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Originally published In Press as doi:10.1074/jbc.M108714200 on September 24, 2001

J. Biol. Chem., Vol. 276, Issue 47, 43887-43893, November 23, 2001
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Regulation of Epithelial Sodium Channel Activity through a Region of the Carboxyl Terminus of the alpha -Subunit
EVIDENCE FOR INTRACELLULAR KINASE-MEDIATED REACTIONS*

Kenneth A. VolkDagger §, Peter M. SnyderDagger , and John B. StokesDagger §||

From the Dagger  Department of Internal Medicine and  Department of Physiology and Biophysics, University of Iowa College of Medicine and the § Veterans Affairs Medical Center, Iowa City, Iowa 52246

The epithelial sodium channel (ENaC) is a heteromultimer composed of three subunits, each having two membrane-spanning domains with intracellular amino and carboxyl termini. Several hormones and proteins regulate channel activity, but the molecular nature of this regulation is unknown. We conducted experiments to determine a possible new site within the carboxyl terminus of the alpha -subunit involved in enhanced channel activity through endogenous kinases. When an alpha -subunit that was truncated to remove a PY motif was expressed in Xenopus oocytes with wild type human beta - and gamma -ENaC subunits, channel activity was greatly enhanced. The removal of the entire intracellular carboxyl terminus of the alpha -subunit eliminated this enhanced basal activity. Using several point mutations, we localized this site to two amino acid residues (Pro595-Gly596) near the second membrane-spanning domain. The nonspecific kinase inhibitor staurosporine inhibits basal channel activity of wild type ENaC but was ineffective in inhibiting channels mutated at this site. The major effect of these mutations was not on channel kinetics but was largely, if not entirely, on the number of active channels on the cell surface. This region is potentially important in effecting kinase-mediated increases in ENaC activity.

* This work was supported in part by National Institutes of Health (NIH) O'Brien Kidney Research Center Grant DK52617, NIH Specialized Center of Research Grant HL55006, and a grant from the Department of Veterans Affairs. The University of Iowa Diabetes and Endocrinology Research Center was supported by NIH Grant DK25295.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence should be addressed: E300 GH, Dept. of Internal Medicine, University of Iowa, Iowa City, IA 52246. Tel.: 319-356-4409; Fax: 319-356-2999; E-mail: john-stokes@uiowa.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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