tyrosine phosphorylation controls ICl,swell, and regulation of ICl,swell by the Src and EGFR kinase families of PTK is antagonistic.




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