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J. Biol. Chem., Vol. 281, Issue 36, 26520-26527, September 8, 2006

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Rapid Translocation and Insertion of the Epithelial Na⁺ Channel in Response to RhoA Signaling^*

Oleh Pochynyuk, Jorge Medina, Nikita Gamper, Harald Genth^¶, James D. Stockand¹, and Alexander Staruschenko

From the Department of Physiology, University of Texas Health Science Center, San Antonio, Texas 78229, Institute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT, United Kingdom, and ^¶Institut fur Toxikologie, Medizinische Hochschule, D-30625 Hannover, Germany

Activity of the epithelial Na⁺ channel (ENaC) is limiting for Na⁺ absorption across many epithelia. Consequently, ENaC is a central effector impacting systemic blood volume and pressure. Two members of the Ras superfamily of small GTPases, K-Ras and RhoA, activate ENaC. K-Ras activates ENaC via a signaling pathway involving phosphatidylinositol 3-kinase and production of phosphatidylinositol 3,4,5-trisphosphate with the phospholipid directly interacting with the channel to increase open probability. How RhoA increases ENaC activity is less clear. Here we report that RhoA and K-Ras activate ENaC through independent signaling pathways and final mechanisms of action. Activation of RhoA signaling rapidly increases the membrane levels of ENaC likely by promoting channel insertion. This process dramatically increases functional ENaC current, resulting in tight spatial-temporal control of these channels. RhoA signals to ENaC via a transduction pathway, including the downstream effectors Rho kinase and phosphatidylinositol-4-phosphate 5-kinase. Phosphatidylinositol 4,5-biphosphate produced by activated phosphatidylinositol 4-phosphate 5-kinase may play a role in targeting vesicles containing ENaC to the plasma membrane.

Received for publication, April 18, 2006 , and in revised form, June 12, 2006.

^* This work was supported by NIDDK Grant RO1-DK-59594 from the National Institutes of Health, American Heart Association-Texas Affiliate Grant 0355012Y (to J. D. S.), and a research fellowship from the National Kidney Foundation (to A. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Physiology, 7756, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. Tel.: 210-567-4332; E-mail: stockand{at}uthscsa.edu.

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