Ilyaskin A, Kißler A, Schreiber F, Korbmacher C, Sure F (2026)
Publication Type: Journal article
Publication year: 2026
Book Volume: 302
Article Number: 113336
Journal Issue: 9
DOI: 10.1016/j.jbc.2026.113336
The epithelial sodium channel (ENaC) is a heterotrimer typically composed of three homologous subunits (α, β, and γ). Humans and several other species express an additional δ-subunit that can replace α-ENaC in heterologous expression systems, thereby modifying channel properties. A unique feature of ENaC is its proteolytic activation. Proteases remove autoinhibitory tracts from the Gating Relief of Inhibition by Proteolysis (GRIP) domains of α- and γ-ENaC. Recent ENaC structural data revealed that these tracts occupy specific binding pockets within their respective subunits. Using molecular dynamics simulations, site-directed mutagenesis, and electrophysiological recordings, we identified a cluster of four functionally important aromatic residues within the binding pocket of the γ-autoinhibitory tract in human αβγ-ENaC. These residues were also essential for ENaC inhibition by the synthetic γ-11 peptide, corresponding to the key portion of the γ-inhibitory tract. The aromatic cluster was conserved in α-ENaC, where it mediated the inhibitory effect of the synthetic α-8 peptide. Interestingly, structurally similar GRIP domains were also identified in δ- and β-ENaC. Our data indicate that the GRIP domains of both β- and δ-ENaC lack corresponding autoregulatory tracts. Moreover, we show that proteolytic activation of human δβγ-ENaC results from cleavage of γ-ENaC, but not δ-ENaC, consistent with the absence of autoregulatory activity of the δ-GRIP domain. In summary, this study demonstrates that the GRIP domains play distinct functional roles across different ENaC subunits. Characterization of the inhibitory sites in γ- and α-ENaC may facilitate the development of novel peptidomimetic ENaC inhibitors with potential (patho)physiological implications.
APA:
Ilyaskin, A., Kißler, A., Schreiber, F., Korbmacher, C., & Sure, F. (2026). Distinct functional roles of the GRIP domains in α-, β-, γ-, and δ-ENaC. Journal of Biological Chemistry, 302(9). https://doi.org/10.1016/j.jbc.2026.113336
MLA:
Ilyaskin, Alexandr, et al. "Distinct functional roles of the GRIP domains in α-, β-, γ-, and δ-ENaC." Journal of Biological Chemistry 302.9 (2026).
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