A Novel Pathway of Epithelial Sodium Channel Activation Involves a Serum- and Glucocorticoid-inducible Kinase Consensus Motif in the C Terminus of the Channel's α-Subunit
| Autor: | Alexei Diakov, Christoph Korbmacher |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
inorganic chemicals
Epithelial sodium channel DNA Complementary Patch-Clamp Techniques Time Factors Xenopus Amino Acid Motifs Phosphatase Protein Serine-Threonine Kinases Biology Models Biological Biochemistry Sodium Channels Immediate-Early Proteins RNA Complementary Amiloride Serine Xenopus laevis Cytosol Animals Protein Isoforms Magnesium Phosphorylation Epithelial Sodium Channels Molecular Biology Alanine urogenital system Kinase Nuclear Proteins Cell Biology respiratory system biology.organism_classification Molecular biology Recombinant Proteins Protein Structure Tertiary Rats Enzyme Activation Mutagenesis Site-Directed Oocytes SGK1 Gene Deletion hormones hormone substitutes and hormone antagonists |
| Zdroj: | Journal of Biological Chemistry. 279:38134-38142 |
| ISSN: | 0021-9258 |
| Popis: | Aldosterone-induced serum- and glucocorticoid-inducible kinase isoform 1 (SGK1) contributes to the regulation of the epithelial sodium channel (ENaC), the activity of which is critical for long term blood pressure control. Aldosterone-induced SGK1 is thought to enhance ENaC surface expression by phosphorylating Nedd4-2 and thereby preventing ENaC retrieval and degradation. In outside-out membrane patches of Xenopus laevis oocytes heterologously expressing ENaC, amiloride-sensitive ENaC currents were enhanced by phosphatase inhibitors and were dependent on cytosolic Mg(2+). This indicates that a kinase is involved in channel regulation. Indeed, recombinant constitutively active SGK1, included in the pipette solution, caused a sustained 2- to 3-fold increase of ENaC currents. Deletion of the C terminus of alphaENaC largely reduced the stimulatory effect of SGK1, whereas stimulation by SGK1 did not require the presence of the C termini of the beta- or gamma-subunits. Replacing the serine residue Ser(621) of the SGK1 consensus motif in the C terminus of the alpha-subunit by an alanine specifically abolished the stimulatory effect of SGK. Our findings indicate that SGK1 can stimulate ENaC activity independently of an inhibition of Nedd4-2-mediated channel retrieval. This defines a novel regulatory pathway likely to be relevant for aldosterone-induced stimulation of ENaC in vivo. |
| Databáze: | OpenAIRE |
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