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J Biol Chem
2019 Aug 16;29433:12507-12520. doi: 10.1074/jbc.RA119.008255.
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An extracellular acidic cleft confers profound H+-sensitivity to epithelial sodium channels containing the δ-subunit in Xenopus laevis.
Wichmann L
,
Dulai JS
,
Marles-Wright J
,
Maxeiner S
,
Szczesniak PP
,
Manzini I
,
Althaus M
.
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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 αβγ- or δβγ-subunit combinations, we demonstrate that Xenopus δβγ-ENaC is profoundly activated by extracellular acidification within biologically relevant ranges (pH 8.0-6.0). This effect was not observed in Xenopus αβγ-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 δ-subunit that contains several acidic amino acid residues that confer proton-sensitivity and enable allosteric inhibition by extracellular sodium ions. We propose that Xenopus δβγ-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.
Anantharam,
Open probability of the epithelial sodium channel is regulated by intracellular sodium.
2006, Pubmed,
Xenbase
Anantharam,
Open probability of the epithelial sodium channel is regulated by intracellular sodium.
2006,
Pubmed
,
Xenbase
Assmann,
The comprehensive analysis of DEG/ENaC subunits in Hydra reveals a large variety of peptide-gated channels, potentially involved in neuromuscular transmission.
2014,
Pubmed
,
Xenbase
Awayda,
Regulation of the epithelial Na(+) channel by extracellular acidification.
2000,
Pubmed
,
Xenbase
Babini,
A new subunit of the epithelial Na+ channel identifies regions involved in Na+ self-inhibition.
2003,
Pubmed
,
Xenbase
Bayley,
Learning to Air-Breathe: The First Steps.
2019,
Pubmed
Bize,
Sodium self-inhibition of human epithelial sodium channel: selectivity and affinity of the extracellular sodium sensing site.
2007,
Pubmed
,
Xenbase
Boscardin,
The function and regulation of acid-sensing ion channels (ASICs) and the epithelial Na(+) channel (ENaC): IUPHAR Review 19.
2016,
Pubmed
Chalfant,
Intracellular H+ regulates the alpha-subunit of ENaC, the epithelial Na+ channel.
1999,
Pubmed
,
Xenbase
Cogswell,
Sodium and potassium intakes among US adults: NHANES 2003-2008.
2012,
Pubmed
Collier,
Extracellular protons regulate human ENaC by modulating Na+ self-inhibition.
2009,
Pubmed
,
Xenbase
Collier,
Identification of extracellular domain residues required for epithelial Na+ channel activation by acidic pH.
2012,
Pubmed
,
Xenbase
Collier,
Intersubunit conformational changes mediate epithelial sodium channel gating.
2014,
Pubmed
,
Xenbase
Coric,
Proton sensitivity of ASIC1 appeared with the rise of fishes by changes of residues in the region that follows TM1 in the ectodomain of the channel.
2005,
Pubmed
Corpet,
Multiple sequence alignment with hierarchical clustering.
1988,
Pubmed
Cottrell,
The first peptide-gated ion channel.
1997,
Pubmed
,
Xenbase
Dymowska,
Acid-sensing ion channels are involved in epithelial Na+ uptake in the rainbow trout Oncorhynchus mykiss.
2014,
Pubmed
Dymowska,
The role of acid-sensing ion channels in epithelial Na+ uptake in adult zebrafish (Danio rerio).
2015,
Pubmed
Evans,
Genetics, Morphology, Advertisement Calls, and Historical Records Distinguish Six New Polyploid Species of African Clawed Frog (Xenopus, Pipidae) from West and Central Africa.
2015,
Pubmed
,
Xenbase
Frazier,
Excretion of H + and NH 4 + by the urinary bladder of the acidotic toad and the effect of short-circuit current on the excretion.
1971,
Pubmed
Giraldez,
The epithelial sodium channel δ-subunit: new notes for an old song.
2012,
Pubmed
Hanukoglu,
Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases.
2016,
Pubmed
Harding,
Metal-ligand geometry relevant to proteins and in proteins: sodium and potassium.
2002,
Pubmed
Humphreys,
Functional characterization and regulation by pH of murine AE2 anion exchanger expressed in Xenopus oocytes.
1994,
Pubmed
,
Xenbase
Ianevski,
SynergyFinder: a web application for analyzing drug combination dose-response matrix data.
2017,
Pubmed
Ji,
Degenerin sites mediate proton activation of deltabetagamma-epithelial sodium channel.
2004,
Pubmed
,
Xenbase
Ji,
Delta-subunit confers novel biophysical features to alpha beta gamma-human epithelial sodium channel (ENaC) via a physical interaction.
2006,
Pubmed
Kashlan,
Na+ inhibits the epithelial Na+ channel by binding to a site in an extracellular acidic cleft.
2015,
Pubmed
,
Xenbase
Kellenberger,
Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure.
2002,
Pubmed
Kerem,
Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism.
1999,
Pubmed
LEAF,
STIMULATION OF SODIUM TRANSPORT IN TOAD BLADDER BY ACIDIFICATION OF MUCOSAL MEDIUM.
1964,
Pubmed
Li,
Two residues in the extracellular domain convert a nonfunctional ASIC1 into a proton-activated channel.
2010,
Pubmed
,
Xenbase
Li,
Leu85 in the beta1-beta2 linker of ASIC1 slows activation and decreases the apparent proton affinity by stabilizing a closed conformation.
2010,
Pubmed
,
Xenbase
Liu,
Structural basis for allosteric regulation of GPCRs by sodium ions.
2012,
Pubmed
Lynagh,
Acid-sensing ion channels emerged over 600 Mya and are conserved throughout the deuterostomes.
2018,
Pubmed
McBean,
Renal function during osmotic stress in the aquatic toad Xenopus laevis.
1970,
Pubmed
,
Xenbase
Noreng,
Structure of the human epithelial sodium channel by cryo-electron microscopy.
2018,
Pubmed
Palmer,
Effects of cell Ca and pH on Na channels from rat cortical collecting tubule.
1987,
Pubmed
SHOEMAKER,
THE EFFECTS OF DEHYDRATION ON ELECTROLYTE CONCENTRATIONS IN A TOAD, BUFO MARINUS.
1964,
Pubmed
Sheng,
Furin cleavage activates the epithelial Na+ channel by relieving Na+ self-inhibition.
2006,
Pubmed
,
Xenbase
Sievers,
Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega.
2011,
Pubmed
Steinmetz,
Cellular mechanisms of urinary acidification.
1974,
Pubmed
Studer,
Evolution of the epithelial sodium channel and the sodium pump as limiting factors of aldosterone action on sodium transport.
2011,
Pubmed
Tavernarakis,
Molecular modeling of mechanotransduction in the nematode Caenorhabditis elegans.
1997,
Pubmed
USSING,
The active ion transport through the isolated frog skin in the light of tracer studies.
1949,
Pubmed
Wichmann,
Incorporation of the δ-subunit into the epithelial sodium channel (ENaC) generates protease-resistant ENaCs in Xenopus laevis.
2018,
Pubmed
,
Xenbase
Yadav,
Searching for Drug Synergy in Complex Dose-Response Landscapes Using an Interaction Potency Model.
2015,
Pubmed
Yang,
The I-TASSER Suite: protein structure and function prediction.
2015,
Pubmed
Zhang,
Inhibition of alphabeta epithelial sodium channels by external protons indicates that the second hydrophobic domain contains structural elements for closing the pore.
1999,
Pubmed
,
Xenbase
