Diakov A, Sure F, Ilyaskin A, Korbmacher C (2025)
Publication Type: Journal article
Publication year: 2025
DOI: 10.1007/s00424-025-03099-z
Serum and glucocorticoid inducible kinase 1 (SGK1) is a key regulator of the epithelial sodium channel (ENaC). In rat ENaC, the serine residue 621 (S621) in the channel’s α-subunit is essential for acute channel activation by SGK1 in outside-out patches. Phosphorylation at S621 probably turns previously silent channels into channels with a high open probability. This is reminiscent of proteolytic ENaC activation resulting from cleavage of the channel’s γ-subunit at specific proximal and distal cleavage sites and the release of an inhibitory peptide tract. The first aim of this study was to demonstrate that human ENaC could also be activated acutely by SGK1 and that this depended on the homologous phosphorylation site S594 in human αENaC. Secondly, we wanted to explore whether human ENaC activation by SGK1 depended on the cleavage state of γENaC. Outside-out patch-clamp recordings in Xenopus laevis oocytes expressing human αβγENaC revealed the critical importance of S594 for acute channel activation by SGK1. The latter was not additive to proteolytic channel activation. Interestingly, preventing proximal cleavage in human γENaC completely abolished the stimulatory effect of SGK1. Moreover, tethering the inhibitory peptide in γENaC to its binding site via an engineered disulfide bond prevented stimulation by SGK1. We conclude that ENaC activation by SGK1 requires prior cleavage of γENaC at its proximal cleavage site. Together, these results reveal that SGK1-mediated stimulation of human ENaC is intricately linked to the proteolytic processing of the channel’s γ-subunit, emphasizing a previously underappreciated interplay between kinase and protease regulatory pathways.
APA:
Diakov, A., Sure, F., Ilyaskin, A., & Korbmacher, C. (2025). Acute activation of human epithelial sodium channel (ENaC) by serum and glucocorticoid inducible kinase 1 (SGK1) requires prior cleavage of the channel’s γ-subunit at its proximal cleavage site. Pflügers Archiv: European Journal of Physiology. https://doi.org/10.1007/s00424-025-03099-z
MLA:
Diakov, Alexei, et al. "Acute activation of human epithelial sodium channel (ENaC) by serum and glucocorticoid inducible kinase 1 (SGK1) requires prior cleavage of the channel’s γ-subunit at its proximal cleavage site." Pflügers Archiv: European Journal of Physiology (2025).
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