V. The epithelial sodium channel and its implication in human diseases

1999 ◽  
Vol 276 (3) ◽  
pp. G567-G571 ◽  
Author(s):  
Edith Hummler ◽  
Jean-Daniel Horisberger
Keyword(s):  
Distal Colon ◽  
Loss Of Function ◽  
Newborn Mice ◽  
Α Subunit ◽  
Salt Wasting ◽  
Lung Fluid ◽  
Wasting Syndrome ◽  
Rate Limiting Step ◽  
Γ Subunit ◽  
Rate Limiting

The epithelial Na+ channel (ENaC) controls the rate-limiting step in the process of transepithelial Na+ reabsorption in the distal nephron, the distal colon, and the airways. Hereditary salt-losing syndromes have been ascribed to loss of function mutations in the α-, β-, or γ-ENaC subunit genes, whereas gain of function mutations (located in the COOH terminus of the β- or γ-subunit) result in hypertension due to Na+ retention (Liddle’s syndrome). In mice, gene-targeting experiments have shown that, in addition to the kidney salt-wasting phenotype, ENaC was essential for lung fluid clearance in newborn mice. Disruption of the α-subunit resulted in a complete abolition of ENaC-mediated Na+ transport, whereas knockout of the β- or γ-subunit had only minor effects on fluid clearance in lung. Disruption of each of the three subunits resulted in a salt-wasting syndrome similar to that observed in humans.

scholarly journals Maturation of the Na,K-ATPase in the Endoplasmic Reticulum in Health and Disease

2021 ◽  
Author(s):  
Vitalii Kryvenko ◽  
Olga Vagin ◽  
Laura A. Dada ◽  
Jacob I. Sznajder ◽  
István Vadász
Keyword(s):  
Endoplasmic Reticulum ◽  
Intracellular Signaling ◽  
Loss Of Function ◽  
Α Subunit ◽  
Rate Limiting Step ◽  
Atpase Subunits ◽  
A Cell ◽  
Health And Disease ◽  
And Function ◽  
Rate Limiting

Abstract The Na,K-ATPase establishes the electrochemical gradient of cells by driving an active exchange of Na+ and K+ ions while consuming ATP. The minimal functional transporter consists of a catalytic α-subunit and a β-subunit with chaperon activity. The Na,K-ATPase also functions as a cell adhesion molecule and participates in various intracellular signaling pathways. The maturation and trafficking of the Na,K-ATPase include co- and post-translational processing of the enzyme in the endoplasmic reticulum (ER) and the Golgi apparatus and subsequent delivery to the plasma membrane (PM). The ER folding of the enzyme is considered as the rate-limiting step in the membrane delivery of the protein. It has been demonstrated that only assembled Na,K-ATPase α:β-complexes may exit the organelle, whereas unassembled, misfolded or unfolded subunits are retained in the ER and are subsequently degraded. Loss of function of the Na,K-ATPase has been associated with lung, heart, kidney and neurological disorders. Recently, it has been shown that ER dysfunction, in particular, alterations in the homeostasis of the organelle, as well as impaired ER-resident chaperone activity may impede folding of Na,K-ATPase subunits, thus decreasing the abundance and function of the enzyme at the PM. Here, we summarize our current understanding on maturation and subsequent processing of the Na,K-ATPase in the ER under physiological and pathophysiological conditions. Graphic Abstract

Differential Regulation of the Epithelial Sodium Channel (ENaC) in Rat Kidney, Lung and Distal Colon in Response to Aldosterone.

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 724-724
Author(s):  
Shyama M E Masilamani ◽  
Gheun-Ho Kim ◽  
Mark A Knepper
Keyword(s):  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
Distal Colon ◽  
Β Subunit ◽  
Dietary Salt ◽  
Α Subunit ◽  
Salt Restriction ◽  
Γ Subunit ◽  
Dietary Salt Restriction ◽  
Epithelial Sodium Channel Enac

P170 The mineralocorticoid hormone, aldosterone increases renal tubule Na absorption via increases in the protein abundances of the α-subunit of the epithelial sodium channel (ENaC) and the 70 kDa form of the γ- subunit of ENaC (JCI 104:R19-R23). This study assesses the affect of dietary salt restriction on the regulation of the epithelial sodium channel (ENaC) in the lung and distal colon, in addition to kidney, using semiquantitative immunoblotting. Rats were placed initially on either a control Na intake (0.02 meq/day), or a low Na intake (0.2 meq/day) for 10 days. The low salt treated rats demonstrated an increase in plasma aldosterone levels at day 10 (control = 0.78 + 0.32 nM; Na restricted = 3.50 + 1.30 nM). In kidney homogenates, there were marked increases in the band density of the α-subunit of ENaC (286 % of control) and the 70 kDa form of γ-subunit of ENaC (262 % of control), but no increase in the abundance of the β-subunit of ENaC. In lung homogenates, there was no significant change in the band densities of the α, β, or γ subunits of ENaC. In distal colon, there was an increase in the band density of the β-subunit of ENaC (311 % of control) and an increase in both the 85 kDa (2355% of control) and 70 kDa (843 % of control) form of the γ subunit of ENaC in response to dietary Na restriction. However, there was no significant difference in the band density of the α-subunit of ENaC. These findings demonstrate tissue specific regulation of the three subunits of ENaC in response to dietary salt restriction.

scholarly journals Role of the glutamate 185 residue in proton translocation mediated by the proton-coupled folate transporter SLC46A1

