The diverse functions of the DEG/ENaC family: linking genetic and physiological insights

Kaulich, Eva; Grundy, Laura J; Schafer, William R; Walker, Denise S.

doi:10.1113/jp283335

Cited by 7 publications

(4 citation statements)

References 237 publications

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“…Additionally, activation of TWK-26 fails to suppress the defecation defects of the flr mutants, namely the shortened defecation interval and expulsion defects. This result is surprising, given that the DMP plays a central role in nutrient absorption, proper growth, and lipid metabolism (Kaulich et al 2023; Suzuki et al 2022). Our finding uniquely uncouples intestinal distension and the DMP from metabolic homeostasis, suggesting that animals may be able to dynamically alter the expression of factors that maintain ion homeostasis to promote efficient uptake and utilization of nutrients.…”

Section: Discussionmentioning

confidence: 99%

The TWK-26 potassium channel governs nutrient absorption in theC. elegansintestine

Torzone,

Breen,

Cohen

et al. 2024

Preprint

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Ion channels are necessary for proper water and nutrient absorption in the intestine, which supports cellular metabolism and organismal growth. While a role for Na+ co-transporters and pumps in intestinal nutrient absorption is well defined, how individual K+ uniporters function to maintain ion homeostasis is poorly understood. UsingCaenorhabditis elegans, we show that a gain-of-function mutation intwk-26, which encodes a two-pore domain K+ ion channel orthologous to human KCNK3, facilitates nutrient absorption and suppresses the metabolic and developmental defects displayed by impaired intestinal MAP Kinase (MAPK) signaling. Mutations indrl-1andflr-4, which encode two components of this MAPK pathway, cause severe growth defects, reduced lipid storage, and a dramatic increase in autophagic lysosomes, which mirror dietary restriction phenotypes. Additionally, these MAPK mutants display structural defects of the intestine and an impaired defecation motor program. We find that activation of TWK-26 reverses the dietary restriction-like state of the MAPK mutants by restoring intestinal nutrient absorption without correcting the intestinal bloating or defecation defects. This study provides unique insight into the mechanisms by which intestinal K+ ion channels support intestinal metabolic homeostasis.

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Section: Discussionmentioning

confidence: 99%

The TWK-26 potassium channel governs nutrient absorption in theC. elegansintestine

Torzone,

Breen,

Cohen

et al. 2024

Preprint

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“…The sequences of ENaC subunits and degenerin (DEG) from the nematode Caenorhabditis elegans are similar, so they are named the DEG/ENaC family, which also includes the mammalian acid-sensing ion channel (ASIC) ( 10 ). Canonical ENaC is a heterotrimer composed of α, β, and γ subunits; the δ subunit can replace the α subunit to form a heterotrimer in non-renal tissues ( 2 ).…”

Section: The Epithelial Sodium Channelmentioning

confidence: 99%

Role of epithelial sodium channel-related inflammation in human diseases

Chen

Zhang

et al. 2023

Front. Immunol.

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The epithelial sodium channel (ENaC) is a heterotrimer and is widely distributed throughout the kidneys, blood vessels, lungs, colons, and many other organs. The basic role of the ENaC is to mediate the entry of Na+ into cells; the ENaC also has an important regulatory function in blood pressure, airway surface liquid (ASL), and endothelial cell function. Aldosterone, serum/glucocorticoid kinase 1 (SGK1), shear stress, and posttranslational modifications can regulate the activity of the ENaC; some ion channels also interact with the ENaC. In recent years, it has been found that the ENaC can lead to immune cell activation, endothelial cell dysfunction, aggravated inflammation involved in high salt-induced hypertension, cystic fibrosis, pseudohypoaldosteronism (PHA), and tumors; some inflammatory cytokines have been reported to have a regulatory role on the ENaC. The ENaC hyperfunction mediates the increase of intracellular Na+, and the elevated exchange of Na+ with Ca2+ leads to an intracellular calcium overload, which is an important mechanism for ENaC-related inflammation. Some of the research on the ENaC is controversial or unclear; we therefore reviewed the progress of studies on the role of ENaC-related inflammation in human diseases and their mechanisms.

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“…Ligand-gated ion channels (LGICs) are cell membrane proteins that convert extracellular chemical signals into transmembrane ionic current, thus contributing to rapid inter-cellular signaling and chemo-sensation 1,2 . The major superfamilies of pentameric LGICs, e.g.…”

Section: Introductionmentioning

confidence: 99%

Structural basis for excitatory neuropeptide signaling

Kalienkova

Dandamudi

Lynagh

2023

Preprint

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Rapid chemo-electric signaling between neurons is mediated by ligand-gated ion channels, cell-surface proteins with an extracellular ligand-binding domain and a membrane-spanning ion channel domain. The degenerin/epithelial sodium channel (DEG/ENaC) superfamily, which occurs throughout the animal kingdom, is unique in its diversity of gating stimuli, with some DEG/ENaCs gated by conventional ligands such as neuropeptides, and others gated by e.g. pH, mechanical force, or enzymatic activity. The mechanism by which ligands bind to and activate DEG/ENaCs is poorly understood. We have therefore dissected the structural basis for neuropeptide binding and gating in a neuropeptide-gated DEG/ENaC, FMRFamide-gated sodium channel 1 (FaNaC1) from the annelid worm Malacoceros fuliginosus, using cryo-electron microscopy. High-resolution structures of FaNaC1 in the ligand-free resting state and in several ligand-bound states reveal the ligand-binding site and capture the ligand-induced conformational changes that mediate channel gating. Complementary mutagenesis experiments confirm the functional roles of particular amino acid residues implicated by the structures. Our results illuminate ligand-induced channel gating in DEG/ENaCs and offer a structural template for the experimental dissection of channel pharmacology and ion conduction in a characteristically metazoan ion channel superfamily.

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The diverse functions of the DEG/ENaC family: linking genetic and physiological insights

Abstract: support-information-section).

Cited by 7 publications

References 237 publications

The TWK-26 potassium channel governs nutrient absorption in theC. elegansintestine

The TWK-26 potassium channel governs nutrient absorption in theC. elegansintestine

Role of epithelial sodium channel-related inflammation in human diseases

Structural basis for excitatory neuropeptide signaling

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