Gain-of-function variant of the human epithelial sodium channel

Chen, Jingxin; Kleyman, Thomas R.; Sheng, Shaohu

doi:10.1152/ajprenal.00563.2012

Cited by 25 publications

(32 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Site-directed mutagenesis studies using human ENaC subunits showed that mutation of these residues to alanine also leads to a decrease in sodium feedback inhibition that controls channel open probability (P o ) (Edelheit et al, 2014, 2011). A human γ subunit variant in the palm domain (L511Q) is associated with an increase in channel open probability (Chen et al, 2013). …”

Section: Conserved Sequence Motifs and Their Functionsmentioning

confidence: 99%

Epithelial sodium channel (ENaC) family: Phylogeny, structure–function, tissue distribution, and associated inherited diseases

Hanukoglu

2016

Gene

345

View full text Add to dashboard Cite

The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na+ ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na+ in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity. In multi-ciliated cells, ENaC is located in cilia and plays an essential role in the regulation of epithelial surface liquid volume necessary for cilial transport of mucus and gametes in the respiratory and reproductive tracts respectively. The subunits that form ENaC (named as alpha, beta, gamma and delta, encoded by genes SCNN1A, SCNN1B, SCNN1G, and SCNN1D) are members of the ENaC/Degenerin superfamily. The earliest appearance of ENaC orthologs is in the genomes of the most ancient vertebrate taxon, Cyclostomata (jawless vertebrates) including lampreys, followed by earliest representatives of Gnathostomata (jawed vertebrates) including cartilaginous sharks. Among Euteleostomi (bony vertebrates), Actinopterygii (ray finned-fishes) branch has lost ENaC genes. Yet, most animals in the Sarcopterygii (lobe-finned fish) branch including Tetrapoda, amphibians and amniotes (lizards, crocodiles, birds, and mammals), have four ENaC paralogs. We compared the sequences of ENaC orthologs from 20 species and established criteria for the identification of ENaC orthologs and paralogs, and their distinction from other members of the ENaC/Degenerin superfamily, especially ASIC family. Differences between ENaCs and ASICs are summarized in view of their physiological functions and tissue distributions. Structural motifs that are conserved throughout vertebrate ENaCs are highlighted. We also present a comparative overview of the genotype-phenotype relationships in inherited diseases associated with ENaC mutations, including multisystem pseudohypoaldosteronism (PHA1B), Liddle syndrome, cystic fibrosis-like disease and essential hypertension.

show abstract

Section: Conserved Sequence Motifs and Their Functionsmentioning

confidence: 99%

Epithelial sodium channel (ENaC) family: Phylogeny, structure–function, tissue distribution, and associated inherited diseases

Hanukoglu

2016

Gene

345

View full text Add to dashboard Cite

show abstract

“…4 Mechanisms by which these hormones regulate renal ENaCs have been the focus of numerous reviews. 2, 3, 9, 26–29 Aldosterone increases expression of the α subunit as well as many other proteins, including the serum and glucocorticoid regulated kinase (SGK1), and the adaptors glucocorticoid-induced leucine zipper 1 (GILZ1) and connector enhancer of kinase suppressor of Ras isoform 3, which enhance surface expression of channels. 2, 30–35 …”

Section: Expression and Regulation Of Enac In The Distal Nephronmentioning

confidence: 99%

“…1–3 The regulated reabsorption of filtered Na + by the nephron has a key role in the regulation of extracellular fluid volume and blood pressure. 4 The role of these channels in the control of blood pressure is highlighted by gain-of-function mutations (Liddle syndrome) and loss-of-function mutations (pseudohypoaldosteronism type I) that are associated with increases or decreases in blood pressure, respectively.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells

et al. 2014

Self Cite

View full text Add to dashboard Cite

This review is focused on the expression and regulation of amiloride-sensitive sodium channels in the epithelial cells of the aldosterone-sensitive distal nephron (ENaC) and amiloride-sensitive sodium channel activity in vascular endothelial and smooth muscle cells. Guyton’s hypothesis stated that blood pressure control is critically dependent on vascular tone and fluid handling by the kidney. With the study of Mendelian forms of hypertension and their corresponding transgenic mouse models, the main components of the aldosterone- and angiotensin-dependent sodium transporters have been identified over the past 20 years. Proteolytic processing of the ENaC external domain, and inhibition by increased sodium concentrations are important features of the ENaC complexes expressed in the distal nephron. In contrast, amiloride-sensitive sodium channels expressed in the vascular system are activated by increased external sodium concentrations, resulting in changes in the mechanical properties and function of endothelial cells. Mechano-sensitivity and shear stress affect both epithelial and vascular sodium channel activity. The synergistic effects and complementary regulation of the epithelial and vascular systems are consistent with the Guytonian model of volume and blood pressure regulation, and may reflect sequential evolution of the two systems. The integration of vascular tone, renal perfusion and regulation of renal sodium reabsorption is the central underpinning of the Guytonian model. We summarize the recent evidence in this review that describes the central role of amiloride-sensitive sodium channels in the efferent (e.g., vascular) and afferent (e.g., epithelial) arms of this homeostatic system.

