The Na+:Cl– Cotransporter Is Activated and Phosphorylated at the Amino-terminal Domain upon Intracellular Chloride Depletion

Pacheco‐Alvarez, Diana; Cristóbal, P. San; Meade, Patricia; Moreno, Erika; Vázquez, Norma; Muñoz, Eva; Diaz, A Cazares; Juárez, María Eugenia; Gíménez, Ignacio; Gamba, Gerardo

doi:10.1074/jbc.m603773200

Cited by 216 publications

(288 citation statements)

References 52 publications

(85 reference statements)

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“…The translocation of NCC to the plasma membrane or stability of NCC did not seem to be affected by S811 [47]. This is in agreement with a study demonstrating that NCC 3 surface abundance is not affected by the phosphorylation status of T60 [35,36,48]. Based on these insights, NCC SV might have a crucial role in renal salt handling.…”

Section: Functional Role Of Nccsvsupporting

confidence: 82%

“…Generally, phosphorylation is considered one of the most important posttranslational modification processes in the regulation of NCC activity. The N-terminal domain of NCC contains several key phosphorylation sites including threonines 48, 55 and 60 (T48, T55, T60) and serines 73, 91 and 124 (S73, S90, S124) [36–38]. Phosphorylation at these sites is important for plasma membrane abundance and influence NCC activity [29,39].…”

Section: Functional Role Of Nccsvmentioning

confidence: 99%

“…Although it is acknowledged that T60 and T55 are phosphorylated via activation of the WNK-SPAK signaling pathway [36,49], the kinase involved in S811 phosphorylation remains to be clarified (Figure 2). Prediction software (pkaPS) from the IMP-IMBA Bioinformatics group [50] suggested that the recognition motif around S811 of NCC SV shows high similarity to a protein kinase A (PKA) consensus site.…”

Section: Functional Role Of Nccsvmentioning

confidence: 99%

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Role of the alternative splice variant of NCC in blood pressure control

2018

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The renal thiazide-sensitive sodium-chloride cotransporter (NCC), located in the distal convoluted tubule (DCT) of the kidney, plays an important role in blood pressure regulation by fine-tuning sodium excretion. The human SLC12A3 gene, encoding NCC, gives rise to three isoforms, of which only the third isoform (NCC3) has been extensively investigated so far. However, recent studies unraveled the importance of the isoforms 1 and 2, collectively referred to as NCC splice variant (NCCSV), in several (patho)physiological conditions. In the human kidney, NCCSV localizes to the apical membrane of the DCT and could constitute a functional route for renal sodium-chloride reabsorption. Analysis of urinary extracellular vesicles (uEVs), a non-invasive method for measuring renal responses, demonstrated that NCCSV abundance changes in response to acute water loading and correlates with patients’ thiazide responsiveness. Furthermore, a novel phosphorylation site at serine 811 (S811), exclusively present in NCCSV, was shown to play an instrumental role in NCCSV as well as NCC3 function. This review aims to summarize these new insights of NCCSV function in humans that broadens the understanding on NCC regulation in blood pressure control.

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Section: Functional Role Of Nccsvsupporting

confidence: 82%

Section: Functional Role Of Nccsvmentioning

confidence: 99%

Section: Functional Role Of Nccsvmentioning

confidence: 99%

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Role of the alternative splice variant of NCC in blood pressure control

2018

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“…21 The images were obtained with an Olympus FV1000 Confocal Laser Scanning Microscope (Olympus, Center Valley, PA, USA), emitting at 488 nm with a 30-mW argon laser. The plasma membrane fluorescence was quantified for all images by measuring pixel intensity using ImageJ (Image Processing Program, NIH, USA) software.…”

