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Integrin-Mediated Regulation of Connexin 43 Expression by Alveolar Epithelial Cells*

Yihe Guo, PhD; Cara Martinez-Williams, BA; D. Eugene Rannels, PhD
Author and Funding Information

*From the Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA. This research was supported by National Institutes of Health grants AHA0150244N, HL31560, and HL10358.

Correspondence to: D. Eugene Rannels, PhD, Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA 17033; e-mail: grannels@psu.edu



Chest. 2002;121(3_suppl):30S-31S. doi:10.1378/chest.121.3_suppl.30S-a
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Extract

Alveolar epithelial cells (AECs) in primary cultures express gap junction (GJ) proteins, connexins (Cxs), and establish GJ intercellular communication. Cx expression is differentially regulated via integrin-mediated interactions of AEC with extracellular matrix (ECM) proteins including fibronectin (FN) and laminin, which exert reciprocal effects. ECM FN increases the expression of Cx43 messenger RNA and protein. Antibodies against FN, α5β1-integrin, or the α5-integrin subunit block FN effects on Cx43 abundance and cause the redistribution of immunopositive Cx43 from the plasma membrane to the cytosol. Anti-α5β1 antibodies had no effect on the AEC expression of Cx43 mRNA over a 24-h exposure but caused the transient phosphorylation (activation) of extracellular signal-regulated kinase (ERK)-1 and ERK-2. These data suggest that FN-mediated integrin ligation activates intracellular kinases that may regulate Cx expression and/or trafficking. Cells thus were treated with the mitogen-activated protein kinase-1 and 2 inhibitor, PD98059. PD98059 did not cause AEC detachment or death after 24 h at concentrations up to 50 μM. The drug reduced Cx43 expression within 24 h in a dose-dependent manner and caused immunopositive Cx43 to redistribute from the membrane to the cytosol. The dimethyl sulfoxide vehicle had no effect. PD98059 had no additional effect in the presence of anti-α5 integrin antibodies, suggesting an action through similar regulatory pathways. Although the drug rapidly reduced ERK phosphorylation, it had little effect on the expression of ERK-1 or ERK-2 proteins. These data suggest that the regulation of Cx expression, and thus of GJ intercellular communication in AECs is exerted through integrin-mediated cell-ECM interactions at the plasma membrane, which are linked to the activation of intracellular kinase-signaling cascades.

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