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¹ Department of Physiology and ² Department of Internal Medicine (Cardiology), and the Pauley Heart Center, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298

Correspondence to Clive M. Baumgarten: clive.baumgarten{at}vcu.edu

Stretch of ß1 integrins activates an outwardly rectifying, tamoxifen-sensitive Cl^– current (Cl^– SAC) via AT1 receptors, NADPH oxidase, and reactive oxygen species, and Cl^– SAC resembles the volume-sensitive Cl^– current (I_Cl,swell). Epidermal growth factor receptor (EGFR) kinase undergoes transactivation upon stretch, integrin engagement, and AT1 receptor activation and, in turn, stimulates NADPH oxidase. Therefore, we tested whether Cl^– SAC is regulated by EGFR kinase signaling and is volume sensitive. Paramagnetic beads coated with mAb for ß1 integrin were attached to myocytes and pulled with an electromagnet. Stretch activated a Cl^– SAC that was 1.13 ± 0.10 pA/pF at +40 mV. AG1478 (10 µM), an EGFR kinase blocker, inhibited 93 ± 13% of Cl^– SAC, and intracellular pretreatment with 1 µM AG1478 markedly suppressed Cl^– SAC activation. EGF (3.3 nM) directly activated an outwardly rectifying Cl^– current (0.81 ± 0.05 pA/pF at +40 mV) that was fully blocked by 10 µM tamoxifen, an I_Cl,swell blocker. Phosphatidylinositol 3-kinase (PI-3K) is downstream of EGFR kinase. Wortmannin (500 nM) and LY294002 (100 µM), blockers of PI-3K, inhibited Cl^– SAC by 67 ± 6% and 91 ± 25% respectively, and the EGF-induced Cl^– current also was fully blocked by LY294002. Furthermore, gp91ds-tat (500 nM), a cell-permeable, chimeric peptide that specifically blocks NADPH oxidase assembly, profoundly inhibited the EGF-induced Cl^– current. Inactive permeant and active impermeant control peptides had no effect. Myocyte shrinkage with hyperosmotic bathing media inhibited the Cl^– SAC and EGF-induced Cl^– current by 88 ± 9% and 127 ± 11%, respectively. These results suggest that ß1 integrin stretch activates Cl^– SAC via EGFR, PI-3K, and NADPH oxidase, and that both the Cl^– SAC and the EGF-induced Cl^– currents are likely to be the volume-sensitive Cl^– current, I_Cl,swell.

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