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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,
Intersubunit conformational changes mediate epithelial sodium channel gating.
2014,
Pubmed
,
Xenbase Collier,
Identification of extracellular domain residues required for epithelial Na+ channel activation by acidic pH.
2012,
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,
The role of acid-sensing ion channels in epithelial Na+ uptake in adult zebrafish (Danio rerio).
2015,
Pubmed Dymowska,
Acid-sensing ion channels are involved in epithelial Na+ uptake in the rainbow trout Oncorhynchus mykiss.
2014,
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,
Delta-subunit confers novel biophysical features to alpha beta gamma-human epithelial sodium channel (ENaC) via a physical interaction.
2006,
Pubmed Ji,
Degenerin sites mediate proton activation of deltabetagamma-epithelial sodium channel.
2004,
Pubmed
,
Xenbase 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 Sheng,
Furin cleavage activates the epithelial Na+ channel by relieving Na+ self-inhibition.
2006,
Pubmed
,
Xenbase SHOEMAKER,
THE EFFECTS OF DEHYDRATION ON ELECTROLYTE CONCENTRATIONS IN A TOAD, BUFO MARINUS.
1964,
Pubmed 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
