Fiche publication
Date publication
janvier 2022
Journal
Frontiers in pharmacology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BONNET Dominique
Tous les auteurs :
Szalai L, Sziráki A, Erdélyi LS, Kovács KB, Tóth M, Tóth AD, Turu G, Bonnet D, Mouillac B, Hunyady L, Balla A
Lien Pubmed
Résumé
The urine concentrating function of the kidney is essential to maintain the water homeostasis of the human body. It is mainly regulated by the arginine-vasopressin (AVP), which targets the type 2 vasopressin receptor (V2R) in the kidney. The inability of V2R to respond to AVP stimulation leads to decreased urine concentration and congenital nephrogenic diabetes insipidus (NDI). NDI is characterized by polyuria, polydipsia, and hyposthenuria. In this study, we identified a point mutation (S127F) in the gene of an NDI patient, and we characterized the impaired function of the V2R mutant in HEK293 cells. Based on our data, the S127F-V2R mutant is almost exclusively located intracellularly in the endoplasmic reticulum (ER), and very few receptors were detected at the cell surface, where the receptor can bind to AVP. The overexpressed S127F-V2R mutant receptor has negligible cAMP generation capability compared to the wild-type receptor in response to AVP stimulation. Since certain misfolded mutant proteins, that are retained in the ER, can be rescued by pharmacological chaperones, we examined the potential rescue effects of two pharmacochaperones on the S127F-V2R. We found that pretreatment with both tolvaptan (an established V2R inverse agonist) and MCF14 compound (a cell-permeable high-affinity agonist for the V2R) were capable of partially restoring the cAMP generating function of the receptor in response to vasopressin stimulation. According to our data, both cell permeant agonists and antagonists can function as pharmacochaperones, and serve as the starting compounds to develop medicines for patients carrying the S127F mutation.
Mots clés
G protein coupled receptor (GPCR), MCF-14, arginin vasopressin, bioluminescence resonance energy transfer (BRET), nephrogenic diabetes insipidus (NDI), pharmacochaperone, tolvaptan, vasopressin receptor 2 (V2R)
Référence
Front Pharmacol. 2022 ;13:811836
