The Evolutionary Path of the Epithelial Sodium Channel δ-subunit in Cetartiodactyla Points to a Role in Sodium Sensing

The epithelial sodium channel (ENaC) plays a key role in osmoregulation in tetrapod vertebrates and is a candidate receptor for salt taste sensation. There are four ENaC subunits (α, β, γ, δ) which form αβγ- or δβγ ENaCs. While αβγ-ENaC is a 'maintenance protein' controlling sodium and potassium homeostasis, δβγ-ENaC might represent a 'stress protein' monitoring high sodium concentrations. The δ-subunit emerged with water-to-land transition of tetrapod vertebrate ancestors. We investigated the evolutionary path of ENaC-coding genes in Cetartiodactyla, a group comprising even-toed ungulates and the cetaceans (whales/dolphins) which transitioned from terrestrial to marine environments in the Eocene. The genes (α-ENaC), (β-ENaC) and (γ-ENaC) are intact in all 22 investigated cetartiodactylan families. While (δ-ENaC) is intact in terrestrial Artiodactyla, it is a pseudogene in 12 cetacean families. A fusion of exons 11 and 12 under preservation of the open reading frame was observed in the Antilopinae, representing a new feature of this clade. Transcripts of and were present in kidney and lung tissues of Bottlenose dolphins, highlighting αβγ-ENaC's role as a maintenance protein. Consistent with loss, Bottlenose dolphins and Beluga whales did not show behavioural differences to stimuli with or without sodium in seawater-equivalent concentrations. These data suggest a function of δ-ENaC as a sodium sensing protein which might have become obsolete in cetaceans after the migration to high-salinity marine environments. Consistently, there is reduced selection pressure or pseudogenisation of in other marine mammals, including sirenians, pinnipeds and sea otter.