ArticleThe Journal of biological chemistry2022
Transmembrane serine protease 2 (TMPRSS2) proteolytically activates the epithelial sodium channel (ENaC) by cleaving the channel's γ-subunit.
Article in The Journal of biological chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 24 citations in OpenAlex.
- Amiloride mitigates respiratory distress caused by WFDC2 deficiency via inhibiting the epithelial sodium channel.Nature communications · 2026Article
- Hyperaldosteronism in Mice Lacking the Distal Polybasic Tract of the γ-Subunit of the Epithelial Sodium Channel During Sodium Restriction.Acta physiologica (Oxford, England) · 2026Article
- Pilot survey among patients taking bromhexine prophylactically against influenza.Journal of family medicine and primary care · 2026Article
- COVID-19 Prophylactic Effect of Bromhexine Hydrochloride.Immunity, inflammation and disease · 2026Article
- Epithelial sodium channel in dendritic cells participates in high-fat-induced inflammatory responses.Molecular biology reports · 2025Article
- 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.Pflugers Archiv : European journal of physiology · 2025Article
- Effects and regulation of ACE2 and TMPRSS2 abundance in healthy humans and in patients with SARS-CoV-2.Biochemical Society transactions · 2025Article
- Ion channel function of polycystin-2/polycystin-1 heteromer revealed by structure-guided mutagenesis.FEBS letters · 2025Article
- Impact of aldosterone deficiency on the development of diuretic resistance in mice.Pflugers Archiv : European journal of physiology · 2025Article
- Automated patch-clamp recordings for detecting activators and inhibitors of the epithelial sodium channel (ENaC).Pflugers Archiv : European journal of physiology · 2025Article
- Transmembrane Serine Protease 2 and Proteolytic Activation of the Epithelial Sodium Channel in Mouse Kidney.Journal of the American Society of Nephrology : JASN · 2025Article
- TMPRSS2 as a Key Player in Viral Pathogenesis: Influenza and Coronaviruses.Biomolecules · 2025Review
- ACE2 and TMPRSS2 in human kidney tissue and urine extracellular vesicles with age, sex, and COVID-19.Pflugers Archiv : European journal of physiology · 2025Article
- Disease-associated missense mutations in the pore loop of polycystin-2 alter its ion channel function in a heterologous expression system.The Journal of biological chemistry · 2024Article
- The small molecule activator S3969 stimulates the epithelial sodium channel by interacting with a specific binding pocket in the channel's β-subunit.The Journal of biological chemistry · 2024Article
- Epithelial NaComprehensive Physiology · 2024Review
- Tmprss2 maintains epithelial barrier integrity and transepithelial sodium transport.Life science alliance · 2024Article
- Select amino acids recover cytokine-altered ENaC function in human bronchial epithelial cells.PloS one · 2024Article
- Proteolytic Activation of the Epithelial Sodium Channel (ENaC): Its Mechanisms and Implications.International journal of molecular sciences · 2023Review
- The Epithelial Sodium Channel-An Underestimated Drug Target.International journal of molecular sciences · 2023Review
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The epithelial sodium channel (ENaC) is a heterotrimer consisting of α-, β-, and γ-subunits. Channel activation requires proteolytic release of inhibitory tracts from the extracellular domains of α-ENaC and γ-ENaC; however, the proteases involved in the removal of the γ-inhibitory tract remain unclear. In several epithelial tissues, ENaC is coexpressed with the transmembrane serine protease 2 (TMPRSS2). Here, we explored the effect of human TMPRSS2 on human αβγ-ENaC heterologously expressed in Xenopus laevis oocytes. We found that coexpression of TMPRSS2 stimulated ENaC-mediated whole-cell currents by approximately threefold, likely because of an increase in average channel open probability. Furthermore, TMPRSS2-dependent ENaC stimulation was not observed using a catalytically inactive TMPRSS2 mutant and was associated with fully cleaved γ-ENaC in the intracellular and cell surface protein fractions. This stimulatory effect of TMPRSS2 on ENaC was partially preserved when inhibiting its proteolytic activity at the cell surface using aprotinin but was abolished when the γ-inhibitory tract remained attached to its binding site following introduction of two cysteine residues (S155C-Q426C) to form a disulfide bridge. In addition, computer simulations and site-directed mutagenesis experiments indicated that TMPRSS2 can cleave γ-ENaC at sites both proximal and distal to the γ-inhibitory tract. This suggests a dual role of TMPRSS2 in the proteolytic release of the γ-inhibitory tract. Finally, we demonstrated that TMPRSS2 knockdown in cultured human airway epithelial cells (H441) reduced baseline proteolytic activation of endogenously expressed ENaC. Thus, we conclude that TMPRSS2 is likely to contribute to proteolytic ENaC activation in epithelial tissues in vivo.
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