Some Assembly Required: Putting the Epithelial Sodium Channel Together

Butterworth, Michael; Weisz, Ora A.; Johnson, John P.

doi:10.1074/jbc.r800044200

Cited by 21 publications

(21 citation statements)

References 57 publications

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“…Multiple mechanisms are known to participate in the regulation of ENaC activity, including limited proteolysis (30,43,44), hormonal mediated effects on translocation and membrane assembly (9,13,45,46), a serum and glucocorticoid-regulated kinase (SGK-1)-mediated phosphorylation of Nedd4 -2 leading to reduced ubiquitination, retrieval and degradation (17,18,47,48), as well as negative and positive hormonal effects mediated by protein kinases including ERK1/2, protein kinases A and C, and phosphatidylinositol 3-kinase, among others (14 -19, 47-49). Added to the above is the present identification of the Cyp2c44 epoxygenase and its EET metabolites as a new class of in vivo regulators of ENaC activity.…”

Section: Discussionmentioning

confidence: 99%

The Cyp2c44 Epoxygenase Regulates Epithelial Sodium Channel Activity and the Blood Pressure Responses to Increased Dietary Salt

Capdevila

Pidkovka

Mei

et al. 2014

Journal of Biological Chemistry

108

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Background: Epoxyeicosatrienoic acids (EETs) regulate sodium excretion in the distal nephron. Results: Lack of a Cyp2c44 epoxygenase blunts the ERK1/2-mediated inhibition of ENaC and causes salt-sensitive hypertension. Conclusion: Cyp2c44 is the epoxygenase responsible for the synthesis of natriuretic EETs during increased salt intake. Significance: Roles for the human CYP2C8 and CYP2C9 epoxygenases as antihypertensive therapeutic targets are proposed.

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Section: Discussionmentioning

confidence: 99%

The Cyp2c44 Epoxygenase Regulates Epithelial Sodium Channel Activity and the Blood Pressure Responses to Increased Dietary Salt

Capdevila

Pidkovka

Mei

et al. 2014

Journal of Biological Chemistry

108

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“…As with many ion channels, ENaC is regulated by factors that alter gating, expression, subunit assembly, membrane translocation, and/or residence time. Multiple mechanisms can alter one or more of these factors, including proteolysis (8,(35)(36)(37)(38); hormonal effects on translocation and membrane assembly (6,7,36,41,43); changes in ubiquitination, retrieval, and degradation (37,38,44,45); and protein kinase-mediated negative or positive effects (8, 10, 11-15, 44, 46). The earlier identification of 11,12-EET and 14,15-EET as ENaC inhibitors (17)(18)(19) and the present characterization of 14,15-EET as an inhibitor of amiloride-sensitive J Naϩ in M1 cells can be added to this list.…”

Section: Discussionmentioning

confidence: 99%

Epoxyeicosatrienoic Acids (EETs) Regulate Epithelial Sodium Channel Activity by Extracellular Signal-regulated Kinase 1/2 (ERK1/2)-mediated Phosphorylation

Pidkovka

Rao

Mei

et al. 2013

Journal of Biological Chemistry

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Background:The epoxygenase metabolites (EETs) inhibit ENaC by unknown mechanisms. Results: 14,15-EET stimulates an ERK1/2-catalyzed inhibitory phosphorylation of the ENaC ␤ and ␥ subunits. Conclusion: A CYP2C44 epoxygenase/ERK1/2-mediated pathway for ENaC regulation has been characterized. Significance: Roles for human CYP2C8 and CYP2C9 as antihypertensive epoxygenases and for the EETs as antihypertensive drug targets are proposed.

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“…The ENaC is a heterotrimer formed by the three subunits, a, b, and g (7,8,9,10). All subunits are thought to have a comparable three-dimensional structure containing two transmembrane segments, intracellular N-and C-termini, and a large extracellular loop (11).…”

Section: Introductionmentioning

confidence: 99%

Five novel mutations in the SCNN1A gene causing autosomal recessive pseudohypoaldosteronism type 1

Welzel

Akın

Büscher³

et al. 2013

European Journal of Endocrinology

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Background: Pseudohypoaldosteronism type 1 (PHA1) is a monogenic disease caused by mutations in the genes encoding the human mineralocorticoid receptor (MR) or the a (SCNN1A), b (SCNN1B) or g (SCNN1G) subunit of the epithelial Na C channel (ENaC). While autosomal dominant mutation of the MR cause renal PHA1, autosomal recessive mutations of the ENaC lead to systemic PHA1. In the latter, affected children suffer from neonatal onset of multi-organ salt loss and often exhibit cystic fibrosis-like pulmonary symptoms. Objective: We searched for underlying mutations in seven unrelated children with systemic PHA1, all offsprings of healthy consanguineous parents. Methods and results: Amplification of the SCNN1A gene and sequencing of all 13 coding exons unraveled mutations in all of our patients. We found five novel homozygous mutations (c.587_588insC in two patients, c.1342_1343insTACA, c.742delG, c.189COA, c.1361-2AOG) and one known mutation (c.1474COT) leading to truncation of the aENaC protein. All parents were asymptomatic heterozygous carriers of the respective mutations, confirming the autosomal recessive mode of inheritance. Five out of seven patients exhibited pulmonary symptoms in the neonatal period. Conclusion: The a subunit is essential for ENaC function and mutations truncating the pore-forming part of the protein leading to systemic PHA1. Based on current knowledge, the pulmonary phenotype cannot be satisfactorily predicted.

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Some Assembly Required: Putting the Epithelial Sodium Channel Together

Cited by 21 publications

References 57 publications

The Cyp2c44 Epoxygenase Regulates Epithelial Sodium Channel Activity and the Blood Pressure Responses to Increased Dietary Salt

The Cyp2c44 Epoxygenase Regulates Epithelial Sodium Channel Activity and the Blood Pressure Responses to Increased Dietary Salt

Epoxyeicosatrienoic Acids (EETs) Regulate Epithelial Sodium Channel Activity by Extracellular Signal-regulated Kinase 1/2 (ERK1/2)-mediated Phosphorylation

Five novel mutations in the SCNN1A gene causing autosomal recessive pseudohypoaldosteronism type 1

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