1. Evolutionary Biology
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Activation by cleavage of the epithelial Na+ channel α and γ subunits independently coevolved with the vertebrate terrestrial migration

  1. Xue-Ping Wang
  2. Deidra M Balchak
  3. Clayton Gentilcore
  4. Nathan L Clark
  5. Ossama B Kashlan  Is a corresponding author
  1. University of Pittsburgh, United States
  2. University of Utah, United States
Research Article
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Cite this article as: eLife 2022;11:e75796 doi: 10.7554/eLife.75796

Abstract

Vertebrates evolved mechanisms for sodium conservation and gas exchange in conjunction with migration from aquatic to terrestrial habitats. Epithelial Na+ channel (ENaC) function is critical to systems responsible for extracellular fluid homeostasis and gas exchange. ENaC is activated by cleavage at multiple specific extracellular polybasic sites, releasing inhibitory tracts from the channel’s α and γ subunits. We found that proximal and distal polybasic tracts in ENaC subunits coevolved, consistent with the dual cleavage requirement for activation observed in mammals. Polybasic tract pairs evolved with the terrestrial migration and the appearance of lungs, coincident with the ENaC activator aldosterone, and appeared independently in the a and g subunits. In summary, sites within ENaC for protease activation developed in vertebrates when renal Na+ conservation and alveolar gas exchange was required for terrestrial survival.

Data availability

Source data for figures 1 and 2 are provided in Supplementary Data. Source data for trait evolution analysis, Figures 3 and Figure 4 are provided as image and Microsoft Excel files. Images and source data of electrophysiology traces in Figure 3 are provided at the Zenodo data repository (10.5281/zenodo.5790375).

The following data sets were generated
    1. Kashlan
    2. Ossama B
    (2021) Figure 3-source data 2
    Zenodo, doi:10.5281/zenodo.5790375.

Article and author information

Author details

  1. Xue-Ping Wang

    Department of Medicine, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Deidra M Balchak

    Department of Medicine, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Clayton Gentilcore

    Department of Medicine, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Nathan L Clark

    Department of Human Genetics, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ossama B Kashlan

    Department of Medicine, University of Pittsburgh, Pittsburgh, United States
    For correspondence
    obk2@pitt.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0537-6720

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (Grant R01 DK125439)

  • Ossama B Kashlan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#20037084 and #21018704) of the University of Pittsburgh. All surgery was performed following tricaine methane sulfonate anesthesia and sacrifice, and every effort was made to minimize suffering.

Reviewing Editor

  1. Kenton J Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States

Publication history

  1. Received: November 23, 2021
  2. Accepted: December 28, 2021
  3. Accepted Manuscript published: January 5, 2022 (version 1)

Copyright

© 2022, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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