2009 ◽  
Vol 297 (1) ◽  
pp. C66-C74 ◽  
Author(s):  
Ersin Selcuk Unal ◽  
Rongbao Zhao ◽  
I. David Goldman
Keyword(s):  
Proton Translocation ◽  
Amino Acid Residues ◽  
Loss Of Function ◽  
Wild Type ◽  
Folate Transport ◽  
Rate Limiting Step ◽  
Proximal Small Intestine ◽  
Transport Cycle ◽  
Rate Limiting

The proton-coupled folate transporter (PCFT) SLC46A1 mediates uphill folate transport into enterocytes in proximal small intestine coupled to the inwardly directed proton gradient. Hereditary folate malabsorption is due to loss-of-function mutations in the PCFT gene. This study addresses the functional role of conserved charged amino acid residues within PCFT transmembrane domains with a detailed analysis of the PCFT E185 residue. D156A-, E185A-, E232A-, R148A-, and R376A-PCFT mutants lost function at pH 5.5, as assessed by transient transfection in folate transport-deficient HeLa cells. At pH 7.4, function was preserved only for E185A-PCFT. Loss of function for E185A-PCFT at pH 5.5 was due to an eightfold decrease in the [3H]methotrexate (MTX) influx Vmax; the MTX influx Ktwas identical to that of wild-type (WT)-PCFT (1.5 μM). Consistent with the intrinsic functionality of E185A-PCFT, [3H]MTX influx at pH 5.5 or 7.4 was trans-stimulated in cells preloaded with nonlabeled MTX or 5-formyltetrahydrofolate. Replacement of E185 with Leu, Cys, His, or Gln resulted in a phenotype similar to E185A-PCFT. However, there was greater preservation of activity (∼38% of WT) for the similarly charged E185D-PCFT at pH 5.5. All E185 substitution mutants were biotin accessible at the plasma membrane at a level comparable to WT-PCFT. These observations suggest that the E185 residue plays an important role in the coupled flows of protons and folate mediated by PCFT. Coupling appears to have a profound effect on the maximum rate of transport, consistent with augmentation of a rate-limiting step in the PCFT transport cycle.

scholarly journals CTP-Synthase 2 from Arabidopsis thaliana is required for complete embryo development

2021 ◽  
Author(s):  
Daniel Hickl ◽  
David Scheuring ◽  
Torsten Möhlmann
Keyword(s):  
Embryo Development ◽  
Promoter Region ◽  
Loss Of Function ◽  
Auxin Response ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Ctp Synthase ◽  
Dna Insertion ◽  
Columella Cells ◽  
Rate Limiting

Pyrimidine de novo synthesis is an essential pathway in all organisms. The final and rate limiting step in the synthesis of the nucleotide CTP is catalyzed by CTP-Synthase (CTPS) and Arabidopsis harbors five isoforms. Single knockouts of each of these do not show apparent phenotypical alterations with the exception of CTPS2. T-DNA insertion lines for this isoform were unable to produce homozygous offspring. Here we show that CTPS2 exhibits a distinct expression pattern throughout embryo development and loss of function mutants were embryo lethal, as siliques from +/ctps2 plants contained nearly 25 % aborted seeds. This phenotype was rescued by complementation with CTPS2 under control of its endogenous promoter. Reporter lines revealed CTPS2 expression only in the tip of columella cells in embryos of the heart and later stages. Furthermore CTPS2 expression in roots, most pronounced in the columella cells, shoots and vasculature tissue of young seedlings was observed. Filial generations of +/ctps2 plants did not germinate properly, even under external cytidine supply. During embryo development CTPS2 expression was similar to the well known auxin reporter DR5. Indeed, the cloned promoter region we used in this study possesses a repeat of an auxin response element. Thus, we conclude that CTPS2 is essential for CTP supply in the developing embryo and a knockout of CTPS2 is embryo lethal.

Ornithine Decarboxylase Activity in Cultured Endothelial Cells Stimulated by Serum, Thrombin and Serotonin

1978 ◽  
Vol 39 (02) ◽  
pp. 496-503 ◽  
Author(s):  
P A D’Amore ◽  
H B Hechtman ◽  
D Shepro
Keyword(s):  
Endothelial Cells ◽  
Ornithine Decarboxylase ◽  
Decarboxylase Activity ◽  
Aortic Endothelial Cells ◽  
Ornithine Decarboxylase Activity ◽  
Rate Limiting Step ◽  
Bovine Aortic Endothelial Cells ◽  
Limiting Step ◽  
Rate Limiting ◽  
Serum Serotonin

SummaryOrnithine decarboxylase (ODC) activity, the rate-limiting step in the synthesis of polyamines, can be demonstrated in cultured, bovine, aortic endothelial cells (EC). Serum, serotonin and thrombin produce a rise in ODC activity. The serotonin-induced ODC activity is significantly blocked by imipramine (10-5 M) or Lilly 11 0140 (10-6M). Preincubation of EC with these blockers together almost completely depresses the 5-HT-stimulated ODC activity. These observations suggest a manner by which platelets may maintain EC structural and metabolic soundness.

Severe salt wasting syndrome due to spontaneous epidural haematoma

2019 ◽  
Author(s):  
Aoife Garrrahy ◽  
Osamah Hakami ◽  
Iona Galloway ◽  
Stephen McNally ◽  
Rory Dwyer ◽  
...  
Keyword(s):  
Epidural Haematoma ◽  
Salt Wasting ◽  
Wasting Syndrome ◽  
Salt Wasting Syndrome

Dynamics of hepatic and peripheral insulin effects suggest common rate-limiting step in vivo

Diabetes ◽  
1993 ◽  
Vol 42 (2) ◽  
pp. 296-306 ◽  
Author(s):  
D. C. Bradley ◽  
R. A. Poulin ◽  
R. N. Bergman
Keyword(s):  
Rate Limiting Step ◽  
Limiting Step ◽  
Rate Limiting
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