Evolution of epithelial sodium channels: current concepts and hypotheses

2020 ◽  
Vol 319 (4) ◽  
pp. R387-R400
Author(s):  
Lukas Wichmann ◽  
Mike Althaus
Keyword(s):  
Sodium Channels ◽  
Fine Tuning ◽  
Sodium Absorption ◽  
Sequence Motifs ◽  
Epithelial Sodium Channels ◽  
Low Salinity ◽  
Terrestrial Habitats ◽  
Molecular Machinery ◽  
Lung Liquid ◽  
Defining Sequence

The conquest of freshwater and terrestrial habitats was a key event during vertebrate evolution. Occupation of low-salinity and dry environments required significant osmoregulatory adaptations enabling stable ion and water homeostasis. Sodium is one of the most important ions within the extracellular liquid of vertebrates, and molecular machinery for urinary reabsorption of this electrolyte is critical for the maintenance of body osmoregulation. Key ion channels involved in the fine-tuning of sodium homeostasis in tetrapod vertebrates are epithelial sodium channels (ENaCs), which allow the selective influx of sodium ions across the apical membrane of epithelial cells lining the distal nephron or the colon. Furthermore, ENaC-mediated sodium absorption across tetrapod lung epithelia is crucial for the control of liquid volumes lining the pulmonary surfaces. ENaCs are vertebrate-specific members of the degenerin/ENaC family of cation channels; however, there is limited knowledge on the evolution of ENaC within this ion channel family. This review outlines current concepts and hypotheses on ENaC phylogeny and discusses the emergence of regulation-defining sequence motifs in the context of osmoregulatory adaptations during tetrapod terrestrialization. In light of the distinct regulation and expression of ENaC isoforms in tetrapod vertebrates, we discuss the potential significance of ENaC orthologs in osmoregulation of fishes as well as the putative fates of atypical channel isoforms in mammals. We hypothesize that ancestral proton-sensitive ENaC orthologs might have aided the osmoregulatory adaptation to freshwater environments whereas channel regulation by proteases evolved as a molecular adaptation to lung liquid homeostasis in terrestrial tetrapods.

Butyrate Induces Intestinal Sodium Absorption via Sp3-Mediated Transcriptional Up-Regulation of Epithelial Sodium Channels

2007 ◽  
Vol 132 (1) ◽  
pp. 236-248 ◽  
Author(s):  
Sebastian Zeissig ◽  
Anja Fromm ◽  
Joachim Mankertz ◽  
Jörg Weiske ◽  
Martin Zeitz ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Sodium Absorption ◽  
Epithelial Sodium Channels

Medullary epithelial sodium channels (ENAC) participate in cerebral blood flow (CBF) autoregulation

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S190-S190
Author(s):  
Eugene Golanov ◽  
Heather Drummond ◽  
Jasleen Shant ◽  
Benjamin Clower ◽  
Betty Chen
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Sodium Channels ◽  
Epithelial Sodium Channels

scholarly journals DNABERT: pre-trained Bidirectional Encoder Representations from Transformers model for DNA-language in genome

2021 ◽  
Author(s):  
Yanrong Ji ◽  
Zhihan Zhou ◽  
Han Liu ◽  
Ramana V Davuluri
Keyword(s):  
Dna Sequences ◽  
Regulatory Elements ◽  
Ease Of Use ◽  
Fine Tuning ◽  
Supplementary Information ◽  
Sequence Motifs ◽  
Semantic Relationship ◽  
Accurate Identification ◽  
Conserved Sequence ◽  
Genome Wide

Abstract Motivation Deciphering the language of non-coding DNA is one of the fundamental problems in genome research. Gene regulatory code is highly complex due to the existence of polysemy and distant semantic relationship, which previous informatics methods often fail to capture especially in data-scarce scenarios. Results To address this challenge, we developed a novel pre-trained bidirectional encoder representation, named DNABERT, to capture global and transferrable understanding of genomic DNA sequences based on up and downstream nucleotide contexts. We compared DNABERT to the most widely used programs for genome-wide regulatory elements prediction and demonstrate its ease of use, accuracy and efficiency. We show that the single pre-trained transformers model can simultaneously achieve state-of-the-art performance on prediction of promoters, splice sites and transcription factor binding sites, after easy fine-tuning using small task-specific labeled data. Further, DNABERT enables direct visualization of nucleotide-level importance and semantic relationship within input sequences for better interpretability and accurate identification of conserved sequence motifs and functional genetic variant candidates. Finally, we demonstrate that pre-trained DNABERT with human genome can even be readily applied to other organisms with exceptional performance. We anticipate that the pre-trained DNABERT model can be fined tuned to many other sequence analyses tasks. Availability and implementation The source code, pretrained and finetuned model for DNABERT are available at GitHub (https://github.com/jerryji1993/DNABERT). Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals The Plant-Derived Glucocorticoid Receptor Agonist Endiandrin A Acts as Co-Stimulator of Colonic Epithelial Sodium Channels (ENaC) via SGK-1 and MAPKs

