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

Hanukoglu, Israel; Hanukoglu, Aaron

doi:10.1016/j.gene.2015.12.061

Cited by 327 publications

(351 citation statements)

References 329 publications

(454 reference statements)

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“…In particular, γ‐ENaC expression was markedly (≈90%) lower. ENaC is a heterotrimer of α, β, and γ subunits, all of which are essential for channel functionality 30. The main target of MR in the kidneys is α‐ENaC, whereas in the intestine, β‐ and γ‐ENaC are the main targets 31, 32, 33.…”

Section: Discussionmentioning

confidence: 99%

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

Nakamura

Kurihara

Kobayashi

et al. 2018

JAHA

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BackgroundMineralocorticoid receptor (MR) has pathological roles in various cell types, including renal tubule cells, myocytes, and smooth muscle cells; however, the role of MR in intestinal epithelial cells (IECs) has not been sufficiently evaluated. The intestine is the sensing organ of ingested sodium; accordingly, intestinal MR is expected to have essential roles in blood pressure (BP) regulation.Methods and ResultsWe generated IEC‐specific MR knockout (IEC‐MR‐KO) mice. With a standard diet, fecal sodium excretion was 1.5‐fold higher in IEC‐MR‐KO mice, with markedly decreased colonic expression of β‐ and γ‐epithelial sodium channel, than in control mice. Urinary sodium excretion in IEC‐MR‐KO mice decreased by 30%, maintaining sodium balance; however, a low‐salt diet caused significant reductions in body weight and BP in IEC‐MR‐KO mice, and plasma aldosterone exhibited a compensatory increase. With a high‐salt diet, intestinal sodium absorption markedly increased to similar levels in both genotypes, without an elevation in BP. Deoxycorticosterone/salt treatment elevated BP and increased intestinal sodium absorption in both genotypes. Notably, the increase in BP was significantly smaller in IEC‐MR‐KO mice than in control mice. The addition of the MR antagonist spironolactone to deoxycorticosterone/salt treatment eliminated the differences in BP and intestinal sodium absorption between genotypes.ConclusionsIntestinal MR regulates intestinal sodium absorption in the colon and contributes to BP regulation. These regulatory effects are associated with variation in epithelial sodium channel expression. These findings suggest that intestinal MR is a new target for studying the molecular mechanism of hypertension and cardiovascular diseases.

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Section: Discussionmentioning

confidence: 99%

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

Nakamura

Kurihara

Kobayashi

et al. 2018

JAHA

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“…ENaC is assembled as a heterotrimer composed of three subunits α, β, and γ or δ, β, and γ [137]. These subunits consitute a family within the ENaC/Degenerin super-family [137].…”

Section: Overviewmentioning

confidence: 99%

“…ENaC is assembled as a heterotrimer composed of three subunits α, β, and γ or δ, β, and γ [137]. These subunits consitute a family within the ENaC/Degenerin super-family [137]. Genes encoding ENaC subunits are found in all vertebrates with the exception of ray-finned fishes [137].…”

Section: Overviewmentioning

confidence: 99%

THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Ligand‐gated ion channels

Alexander

Peters

Kelly

et al. 2017

British J Pharmacology

143

129

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The Concise Guide to PHARMACOLOGY 2017/18 provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13879/full. Ligand-gated ion channels are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate. Conflict of interestThe authors state that there are no conflicts of interest to declare. Overview: Ligand-gated ion channels (LGICs) are integral membrane proteins that contain a pore which allows the regulated flow of selected ions across the plasma membrane. Ion flux is passive and driven by the electrochemical gradient for the permeant ions. These channels are open, or gated, by the binding of a neurotransmitter to an orthosteric site(s) that triggers a conformational change that results in the conducting state. Modulation of gating can occur by the binding of endogenous, or exogenous, modulators to allosteric sites.LGICs mediate fast synaptic transmission, on a millisecond time scale, in the nervous system and at the somatic neuromuscular junction. Such transmission involves the release of a neurotransmitter from a pre-synaptic neurone and the subsequent activation of post-synaptically located receptors that mediate a rapid, phasic, electrical signal (the excitatory, or inhibitory, post-synaptic potential). However, in addition to their traditional role in phasic neurotransmission, it is now established that some LGICs mediate a tonic form of neuronal regulation that results from the activation of extra-synaptic receptors by ambient levels of neurotransmitter. The expression of some LGICs by nonexcitable cells is suggestive of additional ...

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“…26 Evidence of interplay between the mechanisms regulating of CFTR and ENaC surface density has arisen from data showing the concomitant and reciprocal regulation of these channels' activities (reviewed in ref. 27).…”

Section: Regulation Of Enac Density At the Cell Surface By Rab Gtpasesmentioning

confidence: 99%

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

Farinha

Matos

2017

Small GTPases

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The amount of ion channels and transporters present at the plasma membrane is a crucial component of the overall regulation of ion transport. The number of channels present result from an intricate network of proteins that controls the late events of channel trafficking, such as endocytosis, recycling and targeting to lysosomal degradation. Small GTPases of the Rab family are key players in these processes thus contributing to regulation of fluid secretion and ion homeostasis. In epithelia, this involves mainly the balance between the chloride channel CFTR and the sodium channel ENaC, whose misfunction is a hallmark of cystic fibrosis -the commonest recessive disorder in Caucasians. Here, we review the role of GTPases in regulating trafficking of ion channels and transporters, comparing what is known for CFTR and ENaC with other types of channels. We also discuss how feasible would be to target the Rab machinery to handle a disorder such as CF. Trafficking and Rab proteinsRegulation of ion and solute transport at the membrane of cells depends on the balance between the function of each channel or transporter and on the number of molecules present. 1 The latter is regulated by the protein trafficking machinery, which controls the process through which a membrane protein is delivered from its place of synthesis -the membrane of the endoplasmic reticulum -to its final destination -the plasma membrane (PM). Besides these anterograde trafficking pathways, channels and transporters also undergo endocytosis followed by either recycling to the PM or targeting to the lysosomal compartment. These late trafficking events are controlled by several protein partners, that include protein kinases, myosins and small GTPases, among which Rab proteins. 1 Rab GTPases form the biggest subfamily of the Ras superfamily of small GTPases. As most members of this superfamily, they function as molecular switches alternating between 2 conformational status -a GTP-bound active form and a GDP-bound inactive form. 2,3 The human subfamily contains more than 60 members that reversibly associate with different intracellular membranes, due to their post-translational modification with geranylgeranyl groups. 4 This association with membranes promotes interactions with other components of the trafficking machinery, such as coat components, motor proteins and SNAREs. 2 These characteristics make them relevant players in the control of membrane identity, in vesicle formation, motility and function, regulating the trafficking of many different classes of proteins, among which channels and transporters. 5

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

Cited by 327 publications

References 329 publications

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Ligand‐gated ion channels

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

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