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Vol. 14, Issue 9, 3888-3897, September 2003

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The GTP-binding Protein RhoA Mediates Na,K-ATPase Exocytosis in Alveolar Epithelial Cells

Emilia Lecuona ^* , Karen Ridge ^*, Liuska Pesce ^*, Daniel Batlle , and Jacob I. Sznajder ^*

^* Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University, Chicago, Illinois 60611; Division of Nephrology, Department of Medicine, Northwestern University, Chicago, Illinois 60611

Submitted December 2, 2002; Revised May 1, 2003; Accepted May 2, 2003
Monitoring Editor: Guido Guidotti

The purpose of this study was to define the role of the Rho family of small GTPases in the -adrenergic regulation of the Na,K-ATPase in alveolar epithelial cells (AEC). The -adrenergic receptor agonist isoproterenol (ISO) increased the Na,K-ATPase protein abundance at the plasma membrane and activated RhoA in a time-dependent manner. AEC pretreated with mevastatin, a specific inhibitor of prenylation, or transfected with the dominant negative RhoAN19, prevented ISO-mediated Na,K-ATPase exocytosis to the plasma membrane. The ISO-mediated activation of RhoA in AEC occurred via ₂-adrenergic receptors and involved G_s-PKA as demonstrated by incubation with the protein kinase A (PKA)-specific inhibitors H89 and PKI (peptide specific inhibitor), and G_i, as incubation with pertussis toxin or cells transfected with a minigene vector for G_i inhibited the ISO-mediated RhoA activation. However, cells transfected with minigene vectors for G₁₂ and G₁₃ did not prevent RhoA activation by ISO. Finally, the ISO-mediated Na,K-ATPase exocytosis was regulated by the Rho-associated kinase (ROCK), as preincubation with the specific inhibitor Y-27632 or transfection with dominant negative ROCK, prevented the increase in Na,K-ATPase at the plasma membrane. Accordingly, ISO regulates Na,K-ATPase exocytosis in AEC via the activation of ₂-adrenergic receptor, G_s, PKA, G_i, RhoA, and ROCK.

Corresponding author. E-mail address: e-lecuona{at}northwestern.edu.

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