TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed)
A1  - Wichmann, Lukas
A1  - Dulai, Jasdip Singh
A1  - Marles-Wright, Jon
A1  - Maxeiner, Stephan
A1  - Szczesniak, Pawel Piotr
A1  - Manzini, Ivan
A1  - Althaus, Mike
T1  - An extracellular acidic cleft confers profound H+-sensitivity to epithelial sodium channels containing the δ-subunit in Xenopus laevispH-sensitivity of Xenopus δ-ENaC
JF  - The Journal of Biological Chemistry
N2  - The limited sodium availability of freshwater and terrestrial environments was a major physiological challenge during vertebrate evolution. The epithelial sodium channel (ENaC) is present in the apical membrane of sodium-absorbing vertebrate epithelia and evolved as part of a machinery for efficient sodium conservation. ENaC belongs to the degenerin/ENaC protein family and is the only member that opens without an external stimulus. We hypothesized that ENaC evolved from a proton-activated sodium channel present in ionocytes of freshwater vertebrates and therefore investigated whether such ancestral traits are present in ENaC isoforms of the aquatic pipid frog Xenopus laevis. Using whole-cell and single-channel electrophysiology of Xenopus oocytes expressing ENaC isoforms assembled from alpha beta gamma- or delta beta gamma-subunit combinations, we demonstrate that Xenopus delta beta gamma-ENaC is profoundly activated by extracellular acidification within biologically relevant ranges (pH 8.0-6.0). This effect was not observed in Xenopus alpha beta gamma-ENaC or human ENaC orthologs. We show that protons interfere with allosteric ENaC inhibition by extracellular sodium ions, thereby increasing the probability of channel opening. Using homology modeling of ENaC structure and site-directed mutagenesis, we identified a cleft region within the extracellular loop of the delta-subunit that contains several acidic amino acid residues that confer proton-sensitivity and enable allosteric inhibition by extracellular sodium ions. We propose that Xenopus delta beta gamma-ENaC can serve as a model for investigating ENaC transformation from a proton-activated toward a constitutively-active ion channel. Such transformation might have occurred during the evolution of tetrapod vertebrates to enable bulk sodium absorption during the water-to-land transition.
KW  - Xenopus
KW  - epithelial sodium channel (ENaC)
KW  - water-to-land transition
KW  - delta-subunit
KW  - tetrapod
KW  - pH
KW  - allosteric regulation
KW  - evolution
KW  - molecular evolution
KW  - sodium self-inhibition
SN  - 0021-9258
SS  - 0021-9258
U6  - https://doi.org/10.1074/jbc.RA119.008255
DO  - https://doi.org/10.1074/jbc.RA119.008255
PM  - 31248986
VL  - 294
IS  - 33
SP  - 12507
EP  - 12520
S1  - 14
PB  - Elsevier
ER  -