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Am J Physiol Renal Physiol (September 20, 2005). doi:10.1152/ajprenal.00277.2005
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Submitted on July 5, 2005
Accepted on September 12, 2005

Differential Modulation of a Polymorphism in the Carboxyl Terminus of the Alpha Subunit of the Human Epithelial Sodium Channel by Protein Kinase C {delta}

Wusheng Yan1, Laurence Suaud1, Thomas R. Kleyman2*, and Ronald C. Rubenstein3

1 Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
2 Departments of Medicine and of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA, USA
3 Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

* To whom correspondence should be addressed. E-mail: kleyman{at}pitt.edu.

The A663T polymorphism of the {alpha}-subunit of the human epithelial sodium channel (hENaC) increases the functional and surface expression of {alpha}{beta}{gamma}-hENaC in Xenopus oocytes. The context of this residue in the C-terminus of {alpha}-hENaC is important for this effect, as a homologus change in murine ENaC (mENaC), A692T, does not alter functional and surface expression of mENaC. Query of a phosphoprotein database suggested that the {alpha}-T663 residue might be phosphorylated by protein kinase C {delta} (PKC{delta}). General inhibition of PKC with calphostin C decreased the functional and surface expression of {alpha}-T663-hENaC and not {alpha}-A663-hENaC, and was without effect on {alpha}-A692-mENaC, {alpha}-T692-mENaC and a chimeric m(1-678)/h(650-669){alpha}-T663, m{beta}{gamma} ENaC. These data suggest that residues outside of the {alpha}-hENaC C-terminus are important for modulation of {alpha}-T663-hENaC trafficking by PKC. In contrast, expression of PKC{delta} decreased the functional and surface expression of {alpha}-T663-hENaC and the functional expression of m(1-678)/h(650-669){alpha}-T663, m{beta}{gamma} ENaC, and was without effect on {alpha}-A663-hENaC, {alpha}-A692-mENaC or {alpha}-T692-mENaC. PKC{delta} did not phosphorylate the C-terminus of either {alpha}-T663-hENaC or {alpha}-A663-hENaC in vitro, suggesting that it acts indirectly to regulate hENaC trafficking. {alpha}-T663-hENaC was retrieved from the oocyte membrane slower than {alpha}-A663-hENaC, and calphostin C increased the rate of {alpha}-T663-hENaC removal from the oocyte membrane to a rate similar to that of {alpha}-A663- hENaC. In contrast, PKC{delta} did not alter the rate of removal of {alpha}-T663-hENaC from the oocyte membrane, suggesting that PKC{delta} altered rates of {alpha}-T663-hENaC biosynthesis and/or delivery to the plasma membrane. These data are consistent with PKC isoform-specific effects on the intracellular trafficking of {alpha}-T663 vs. {alpha}-A663-hENaC.




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