Section: Immunofluorescence Microscopymentioning

confidence: 99%

Novel NCC mutants and functional analysis in a new cohort of patients with Gitelman syndrome

et al. 2011

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Gitelman syndrome (GS) is an autosomal recessive disorder characterized by hypokalemic metabolic alkalosis in conjunction with significant hypomagnesemia and hypocalciuria. The GS phenotype is caused by mutations in the solute carrier family 12, member 3 (SLC12A3) gene that encodes the thiazide-sensitive NaCl cotransporter (NCC). We analyzed DNA samples of 163 patients with a clinical suspicion of GS by direct sequencing of all 26 exons of the SLC12A3 gene. In total, 114 different mutations were identified, 31 of which have not been reported before. These novel variants include 3 deletions, 18 missense, 6 splice site and 4 nonsense mutations. We selected seven missense mutations to investigate their effect on NCC activity and plasma membrane localization by using the Xenopus laevis oocyte expression system. The Thr392Ile mutant did not display transport activity (probably class 2 mutation), while the Asn442Ser and Gln1030Arg NCC mutants showed decreased plasma membrane localization and consequently function, likely due to impaired trafficking (class 3 mutation). Even though the NaCl uptake was hampered for NCC mutants Glu121Asp, Pro751Leu, Ser475Cys and Tyr489His, the transporters reached the plasma membrane (class 4 mutation), suggesting an effect on NCC regulation or ion affinity. The present study shows the identification of 38 novel mutations in the SLC12A3 gene and provides insight into the mechanisms that regulate NCC.

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“…This active state could be what PHAII mutations in WNK4 mimic (12). The observation that NCC activity is associated with its phosphorylation of N-terminal threonines 53 and 58 and serine 71 (13) opened the possibility to assess NCC "activity" in vivo indirectly using specific phospho antibodies (14).…”

mentioning

confidence: 99%

Activation of the renal Na ⁺ :Cl ⁻ cotransporter by angiotensin II is a WNK4-dependent process

Castañeda‐Bueno

Cervantes-Pérez²,

Vázquez³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Pseudohypoaldosteronism type II is a salt-sensitive form of hypertension with hyperkalemia in humans caused by mutations in the with-no-lysine kinase 4 (WNK4). Several studies have shown that WNK4 modulates the activity of the renal Na + Cl − cotransporter, NCC. Because the renal consequences of WNK4 carrying pseudoaldosteronism type II mutations resemble the response to intravascular volume depletion (promotion of salt reabsorption without K + secretion), a condition that is associated with high angiotensin II (AngII) levels, it has been proposed that AngII signaling might affect WNK4 modulation of the NCC. In Xenopus laevis oocytes, WNK4 is required for modulation of NCC activity by AngII. To demonstrate that WNK4 is required in the AngII-mediated regulation of NCC in vivo, we used a total WNK4-knockout mouse strain (WNK4 −/− ). WNK4 mRNA and protein expression were absent in WNK4 −/− mice, which exhibited a mild Gitelman-like syndrome, with normal blood pressure, increased plasma renin activity, and reduced NCC expression and phosphorylation at T-58. Immunohistochemistry revealed normal morphology of the distal convoluted tubule with reduced NCC expression. Low-salt diet or infusion of AngII for 4 d induced phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and of NCC at S-383 and T-58, respectively, in WNK4 +/+ but not WNK4 −/− mice. Thus, the absence of WNK4 in vivo precludes NCC and SPAK phosphorylation promoted by a low-salt diet or AngII infusion, suggesting that AngII action on the NCC occurs via a WNK4-SPAK-dependent signaling pathway. Additionally, stimulation of aldosterone secretion by AngII, but not by a high-K + diet, was impaired in WNK4 −/− mice. distal tubule | diuretics | thiazide | renin-angiotensin-aldosterone system

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The Na+:Cl– Cotransporter Is Activated and Phosphorylated at the Amino-terminal Domain upon Intracellular Chloride Depletion

Cited by 216 publications

References 52 publications

Role of the alternative splice variant of NCC in blood pressure control

Role of the alternative splice variant of NCC in blood pressure control

Novel NCC mutants and functional analysis in a new cohort of patients with Gitelman syndrome

Activation of the renal Na ⁺ :Cl ⁻ cotransporter by angiotensin II is a WNK4-dependent process

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The Na+:Cl– Cotransporter Is Activated and Phosphorylated at the Amino-terminal Domain upon Intracellular Chloride Depletion

Cited by 216 publications

References 52 publications

Role of the alternative splice variant of NCC in blood pressure control

Role of the alternative splice variant of NCC in blood pressure control

Novel NCC mutants and functional analysis in a new cohort of patients with Gitelman syndrome

Activation of the renal Na + :Cl − cotransporter by angiotensin II is a WNK4-dependent process

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Activation of the renal Na ⁺ :Cl ⁻ cotransporter by angiotensin II is a WNK4-dependent process