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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.
Wichmann et al. (Wed,) studied this question.