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

Elife. 2022 Jan 5:11: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 α and γ subunits. In summary, sites within ENaC for protease activation developed in vertebrates when renal Na+ conservation and alveolar gas exchange were required for terrestrial survival.

Keywords: E. calabaricus; N. forsteri; epithelial Na+ channel; evolutionary biology; furin; proteolytic activation; vertebrate land invasion; xenopus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amphibian Proteins / genetics
  • Amphibian Proteins / metabolism
  • Animals
  • Epithelial Sodium Channels / genetics*
  • Epithelial Sodium Channels / metabolism
  • Evolution, Molecular*
  • Fish Proteins / genetics
  • Fish Proteins / metabolism
  • Fishes / genetics*
  • Fishes / metabolism
  • Xenopus laevis / genetics*
  • Xenopus laevis / metabolism

Substances

  • Amphibian Proteins
  • Epithelial Sodium Channels
  • Fish Proteins