Functional Characterization of Vasopressin Type 2 Receptor Substitutions (R137H/C/L) Leading to Nephrogenic Diabetes Insipidus and Nephrogenic Syndrome of Inappropriate Antidiuresis: Implications for Treatments

Rochdi, Moulay Driss; Vargas, Gabriel; Carpentier, Éric Le; Oligny-Longpré, Geneviève; Chen, Stanford; Kovoor, Abraham; Gitelman, Stephen E.; Rosenthal, Stephen M.; Zastrow, Mark von; Bouvier, Michel

doi:10.1124/mol.109.061804

Cited by 63 publications

(79 citation statements)

References 32 publications

(50 reference statements)

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“…These data suggest that although basal endocytosis is β-arrestin-independent, it involves dynamin. Dominant-negative dynamin was shown to increase cell surface expression and β-arrestin/AP2 interaction of R137C/L receptors, which raises the possibility that the mutant receptors were trapped in the plasma membrane and accumulated in receptor-β-arrestin-AP2 complex (8). In contrast, F229V-V2R did not show increased β-arrestin/AP2 interaction in the case of co-expression of dominant-negative dynamin.…”

Section: Discussionmentioning

confidence: 79%

“…Taken together, the constitutive active conformation of I130N-V2R in the absence of AVP differs from the agonist-induced active conformation of the receptor and clearly differs from the AVP-induced conformation of the wild-type receptor. In this regard, the I130N-V2R is similar to the F229V-V2R, since both share the characteristic property of the lack of basal β-arrestin2 binding, but not to R137C and R137L (7,8,11).…”

Section: Discussionmentioning

confidence: 95%

“…Basal activity of R137C and R137L mutant V2Rs had similar properties to the NDI-causing R137H missense mutation, since the conformation of the mutant receptors also induced agonist-independent β-arrestin2 interaction (5,7). Characterization of the R137C/L mutants revealed that although AVP stimulation caused increased β-arrestin binding, the agonist-induced cAMP generation was negligible, despite the affinity of the mutants toward AVP being unchanged (8). The data of Rochdi et al may explain the clinical finding, that both the R137C and R137L mutations were insensitive to acute inverse agonist tolvaptan treatment (9,10).…”

Section: Introductionmentioning

confidence: 99%

“…We investigated the effect of dominant-negative dynamins in order to characterize the internalization properties of the I130N-V2R (8,11). The wild-type dynamin1 could be used as a control, since there was no difference between the cotransfection of empty pcDNA3.1 or dynamin1 (Suppl.…”

Section: Investigation Of the Internalization Propertiesmentioning

confidence: 99%

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Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis

Erdélyi

Mann

Morris-Rosendahl

et al. 2015

Kidney International

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Nephrogenic syndrome of inappropriate diuresis is a recently-discovered rare disease caused by gain-of-function mutations of the V2 vasopressin receptor gene, AVPR2. To date, mutations of Phe229 and Arg137 have been identified as gain-of-function mutations in V2 vasopressin receptor (V2R). The mutant receptors lead to hyponatremia, which may lead to clinical symptoms in infants. In this study, we present a newly-identified Ile130Asn (I130N) substitution, causing NSIAD in a family. Characterization of the mutation revealed basal constitutive activity of V2R. We have demonstrated that the I130N mutation results in constitutive cAMP generation in HEK293 cells. Basal activity of the mutant receptor could be blocked by the inverse agonist tolvaptan and arginine-vasopressin stimulation enhanced the cAMP production of I130N-V2R. The mutation causes a biased receptor conformation since the basal cAMP generation activity of I130N does not lead to interaction with β-arrestin. The constitutive activity of the mutant receptor causes constitutive dynamindependent and β-arrestin-independent internalization. The inhibition of the basal internalization using dominant-negative dynamin resulted in an increased cell surface expression. In contrast to the constitutive internalization, agonist-induced endocytosis was β-arrestin dependent. Based on our findings, tolvaptan could be used for treatment of hyponatremia, shown in patients with nephrogenic syndrome of inappropriate diuresis who carry the I130N-V2R mutation.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Investigation Of the Internalization Propertiesmentioning

confidence: 99%

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Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis

Erdélyi

Mann

Morris-Rosendahl

et al. 2015

Kidney International

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“…The interactions between ␤-arrestins and ApelinR were monitored by BRET, as previously described (40). Briefly, the ␤-arrestin1-RlucII or the ␤-arrestin2-RlucII-encoding plasmids were transfected along with the YFP-tagged wild-type ApelinR construct in HEK293T cells.…”

Section: ␤-Arrestin Recruitment Assaysmentioning

confidence: 99%

Biased Signaling Favoring Gi over β-Arrestin Promoted by an Apelin Fragment Lacking the C-terminal Phenylalanine

Ceraudo¹,

Galanth²,

Carpentier³

et al. 2014

Journal of Biological Chemistry

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103

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Background: Apelin receptor represents a therapeutic target for cardiovascular diseases. Results: Apelin 17 activates ERK1/2 in a ␤-arrestin-dependent and G protein-dependent manner, whereas apelin 17 with deleted C-terminal phenylalanine only signals through the G protein. Conclusion:Biased signaling promoted by an apelin fragment lacking the C-terminal phenylalanine is favoring G i over ␤-arrestin. Significance: Apelin receptor ␤-arrestin signaling may account for apelin hypotensive activity.

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Physiology of the Developing Kidney: Sodium and Water Homeostasis and Its Disorders

Madden

Trachtman

2015

Pediatric Nephrology

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Functional Characterization of Vasopressin Type 2 Receptor Substitutions (R137H/C/L) Leading to Nephrogenic Diabetes Insipidus and Nephrogenic Syndrome of Inappropriate Antidiuresis: Implications for Treatments

Cited by 63 publications

References 32 publications

Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis

Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis

Biased Signaling Favoring Gi over β-Arrestin Promoted by an Apelin Fragment Lacking the C-terminal Phenylalanine

Physiology of the Developing Kidney: Sodium and Water Homeostasis and Its Disorders

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