show abstract

“…2). Previous studies suggest that channels with a high intrinsic P o are less sensitive to extracellular Na ϩ (9,24,31,45) and stimulation by mechanical forces (7,8). As shown in Fig.…”

Section: Resultsmentioning

confidence: 83%

Gamma subunit second transmembrane domain contributes to epithelial sodium channel gating and amiloride block

Shi¹,

Kleyman

2013

American Journal of Physiology-Renal Physiology

Self Cite

View full text Add to dashboard Cite

Shi S, Kleyman TR. Gamma subunit second transmembrane domain contributes to epithelial sodium channel gating and amiloride block. The epithelial sodium channel (ENaC) is comprised of three homologous subunits. Channels composed solely of ␣-and ␤-subunits (␣␤-channels) exhibit a very high open probability (P o) and reduced sensitivity to amiloride, in contrast to channels composed of ␣-and ␥-subunits or of all three subunits (i.e., ␣␥-and ␣␤␥-channels). A mutant channel comprised of ␣-and ␤-subunits, and a chimeric ␥-subunit where the region immediately preceding (␤12 and wrist) and encompassing the second transmembrane domain (TM2) was replaced with the corresponding region of the ␤-subunit (␥-␤TM2), displayed characteristics reminiscent of ␣␤-channels, including a reduced amiloride potency of block and a loss of Na ϩ self-inhibition (reflecting an increased Po). Substitutions at key pore-lining residues of the ␥-␤TM2 chimera enhanced the Na ϩ self-inhibition response, whereas key ␥-subunit substitutions reduced the response. Furthermore, multiple sites within the TM2 domain of the ␥-subunit were required to confer high amiloride potency. In summary, we have identified novel pore-lining residues of the ␥-subunit of ENaC that are important for proper channel gating and its interaction with amiloride.ENaC; amiloride; open probability; sodium; subunit THE EPITHELIAL NA ϩ CHANNEL (ENaC)/degenerin family encodes a group of structurally related ion channels that are highly selective for Na ϩ and sensitive to amiloride and its derivatives (16,21). Members of the ENaC/degenerin family are involved in many fundamental biological processes, including Na ϩ absorption and volume regulation (ENaCs), mechanosensation (ENaCs and Caenorhabditis elegans degenerins), and nociception [acid-sensing ion channels (ASICs); Refs. 11,16,44]. ENaCs are heterotrimeric channels composed of three homologous subunits, termed ␣, ␤, and ␥. The second transmembrane helix from each subunit contributes to the channel pore where the gate, selectivity filter, and amiloride binding site likely reside (16,32,37,43).ENaCs with different subunit compositions have been reconstituted in heterologous expression systems (4,12,14,27). Previous studies by Fyfe and Canessa (12) and by McNicholas and Canessa (27) have shown that rat ENaCs composed solely of ␣-and ␤-subunits exhibit functional properties that differ from channels including the ␥-subunit (i.e., ␣␤␥-channels or ␣␥-channels). When expressed in Xenopus oocytes, ␣␤-channels were more permeable to Na ϩ than Li ϩ and less sensitive to amiloride and related analogs (27). At the single channel level, the ␣␤-channel displayed a smaller conductance and higher open probability (P o ; Ref. 12). These observations suggest that the ␥-subunit has roles in restraining ENaC activity and enhancing the potency of amiloride block on channel activity. However, the sites within the ␥-subunit that account for distinct properties of ␣␤␥-and ␣␥-channels, compared with ␣␤-channels, have not been elucidated.The function...

show abstract

Gain-of-function variant of the human epithelial sodium channel

Cited by 25 publications

References 45 publications

Epithelial sodium channel (ENaC) family: Phylogeny, structure–function, tissue distribution, and associated inherited diseases

Epithelial sodium channel (ENaC) family: Phylogeny, structure–function, tissue distribution, and associated inherited diseases

Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells

Gamma subunit second transmembrane domain contributes to epithelial sodium channel gating and amiloride block

Contact Info

Product

Resources

About