ArticleThe Journal of biological chemistry2014
Proteolytic activation of the human epithelial sodium channel by trypsin IV and trypsin I involves distinct cleavage sites.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 35 citations in OpenAlex.
- Molecular mechanism of Golden Pomfret myofibrillar protein digestion inhibition by malondialdehyde-mediated oxidation based on peptidomics analysis.Food chemistry: X · 2025Article
- Functional properties of the γ-ENaC-A635V mutation in a patient with severe hyponatremia.Hormones (Athens, Greece) · 2025Article
- Case Report: Functional investigation of the γENaC G532S mutation presenting as mild PHA-1B3.Frontiers in medicine · 2025Article
- 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
- Increased ENaC-mediated liquid absorption across vitamin-D deficient human airway epithelia.American journal of physiology. Cell physiology · 2024Article
- The Epithelial Sodium Channel-An Underestimated Drug Target.International journal of molecular sciences · 2023Review
- Transmembrane serine protease 2 (TMPRSS2) proteolytically activates the epithelial sodium channel (ENaC) by cleaving the channel's γ-subunit.The Journal of biological chemistry · 2022Article
- ENaC activation by proteases.Acta physiologica (Oxford, England) · 2022Review
- Epithelial Sodium Channel Alpha Subunit (αENaC) Is Associated with Inverse Salt Sensitivity of Blood Pressure.Biomedicines · 2022Article
- Proteolytic activation of the epithelial sodium channel (ENaC) by factor VII activating protease (FSAP) and its relevance for sodium retention in nephrotic mice.Pflugers Archiv : European journal of physiology · 2022Article
- Proteolytic ENaC activation in health and disease-a complicated puzzle.Pflugers Archiv : European journal of physiology · 2022Article
- Zymogen-locked mutant prostasin (Prss8) leads to incomplete proteolytic activation of the epithelial sodium channel (ENaC) and severely compromises triamterene tolerance in mice.Acta physiologica (Oxford, England) · 2021Article
- Novel Mutations in the TMPRSS3 Gene may Contribute to Taiwanese Patients with Nonsyndromic Hearing Loss.International journal of molecular sciences · 2020Article
- The degenerin region of the human bile acid-sensitive ion channel (BASIC) is involved in channel inhibition by calcium and activation by bile acids.Pflugers Archiv : European journal of physiology · 2018Article
- Bile acids potentiate proton-activated currents inPhysiological reports · 2017Article
- Activation of the Human Epithelial Sodium Channel (ENaC) by Bile Acids Involves the Degenerin Site.The Journal of biological chemistry · 2016Article
- The function and regulation of acid-sensing ion channels (ASICs) and the epithelial Na(+) channel (ENaC): IUPHAR Review 19.British journal of pharmacology · 2016Review
- Urinary serine proteases and activation of ENaC in kidney--implications for physiological renal salt handling and hypertensive disorders with albuminuria.Pflugers Archiv : European journal of physiology · 2015Review
- Epithelial Sodium Channel-Mediated Sodium Transport Is Not Dependent on the Membrane-Bound Serine Protease CAP2/Tmprss4.PloS one · 2015Article
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Authors and funding
12 authors at 5 institutions in 5 countries.
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Abstract
Proteolytic activation is a unique feature of the epithelial sodium channel (ENaC). However, the underlying molecular mechanisms and the physiologically relevant proteases remain to be identified. The serine protease trypsin I can activate ENaC in vitro but is unlikely to be the physiologically relevant activating protease in ENaC-expressing tissues in vivo. Herein, we investigated whether human trypsin IV, a form of trypsin that is co-expressed in several extrapancreatic epithelial cells with ENaC, can activate human ENaC. In Xenopus laevis oocytes, we monitored proteolytic activation of ENaC currents and the appearance of γENaC cleavage products at the cell surface. We demonstrated that trypsin IV and trypsin I can stimulate ENaC heterologously expressed in oocytes. ENaC cleavage and activation by trypsin IV but not by trypsin I required a critical cleavage site (Lys-189) in the extracellular domain of the γ-subunit. In contrast, channel activation by trypsin I was prevented by mutating three putative cleavage sites (Lys-168, Lys-170, and Arg-172) in addition to mutating previously described prostasin (RKRK(178)), plasmin (Lys-189), and neutrophil elastase (Val-182 and Val-193) sites. Moreover, we found that trypsin IV is expressed in human renal epithelial cells and can increase ENaC-mediated sodium transport in cultured human airway epithelial cells. Thus, trypsin IV may regulate ENaC function in epithelial tissues. Our results show, for the first time, that trypsin IV can stimulate ENaC and that trypsin IV and trypsin I activate ENaC by cleavage at distinct sites. The presence of distinct cleavage sites may be important for ENaC regulation by tissue-specific proteases.
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