Cargando…

The Vasopressin Receptor 2 Mutant R137L Linked to the Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) Signals through an Alternative Pathway that Increases AQP2 Membrane Targeting Independently of S256 Phosphorylation

NSIAD is a rare X-linked condition, caused by activating mutations in the AVPR2 gene coding for the vasopressin V2 receptor (V2R) associated with hyponatremia, despite undetectable plasma vasopressin levels. We have recently provided in vitro evidence that, compared to V2R-wt, expression of activati...

Descripción completa

Detalles Bibliográficos
Autores principales: Ranieri, Marianna, Venneri, Maria, Pellegrino, Tommaso, Centrone, Mariangela, Di Mise, Annarita, Cotecchia, Susanna, Tamma, Grazia, Valenti, Giovanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349359/
https://www.ncbi.nlm.nih.gov/pubmed/32486031
http://dx.doi.org/10.3390/cells9061354
_version_ 1783557045400633344
author Ranieri, Marianna
Venneri, Maria
Pellegrino, Tommaso
Centrone, Mariangela
Di Mise, Annarita
Cotecchia, Susanna
Tamma, Grazia
Valenti, Giovanna
author_facet Ranieri, Marianna
Venneri, Maria
Pellegrino, Tommaso
Centrone, Mariangela
Di Mise, Annarita
Cotecchia, Susanna
Tamma, Grazia
Valenti, Giovanna
author_sort Ranieri, Marianna
collection PubMed
description NSIAD is a rare X-linked condition, caused by activating mutations in the AVPR2 gene coding for the vasopressin V2 receptor (V2R) associated with hyponatremia, despite undetectable plasma vasopressin levels. We have recently provided in vitro evidence that, compared to V2R-wt, expression of activating V2R mutations R137L, R137C and F229V cause a constitutive redistribution of the AQP2 water channel to the plasma membrane, higher basal water permeability and significantly higher basal levels of p256-AQP2 in the F229V mutant but not in R137L or R137C. In this study, V2R mutations were expressed in collecting duct principal cells and the associated signalling was dissected. V2R-R137L and R137C mutants had significantly higher basal pT269-AQP2 levels -independently of S256 and PKA-which were reduced to control by treatment with Rho kinase (ROCK) inhibitor. Interestingly, ROCK activity was found significantly higher in V2R-R137L along with activation of the Gα12/13–Rho–ROCK pathway. Of note, inhibition of ROCK reduced the basal elevated osmotic water permeability to control. To conclude, our data demonstrate for the first time that the gain-of-function mutation of the V2R, R137L causing NSIAD, signals through an alternative PKA-independent pathway that increases AQP2 membrane targeting through ROCK-induced phosphorylation at S/T269 independently of S256 of AQP2.
format Online
Article
Text
id pubmed-7349359
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-73493592020-07-22 The Vasopressin Receptor 2 Mutant R137L Linked to the Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) Signals through an Alternative Pathway that Increases AQP2 Membrane Targeting Independently of S256 Phosphorylation Ranieri, Marianna Venneri, Maria Pellegrino, Tommaso Centrone, Mariangela Di Mise, Annarita Cotecchia, Susanna Tamma, Grazia Valenti, Giovanna Cells Article NSIAD is a rare X-linked condition, caused by activating mutations in the AVPR2 gene coding for the vasopressin V2 receptor (V2R) associated with hyponatremia, despite undetectable plasma vasopressin levels. We have recently provided in vitro evidence that, compared to V2R-wt, expression of activating V2R mutations R137L, R137C and F229V cause a constitutive redistribution of the AQP2 water channel to the plasma membrane, higher basal water permeability and significantly higher basal levels of p256-AQP2 in the F229V mutant but not in R137L or R137C. In this study, V2R mutations were expressed in collecting duct principal cells and the associated signalling was dissected. V2R-R137L and R137C mutants had significantly higher basal pT269-AQP2 levels -independently of S256 and PKA-which were reduced to control by treatment with Rho kinase (ROCK) inhibitor. Interestingly, ROCK activity was found significantly higher in V2R-R137L along with activation of the Gα12/13–Rho–ROCK pathway. Of note, inhibition of ROCK reduced the basal elevated osmotic water permeability to control. To conclude, our data demonstrate for the first time that the gain-of-function mutation of the V2R, R137L causing NSIAD, signals through an alternative PKA-independent pathway that increases AQP2 membrane targeting through ROCK-induced phosphorylation at S/T269 independently of S256 of AQP2. MDPI 2020-05-29 /pmc/articles/PMC7349359/ /pubmed/32486031 http://dx.doi.org/10.3390/cells9061354 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ranieri, Marianna
Venneri, Maria
Pellegrino, Tommaso
Centrone, Mariangela
Di Mise, Annarita
Cotecchia, Susanna
Tamma, Grazia
Valenti, Giovanna
The Vasopressin Receptor 2 Mutant R137L Linked to the Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) Signals through an Alternative Pathway that Increases AQP2 Membrane Targeting Independently of S256 Phosphorylation
