Premium
Characterization of the Inherited I130N Substitution in V2 Vasopressin Receptor Revealed a Gain‐of‐Function Mutation Leading to NSIAD
Author(s) -
Erdélyi László,
Mann Alexander,
Várnai Péter,
Balla András,
Hunyady László
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.809.8
Subject(s) - internalization , mutant , mutation , receptor , vasopressin , arginine vasopressin receptor 2 , arginine , agonist , biology , endocrinology , medicine , chemistry , biochemistry , antagonist , amino acid , gene
Nephrogenic syndrome of inappropriate diuresis (NSIAD) is a recently discovered disease based on the mutation of the V2 vasopressin receptor (V2R). To date the mutation of the 229 phenylalanine and the 137 arginine was identified as a molecular basis of the gain‐of‐function mutation. Here we present a newly discovered I130N substitution, identified in a German family. Functional characterization revealed constitutive activity of the mutant V2R. The cAMP concentration was monitored with a Epac‐based bioluminescence resonance energy transfer (BRET) sensor. Constitutive activity of the I130N receptor could be inhibited with V2R inverse agonist Tolvaptan and stimulation of the mutant receptor with AVP resulted a further increased cAMP concentration. Flow cytometry showed a significantly lower plasma membrane expression of the mutant receptor. The change in the amount of cell surface receptors was found to be due the constitutive internalization of the mutant receptor. This constitutive internalization could be inhibited with Tolvaptan. Hyponatraemia of the patients was found to be the consequence of the I130N substitution in V2R. The mutation leads to constitutive active receptor, resulting an increased cAMP concentration in the cells and also to constitutive internalization. The mutation generates an active conformation which can be inhibited with Tolvaptan. The inherited mutation may have significance in infancy. Hyponatraemia in infants could be improved with Tolvaptan regarding to the I130N mutation. This work was supported by OTKA100883.