The Constitutively Active V2 Receptor Mutants Conferring NSIAD Are Weakly Sensitive to Agonist and Antagonist Regulation
| Autor: | Christiane Mendre, Mohammed Akli Ayoub, Anne-Laure Adra-Delenne, Ghislaine Geelen, Thierry Durroux, Bruno Ranchin, Denis Morin, Bernard Mouillac, J. Tenenbaum, Sanja Perkovska, Giamperro Bricca |
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| Rok vydání: | 2009 |
| Předmět: |
Agonist
Receptors Vasopressin Arrestins Vasopressins medicine.drug_class lcsh:Medicine Biology Partial agonist Cell Biology/Cell Signaling Inappropriate ADH Syndrome Arginine vasopressin receptor 2 Chlorocebus aethiops Fluorescence Resonance Energy Transfer medicine Animals Humans Inverse agonist lcsh:Science Receptor beta-Arrestins G protein-coupled receptor Pharmacology Multidisciplinary Beta-Arrestins lcsh:R Antidiuretic Hormone Receptor Antagonists Molecular biology Cell biology Nephrology COS Cells lcsh:Q Mutant Proteins Research Article Protein Binding |
| Zdroj: | PLoS ONE PLoS ONE, Vol 4, Iss 12, p e8383 (2009) |
| ISSN: | 1932-6203 |
| Popis: | Patients having the nephrogenic syndrome of inappropriate antidiuresis present either the R137C or R137L V2 mutated receptor. While the clinical features have been characterized, the molecular mechanisms of functioning of these two mutants remain elusive. In the present study, we compare the pharmacological properties of R137C and R137L mutants with the wild-type and the V2 D136A receptor, the latter being reported as a highly constitutively active receptor. We have performed binding studies, second messenger measurements and BRET experiments in order to evaluate the affinities of the ligands, their agonist and antagonist properties and the ability of the receptors to recruit beta-arrestins, respectively. The R137C and R137L receptors exhibit small constitutive activities regarding the G(s) protein activation. In addition, these two mutants induce a constitutive beta-arrestin recruitment. Of interest, they also exhibit weak sensitivities to agonist and to inverse agonist in term of G(s) protein coupling and beta-arrestin recruitment. The small constitutive activities of the mutants and the weak regulation of their functioning by agonist suggest a poor ability of the antidiuretic function to be adapted to the external stimuli, giving to the environmental factors an importance which can explain some of the phenotypic variability in patients having NSIAD. |
| Databáze: | OpenAIRE |
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