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Differential modulation of a polymorphism in the COOH terminus of the -subunit of the human epithelial sodium channel by protein kinase C

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

Submitted 5 July 2005 ; accepted in final form 12 September 2005

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

trafficking; oocyte; phosphorylation

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