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Incorporation of the -subunit into the epithelial sodium channel (ENaC) generates protease-resistant ENaCs in Xenopus laevis

  • The epithelial sodium channel (ENaC) is a critical regulator of vertebrate electrolyte homeostasis. ENaC is the only constitutively open ion channel in the degenerin/ENaC protein family, and its expression, membrane abundance, and open probability therefore are tightly controlled. The canonical ENaC is composed of three subunits (, , and ), but a fourth -subunit may replace and form atypical -ENaCs. Using Xenopus laevis as a model, here we found that mRNAs of the - and -subunits are differentially expressed in different tissues and that -ENaC predominantly is present in the urogenital tract. Using whole-cell and single-channel electrophysiology of oocytes expressing Xenopus - or -ENaC, we demonstrate that the presence of the -subunit enhances the amount of current generated by ENaC due to an increased open probability, but also changes current into a transient form. Activity of canonical ENaCs is critically dependent on proteolytic processing of the - and -subunits, and immunoblotting with epitope-tagged ENaC subunits indicated that, unlike -ENaC, the -subunit does not undergo proteolytic maturation by the endogenous protease furin. Furthermore, currents generated by -ENaC were insensitive to activation by extracellular chymotrypsin, and presence of the -subunit prevented cleavage of -ENaC at the cell surface. Our findings suggest that subunit composition constitutes an additional level of ENaC regulation, and we propose that the Xenopus -ENaC subunit represents a functional example that demonstrates the importance of proteolytic maturation during ENaC evolution.

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Metadaten
Document Type:Article
Language:English
Author:Lukas Wichmann, Kirsty Sophia Vowinkel, Alexander Perniss, Ivan Manzini, Mike Althaus
Parent Title (English):The Journal of Biological Chemistry
Volume:293
Issue:18
Number of pages:12
First Page:6647
Last Page:6658
ISSN:0021-9258
DOI:https://doi.org/10.1074/jbc.RA118.002543
PMID:https://pubmed.ncbi.nlm.nih.gov/29576549
Publisher:Elsevier
Date of first publication:2018/05/25
Keyword:Xenopus laevis; chymotrypsin; delta-subunit; electrophysiology; epithelial sodium channel (ENaC); furin; patch clamp; protease
Departments, institutes and facilities:Institut für funktionale Gen-Analytik (IFGA)
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Entry in this database:2023/03/22