Intracellular trafficking of a polymorphism in the COOH terminus of the α-subunit of the human epithelial sodium channel is modulated by casein kinase 1

Wusheng Yan, Lynn Spruce, Michael M. Rosenblatt, Thomas R. Kleyman, Ronald C. Rubenstein

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

The A663T polymorphism of the α-subunit of the human epithelial sodium channel (hENaC) increases the functional and surface expression of αβγ-hENaC in Xenopus laevis oocytes, and the context of this residue in the COOH terminus of α-hENaC is important for this effect. Query of a phosphoprotein database suggested that the α-T663 residue of hENaC might be a substrate for phosphorylation by casein kinase 1 (CK1). We tested the hypotheses that phosphorylation of α-T663-hENaC by CK1 would regulate the increased functional and surface expression of α-T663-hENaC vs. α-A663-hENaC in oocytes. General inhibition of CK1 with IC261 decreased the functional and surface expression of α-T663-hENaC, but not α-A663-hENaC. This decrease in α-T663-hENaC functional expression resulted from reduced delivery of α-T663-hENaC to the oocyte membrane. IC261 also inhibited the functional expression of α-T692-mENaC and a chimeric m(1-678)/h(650-669)α-T663, mβγ ENaC, but not α-A692-mENaC or m(1-678)/h(650-669)α-A663, mβγ ENaC. These data suggest that additional residues outside of the α-hENaC COOH terminus are important for modulation of α-T663-hENaC trafficking by CK1. Overexpression of CK1α did not alter functional expression of α-T663-hENaC. In contrast, modest overexpression of CK1δ enhanced, whereas higher levels of CK1δ overexpression inhibited α-T663-hENaC functional expression. CK1 did not phosphorylate the COOH terminus of either α-T663-hENaC or α-A663-hENaC in vitro. These data suggest that CK1, and perhaps specifically CK1δ, regulates the intracellular trafficking of the α-A663T functional polymorphism of hENaC indirectly by altering the rate of α-T663-hENaC biosynthesis and/or delivery to the plasma membrane.

Original languageEnglish
Pages (from-to)F868-F876
JournalAmerican Journal of Physiology - Renal Physiology
Volume293
Issue number3
DOIs
StatePublished - Sep 2007

Keywords

  • Phosphorylation
  • Xenopus laevis oocytes

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