Abstract
The epithelial sodium channel (ENaC) plays a key role in salt and water homeostasis in tetrapod vertebrates. There are four ENaC subunits (α, β, γ, δ), forming heterotrimeric αβγ- or δβγ-ENaCs. Although the physiology of αβγ-ENaC is well understood, for decades the field has stalled with respect to δβγ-ENaC due to the lack of mammalian model organisms. The SCNN1D gene coding for δ-ENaC was previously believed to be absent in rodents, hindering studies using standard laboratory animals. We analyzed all currently available rodent genomes and discovered that SCNN1D is present in rodents but was independently lost in five rodent lineages, including the Muridae (mice and rats). The independent loss of SCNN1D in rodent lineages may be constrained by phylogeny and taxon-specific adaptation to dry habitats, however habitat aridity does not provide a selection pressure for maintenance of SCNN1D across Rodentia. A fusion of two exons coding for a structurally flexible region in the extracellular domain of δ-ENaC appeared in the Hystricognathi (a group that includes guinea pigs). This conserved pattern evolved at least 41 Ma and represents a new autapomorphic feature for this clade. Exon fusion does not impair functionality of guinea pig (Cavia porcellus) δβγ-ENaC expressed in Xenopus oocytes. Electrophysiological characterization at the whole-cell and single-channel level revealed conserved biophysical features and mechanisms controlling guinea pig αβγ- and δβγ-ENaC function as compared with human orthologs. Guinea pigs therefore represent commercially available mammalian model animals that will help shed light on the physiological function of δ-ENaC.
Highlights
Water-to-land transition in the Devonian period, a key event in the evolution of tetrapod vertebrates (Daeschler et al 2006), required significant physiological adaptations, including efficient mechanisms of sodium and water homeostasis which involve complex transport mechanisms in vertebrate kidneys (Kuo and Ehrlich. 2012; Rossier et al 2015)
To categorise the characteristics common to all four SCNN1 genes and the particular differences that we observed regarding the evolution of SCNN1D, and to facilitate future comparisons, we propose a standardisation of the nomenclature for the exons of all SCNN1 genes
This study closes an intriguing gap in knowledge regarding functional δ-ENaC in rodents, which has puzzled the field of ENaC research for more than twenty years - to the point that rodents had been assumed to lack a functional SCNN1D gene (Kleyman and Eaton 2020; Paudel et al 2021)
Summary
Water-to-land transition in the Devonian period, a key event in the evolution of tetrapod vertebrates (Daeschler et al 2006), required significant physiological adaptations, including efficient mechanisms of sodium and water homeostasis which involve complex transport mechanisms in vertebrate kidneys (Kuo and Ehrlich. 2012; Rossier et al 2015). Vasopressin controls aquaporin-mediated renal water re-absorption and the renin-angiotensin-aldosterone system (RAAS) fine-tunes renal sodium re-absorption via epithelial sodium channels (ENaCs) (Rossier et al 2015). ENaCs are constitutively active ion channels, but channel activity can be adjusted by a multitude of regulatory mechanisms and stimuli (Kleyman and Eaton 2020). Whereas hormones such as aldosterone control ENaC subunit expression (Rossier et al 2015), the abundance of ENaCs in the plasma membrane is controlled by a complex intracellular signalling network that regulates trafficking to and removal from the plasma membrane (Baines 2013). Mutations that result in enhanced (αβγ-) ENaC activity cause Liddle syndrome (Shimkets et al 1994), a hereditary form of hypertension, whereas mutations reducing ENaC activity cause hypotension and severe salt-wasting (pseudohypoaldosteronism type 1) (Chang et al 1996)
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