title The Vasopressin Receptor 2 Mutant R137L Linked to the Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) Signals through an Alternative Pathway that Increases AQP2 Membrane Targeting Independently of S256 Phosphorylation
title_full The Vasopressin Receptor 2 Mutant R137L Linked to the Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) Signals through an Alternative Pathway that Increases AQP2 Membrane Targeting Independently of S256 Phosphorylation
title_fullStr The Vasopressin Receptor 2 Mutant R137L Linked to the Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) Signals through an Alternative Pathway that Increases AQP2 Membrane Targeting Independently of S256 Phosphorylation
title_full_unstemmed The Vasopressin Receptor 2 Mutant R137L Linked to the Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) Signals through an Alternative Pathway that Increases AQP2 Membrane Targeting Independently of S256 Phosphorylation
title_short The Vasopressin Receptor 2 Mutant R137L Linked to the Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) Signals through an Alternative Pathway that Increases AQP2 Membrane Targeting Independently of S256 Phosphorylation
title_sort vasopressin receptor 2 mutant r137l linked to the nephrogenic syndrome of inappropriate antidiuresis (nsiad) signals through an alternative pathway that increases aqp2 membrane targeting independently of s256 phosphorylation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349359/
https://www.ncbi.nlm.nih.gov/pubmed/32486031
http://dx.doi.org/10.3390/cells9061354
work_keys_str_mv AT ranierimarianna thevasopressinreceptor2mutantr137llinkedtothenephrogenicsyndromeofinappropriateantidiuresisnsiadsignalsthroughanalternativepathwaythatincreasesaqp2membranetargetingindependentlyofs256phosphorylation
AT vennerimaria thevasopressinreceptor2mutantr137llinkedtothenephrogenicsyndromeofinappropriateantidiuresisnsiadsignalsthroughanalternativepathwaythatincreasesaqp2membranetargetingindependentlyofs256phosphorylation
AT pellegrinotommaso thevasopressinreceptor2mutantr137llinkedtothenephrogenicsyndromeofinappropriateantidiuresisnsiadsignalsthroughanalternativepathwaythatincreasesaqp2membranetargetingindependentlyofs256phosphorylation
AT centronemariangela thevasopressinreceptor2mutantr137llinkedtothenephrogenicsyndromeofinappropriateantidiuresisnsiadsignalsthroughanalternativepathwaythatincreasesaqp2membranetargetingindependentlyofs256phosphorylation
AT dimiseannarita thevasopressinreceptor2mutantr137llinkedtothenephrogenicsyndromeofinappropriateantidiuresisnsiadsignalsthroughanalternativepathwaythatincreasesaqp2membranetargetingindependentlyofs256phosphorylation
AT cotecchiasusanna thevasopressinreceptor2mutantr137llinkedtothenephrogenicsyndromeofinappropriateantidiuresisnsiadsignalsthroughanalternativepathwaythatincreasesaqp2membranetargetingindependentlyofs256phosphorylation
AT tammagrazia thevasopressinreceptor2mutantr137llinkedtothenephrogenicsyndromeofinappropriateantidiuresisnsiadsignalsthroughanalternativepathwaythatincreasesaqp2membranetargetingindependentlyofs256phosphorylation
AT valentigiovanna thevasopressinreceptor2mutantr137llinkedtothenephrogenicsyndromeofinappropriateantidiuresisnsiadsignalsthroughanalternativepathwaythatincreasesaqp2membranetargetingindependentlyofs256phosphorylation
AT ranierimarianna vasopressinreceptor2mutantr137llinkedtothenephrogenicsyndromeofinappropriateantidiuresisnsiadsignalsthroughanalternativepathwaythatincreasesaqp2membranetargetingindependentlyofs256phosphorylation
AT vennerimaria vasopressinreceptor2mutantr137llinkedtothenephrogenicsyndromeofinappropriateantidiuresisnsiadsignalsthroughanalternativepathwaythatincreasesaqp2membranetargetingindependentlyofs256phosphorylation
AT pellegrinotommaso vasopressinreceptor2mutantr137llinkedtothenephrogenicsyndromeofinappropriateantidiuresisnsiadsignalsthroughanalternativepathwaythatincreasesaqp2membranetargetingindependentlyofs256phosphorylation
AT centronemariangela vasopressinreceptor2mutantr137llinkedtothenephrogenicsyndromeofinappropriateantidiuresisnsiadsignalsthroughanalternativepathwaythatincreasesaqp2membranetargetingindependentlyofs256phosphorylation
AT dimiseannarita vasopressinreceptor2mutantr137llinkedtothenephrogenicsyndromeofinappropriateantidiuresisnsiadsignalsthroughanalternativepathwaythatincreasesaqp2membranetargetingindependentlyofs256phosphorylation
AT cotecchiasusanna vasopressinreceptor2mutantr137llinkedtothenephrogenicsyndromeofinappropriateantidiuresisnsiadsignalsthroughanalternativepathwaythatincreasesaqp2membranetargetingindependentlyofs256phosphorylation
AT tammagrazia vasopressinreceptor2mutantr137llinkedtothenephrogenicsyndromeofinappropriateantidiuresisnsiadsignalsthroughanalternativepathwaythatincreasesaqp2membranetargetingindependentlyofs256phosphorylation
AT valentigiovanna vasopressinreceptor2mutantr137llinkedtothenephrogenicsyndromeofinappropriateantidiuresisnsiadsignalsthroughanalternativepathwaythatincreasesaqp2membranetargetingindependentlyofs256phosphorylation