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e49426 ◽  
Author(s):  
Dana Kuntzsch ◽  
Theresa Bergann ◽  
Petra Dames ◽  
Anja Fromm ◽  
Michael Fromm ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Sodium Channels ◽  
Receptor Agonist ◽  
Epithelial Sodium Channels

scholarly journals Proteolytic Regulation of Epithelial Sodium Channels by Urokinase Plasminogen Activator

2015 ◽  
Vol 290 (9) ◽  
pp. 5241-5255 ◽  
Author(s):  
Hong-Long Ji ◽  
Runzhen Zhao ◽  
Andrey A. Komissarov ◽  
Yongchang Chang ◽  
Yongfeng Liu ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Sodium Channels ◽  
Urokinase Plasminogen Activator ◽  
Epithelial Sodium Channels

scholarly journals Ethanol Alters Alveolar Fluid Balance via Nadph Oxidase (NOX) Signaling to Epithelial Sodium Channels (ENaC) in the Lung

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e54750 ◽  
Author(s):  
Charles A. Downs ◽  
David Q. Trac ◽  
Lisa H. Kreiner ◽  
Amity F. Eaton ◽  
Nicholle M. Johnson ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Sodium Channels ◽  
Fluid Balance ◽  
Epithelial Sodium Channels

scholarly journals Epithelial Sodium Channels in Pulmonary Epithelial Progenitor and Stem Cells

2016 ◽  
Vol 12 (9) ◽  
pp. 1150-1154 ◽  
Author(s):  
Yang Liu ◽  
Bi-Jie Jiang ◽  
Run-Zhen Zhao ◽  
Hong-Long Ji
Keyword(s):  
Stem Cells ◽  
Sodium Channels ◽  
Epithelial Sodium Channels

scholarly journals Plasmin improves oedematous blood-gas barrier by cleaving epithelial sodium channels

2020 ◽  
Author(s):  
Runzhen Zhao ◽  
Gibran Ali ◽  
Hong-Guang Nie ◽  
Yongchang Chang ◽  
Deepa Bhattarai ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Sodium Channels ◽  
List Type ◽  
Cleavage Sites ◽  
Blood Gas ◽  
Alveolar Fluid Clearance ◽  
Epithelial Sodium Channels ◽  
Lung Oedema ◽  
Human Lungs ◽  
Oedema Fluid

ABSTRACTBackground and PurposeLung oedema in association with suppressed fibrinolysis is a hallmark of lung injury. We aimed to test whether plasmin cleaves epithelial sodium channels (ENaC) to resolve lung oedema fluid.Experimental ApproachesHuman lungs and airway acid-instilled mice were used for analysing fluid resolution. In silico prediction, mutagenesis, Xenopus oocytes, immunoblotting, voltage clamp, mass spectrometry, protein docking, and alveolar fluid clearance were combined for identifying plasmin specific cleavage sites and benefits.Key ResultsPlasmin led to a marked increment in lung fluid resolution in both human lungs ex vivo and injured mice. Plasmin specifically activated αβγENaC channels in oocytes in a time-dependent manner. Deletion of four consensus proteolysis tracts (αΔ432-444, γΔ131-138, γΔ178-193, and γΔ410-422) eliminated plasmin-induced activation significantly. Further, immunoblotting assays identified 7 cleavage sites (K126, R135, K136, R153, K168, R178, K179) for plasmin to trim both furin-cleaved C-terminal fragments and full-length human γENaC proteins. In addition to confirming the 7 cleavage sites, 9 new sites (R122, R137, R138, K150, K170, R172, R180, K181, K189) in synthesized peptides were found to be cleaved by plasmin with mass spectrometry. These cleavage sites were located in the finger and the thumb, particularly the GRIP domain of human ENaC 3D model composed of two proteolytic centres for plasmin. Novel uncleaved sites beyond the GRIP domain in both α and γ subunits were identified to interrupt the plasmin cleavage-induced conformational change in ENaC channel complexes. Additionally, plasmin could regulate ENaC activity via the G protein signal.Conclusion and ImplicationsWe demonstrate that plasmin could cleave ENaC to benefit the blood-gas exchange by resolving oedema fluid as a potent fibrinolytic therapy for oedematous pulmonary diseases.Bullet point summaryWhat is already knowSerine proteases proteolytically cleave epithelial sodium channels, including plasmin and uPA acutely.Activity of epithelial sodium channels is increased post proteolysis.What this study addsPlasmin cleaves up to 16 sites composed of two proteolytic centres in both full-length and furin-cleaved human γ subunit of epithelial sodium channels in hours.Non-proteolytic sites in both α and γ subunits interrupt the plasmin cleavage-induced channel gating.Intratracheally instilled plasmin facilitates alveolar fluid clearance in normal human and injured mouse lungs.Clinical significanceActivation of human lung epithelial sodium channels by plasmin may benefit lung oedema resolution as a novel therapy for ARDS.

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