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The serine-threonine protein phosphatases that regulate the thiazide-sensitive NaCl cotransporter
The activity of the Na(+)-Cl(-) cotransporter (NCC) in the distal convoluted tubule (DCT) is finely tuned by phosphorylation networks involving serine/threonine kinases and phosphatases. While much attention has been paid to the With-No-lysine (K) kinase (WNK)- STE20-related Proline Alanine rich Kin...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9974657/ https://www.ncbi.nlm.nih.gov/pubmed/36875042 http://dx.doi.org/10.3389/fphys.2023.1100522 |
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author | Carbajal-Contreras, Héctor Gamba, Gerardo Castañeda-Bueno, María |
author_facet | Carbajal-Contreras, Héctor Gamba, Gerardo Castañeda-Bueno, María |
author_sort | Carbajal-Contreras, Héctor |
collection | PubMed |
description | The activity of the Na(+)-Cl(-) cotransporter (NCC) in the distal convoluted tubule (DCT) is finely tuned by phosphorylation networks involving serine/threonine kinases and phosphatases. While much attention has been paid to the With-No-lysine (K) kinase (WNK)- STE20-related Proline Alanine rich Kinase (SPAK)/Oxidative Stress Responsive kinase 1 (OSR1) signaling pathway, there remain many unanswered questions regarding phosphatase-mediated modulation of NCC and its interactors. The phosphatases shown to regulate NCC’s activity, directly or indirectly, are protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A), calcineurin (CN), and protein phosphatase 4 (PP4). PP1 has been suggested to directly dephosphorylate WNK4, SPAK, and NCC. This phosphatase increases its abundance and activity when extracellular K(+) is increased, which leads to distinct inhibitory mechanisms towards NCC. Inhibitor-1 (I1), oppositely, inhibits PP1 when phosphorylated by protein kinase A (PKA). CN inhibitors, like tacrolimus and cyclosporin A, increase NCC phosphorylation, giving an explanation to the Familial Hyperkalemic Hypertension-like syndrome that affects some patients treated with these drugs. CN inhibitors can prevent high K(+)-induced dephosphorylation of NCC. CN can also dephosphorylate and activate Kelch-like protein 3 (KLHL3), thus decreasing WNK abundance. PP2A and PP4 have been shown in in vitro models to regulate NCC or its upstream activators. However, no studies in native kidneys or tubules have been performed to test their physiological role in NCC regulation. This review focuses on these dephosphorylation mediators and the transduction mechanisms possibly involved in physiological states that require of the modulation of the dephosphorylation rate of NCC. |
format | Online Article Text |
id | pubmed-9974657 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-99746572023-03-02 The serine-threonine protein phosphatases that regulate the thiazide-sensitive NaCl cotransporter Carbajal-Contreras, Héctor Gamba, Gerardo Castañeda-Bueno, María Front Physiol Physiology The activity of the Na(+)-Cl(-) cotransporter (NCC) in the distal convoluted tubule (DCT) is finely tuned by phosphorylation networks involving serine/threonine kinases and phosphatases. While much attention has been paid to the With-No-lysine (K) kinase (WNK)- STE20-related Proline Alanine rich Kinase (SPAK)/Oxidative Stress Responsive kinase 1 (OSR1) signaling pathway, there remain many unanswered questions regarding phosphatase-mediated modulation of NCC and its interactors. The phosphatases shown to regulate NCC’s activity, directly or indirectly, are protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A), calcineurin (CN), and protein phosphatase 4 (PP4). PP1 has been suggested to directly dephosphorylate WNK4, SPAK, and NCC. This phosphatase increases its abundance and activity when extracellular K(+) is increased, which leads to distinct inhibitory mechanisms towards NCC. Inhibitor-1 (I1), oppositely, inhibits PP1 when phosphorylated by protein kinase A (PKA). CN inhibitors, like tacrolimus and cyclosporin A, increase NCC phosphorylation, giving an explanation to the Familial Hyperkalemic Hypertension-like syndrome that affects some patients treated with these drugs. CN inhibitors can prevent high K(+)-induced dephosphorylation of NCC. CN can also dephosphorylate and activate Kelch-like protein 3 (KLHL3), thus decreasing WNK abundance. PP2A and PP4 have been shown in in vitro models to regulate NCC or its upstream activators. However, no studies in native kidneys or tubules have been performed to test their physiological role in NCC regulation. This review focuses on these dephosphorylation mediators and the transduction mechanisms possibly involved in physiological states that require of the modulation of the dephosphorylation rate of NCC. Frontiers Media S.A. 2023-02-15 /pmc/articles/PMC9974657/ /pubmed/36875042 http://dx.doi.org/10.3389/fphys.2023.1100522 Text en Copyright © 2023 Carbajal-Contreras, Gamba and Castañeda-Bueno. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Physiology Carbajal-Contreras, Héctor Gamba, Gerardo Castañeda-Bueno, María The serine-threonine protein phosphatases that regulate the thiazide-sensitive NaCl cotransporter |
title | The serine-threonine protein phosphatases that regulate the thiazide-sensitive NaCl cotransporter |
title_full | The serine-threonine protein phosphatases that regulate the thiazide-sensitive NaCl cotransporter |
title_fullStr | The serine-threonine protein phosphatases that regulate the thiazide-sensitive NaCl cotransporter |
title_full_unstemmed | The serine-threonine protein phosphatases that regulate the thiazide-sensitive NaCl cotransporter |
title_short | The serine-threonine protein phosphatases that regulate the thiazide-sensitive NaCl cotransporter |
title_sort | serine-threonine protein phosphatases that regulate the thiazide-sensitive nacl cotransporter |
topic | Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9974657/ https://www.ncbi.nlm.nih.gov/pubmed/36875042 http://dx.doi.org/10.3389/fphys.2023.1100522 |
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