Nephrogenic diabetes insipidus (NDI) is characterized by renal tubular resistance to the antidiuretic effect of arginine vasopressin (AVP). NDI may be inherited as an autosomal dominant or X-linked recessive disorder. The autosomal dominant form of NDI results from mutations of the aquaporin 2 gene (AQP2). AQP2 encodes a water channel of the renal collecting duct. Its disruption causes autosomal dominant NDI (113,114) and occasionally recessive forms of the disease.
The gene encoding the V2 vasopressin receptor (AVPR2), located in the Xq28 region (115), is responsible for the X-linked nephrogenic diabetes insipidus. AVPR2 belongs to the cyclic nonapeptide-binding GPCR subfamily that also includes the V1a and V1b vasopressin receptors and the oxytocin receptor. AVPR2 is expressed predominantly in the distal convoluted tubule and collecting ducts of the nephron. Its primary role is to respond to the pituitary hormone AVP by stimulating mechanisms that concentrate the urine and maintain water homeostasis. More than 40 different single-nucleotide mutations, without any significant differences in phenotypic expression, have been reported in different families (116).
The variety of AVPR2 mutations that are known to cause X-linked NDI include SNPs, insertions, and deletions (117). For example, familial NDI may result from substitutions of Ser167Thr—a residue conserved across many GPCRs—and Leu44Pro. The Hopewell mutation, a Trp71 truncation, results in NDI in the largest
North American NDI pedigree. Most affecteds originate from Colchester County in Nova Scotia. In nearby Quebec, however, mutations were found in three families. These mutations include an Arg137His, a Arg113Trp, and an nt.804delG frame-shift mutation. A large kindred from Utah carries a Leu312 truncation mutation, and an Iranian family has been shown to harbor an Ala132Asp mutation. The geographical isolation of AVPR2-associated NDI mutations is consistent with evidence that suggests that de novo mutations are relatively common in X-linked diseases (118).
126.96.36.199 Loss-of-Function V2 Vasopressin Receptor Mutations
Among those mutations that are more fully characterized in vitro are the missense mutations Cys112Arg, Asn317Lys, and Trp323Ser. These mutations, however, are associated with a range of phenotypes even among patients who share the same mutations (119). This suggests that some mutations of the AVPR2 gene may have varying degrees of penetrance depending on other genetic and environmental factors (115,120).
A variety of AVPR2 nonsense mutations causes the most severely affected NDI phenotypes (121). Although truncation frequently occurs within TM domain 3, severe phenotypes have also been reported as a consequence of the Arg137His mutation. The Arg137His mutation is representative of variant receptors that are unable to activate stimulatory Gs proteins (122). The receptor fails to respond to agonist through stimulated adenylyl cyclase activity. Many other AVPR2 mutations, such as frame-shift and small in-frame deletions, also result in AVPR2s that fail to couple to Gsa (123).
The Arg137His AVPR2 variant has been the subject of detailed study in heterologous expression systems (123). Vasopressin binds the variant with affinity similar to the wild type; however, it fails to stimulate Gsa. This evidence suggests that the conservation of an arginine at this position is necessary for receptor-coupled G protein activity (115,123,124).
In fact, Arg137 is part of the DRY motif at the boundary between the third TM region and the second intracellular loop that is found in the majority of this group of GPCRs (125). Data regarding the function of the Arg137His mutation of the AVPR2 (123) resulted in the identification of an homologous residue in the human P2-adrenergic receptor, Arg131His, that has a similar function. Thus, the arginine in the DRY sequence may be essential for dissociation of the G protein following activation (124). In addition, some V2 vasopressin mutations may act to induce constitutive arrestin-mediated desensitization in some patients who also carry the Arg137His mutation (126).
188.8.131.52 Downregulation of V2 Receptor and Constitutively Phosphorylated Mutations
The Arg137His receptor, in contrast to the wild-type vasopressin receptor, is constitutively phosphorylated in vitro. This often leads to receptor sequestration in arrestin-associated intracellular vesicles even in the absence of agonist. This may result in a disruption of the normal affinity of arrestins for phosphorylated GPCR in some NDI phenotypes. Should this be accompanied by inadequate dephosphorylation of the internalized receptor, significantly fewer receptors would be recycled back to the plasma membrane.
The discovery of a disruption to downregulation in some cases of NDI, however, may present a future NDI intervention. An intervention that targets V2 vasopressin desensitization (126) may be analogous to the permeant antagonist that recovers the function of GnRHRs before they are degraded or expressed incorrectly at the membrane (97,98,109). Thus, it may be possible to treat NDI by pharmacological targeting of desensitization in patients who harbor certain AVPR2 mutations.
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