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AVPR2  -  arginine vasopressin receptor 2

Homo sapiens

Synonyms: ADHR, AVPR V2, Antidiuretic hormone receptor, DI1, DIR, ...
 
 
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Disease relevance of AVPR2

 

Psychiatry related information on AVPR2

  • Identification of mutations in the AVPR2 gene can facilitate early diagnosis of NDI, which can prevent serious complications such as growth retardation and mental retardation [6].
  • The R137H mutation results in a failure of V2R to stimulate adenylate cyclase and has been associated consistently with severe NDI and the inability to increase urinary osmolality to greater than plasma osmolality during water deprivation and/or infusion of 1-desamino-8-d-arginine vasopressin [7].
  • The findings do not solve the uncertainties in the pathogenesis of enuresis but they suggest there might be a difference between enuretic children and controls at the ADH receptor level [8].
  • The developmental, individual-difference, relationship-based model (DIR), a theoretical and applied framework for comprehensive intervention, examines the functional developmental capacities of children in the context of their unique biologically based processing profile and their family relationships and interactive patterns [9].
 

High impact information on AVPR2

  • Brief report: a molecular defect in the vasopressin V2-receptor gene causing nephrogenic diabetes insipidus [10].
  • We show here that the structural AVPR2 gene is localized between DXS52 and G6PD, which is within the genetic map location of DIR [1].
  • The genetic map location of the DIR gene on chromosome Xq28 coincides with the physical map location of the functional vasopressin renal V2-type receptor [1].
  • We also tested eight X-linked DIR probands and their families for mutations in one of the most conserved extracellular regions of AVPR2: in three of them, we have identified point mutations resulting in non-conservative amino acid substitutions which cosegregated with DIR in all families [1].
  • We used animal models orthologous to the human disorders to test whether a vasopressin V2 receptor (VPV2R) antagonist, OPC31260, would be effective against early or established disease [11].
 

Chemical compound and disease context of AVPR2

 

Biological context of AVPR2

  • Patients who have congenital NDI and bear mutations in the AVPR2 or AQP2 genes have a "pure" NDI phenotype with loss of water but normal conservation of sodium, potassium, chloride, and calcium [16].
  • These include a point mutation in the seventh transmembrane domain (S315R), a frameshift mutation in the third intracellular loop (804delG), and two nonsense mutations that code for AVPR2 truncated within the first cytoplasmic loop (W71X) and in the proximal portion of the carboxyl tail (R337X) [17].
  • Skewed X-inactivation is the most likely explanation for the clinical manifestation of NDI in female carriers of an AVPR2 mutation [18].
  • RESULTS: We identified two novel missense mutations (AQP2:p.Gly100Arg and p.Gly180Ser) in AQP2 and one novel missense mutation (AVPR2:p.Gly122Asp), one previously reported missense mutation (AVPR2:p.Arg137His) and one novel contiguous deletion (AVPR2:c.25 + 273_ARHGAP4o:2650-420del) affecting AVPR2 [19].
  • Urinary AQP2 excretion was normal, as was the DNA sequence of AVPR2 and AQP2 [20].
 

Anatomical context of AVPR2

  • When studied in vitro, most AVPR2 mutations result in receptors that are trapped intracellularly and are unable to reach the plasma membrane [21].
  • Premature truncation of the AVPR2 (delG102) led to a drastically reduced receptor protein expression in transfected COS-7 cells and, as expected, precluded specific AVPR2 functions [22].
  • To date, approximately 277 families with 185 germ-line mutations in the AVPR2 gene have been described worldwide [23].
  • However, although the nature and expression of both vasopressin V1 receptors and human VACM are apparently unaffected by dedifferentiation in SCCL, only the abnormal (and probably nonfunctional) form of the V2 receptor could be demonstrated in variant cell line NCI H82 [24].
  • Activation of the adenylate cyclase-coupled V2R in LLC-PK1 cells induced phosphorylation of adenosine 3',5'-cyclic monophosphate (cAMP) responsive element binding protein (CREB) and expression of c-Fos [25].
 

Associations of AVPR2 with chemical compounds

  • As a model system, we studied a mutant V2 vasopressin receptor (AVPR2) containing the inactivating E242X nonsense mutation which mimics human X-linked nephrogenic diabetes insipidus (XNDI) when introduced into mice via gene targeting techniques [26].
  • Extrarenal responses to infusion of the strong V2 agonist 1-desamino-8-D-arginine vasopressin allowed AVPR2- and AQP2-associated forms of CNDI to be distinguished in three patients [27].
  • Additionally, one patient revealed a genomic deletion of 3.2 kb encompassing most of the AVPR2 gene and the last exon/3'-region of C1 gene, which is in close proximity to the AVPR2 locus [28].
  • Most missense AVPR2 mutations lead to receptors that are trapped intracellularly; a few mutant receptors reach the cell surface but are unable to bind AVP or to properly trigger an intracellular cyclic adenosine monophosphate signal [4].
  • We describe a novel Belgian family with X-linked NDI caused by substitution of a histidine for an arginine at position 137 (R137H) of AVPR2 [7].
 

Physical interactions of AVPR2

  • AQP2 is redistributed to the apical membrane of collecting duct cells through activation of a cAMP signaling cascade initiated by the binding of vasopressin to its V2-receptor [29].
  • Requirement of the third intracellular loop of the V2R for G(s) activation was identified by introducing V2R segments into the Gq coupled V1aR [Liu, J. and Wess, J. (1996) J. Biol. Chem. 271, 8772-8778]; the same approach recognized glutamate 231 and glutamine 225 at the amino terminus of loop 3i as being needed for signal transduction [30].
  • Leu-AVP was a weak agonist with approximately 30-fold reduced binding to the human V2 receptor [31].
  • The gene responsible for the X-linked NDI, the G-protein-coupled vasopressin V2 receptor, has been localized on the Xq28 region [32].
 

Regulatory relationships of AVPR2

  • V2 receptor antagonists reverse the water retention and down-regulate AQP-2 water channels [33].
  • Vasopressin-induced vWF secretion is mimicked by DDAVP and inhibited by the selective V2R antagonist SR121463B [34].
  • A pronounced difference was observed for this mutant V2R between the stimulation of adenylyl cyclase activity promoted by AVP and the V2 vasopressin receptor agonist deamino[Cys1,D-Arg8]-vasopressin, suggesting an involvement of Gly201 in the selectivity of the receptor for different ligands [35].
  • In contrast, the V1a receptor mainly in the luminal membrane of distal nephron regulates basolateral V2 receptor-mediated action with regard to water and ion transport through the activation of G(q/11) and phosphoinositide turnover [36].
  • Loss of V1 receptor-stimulating activity and V2 receptor-stimulating activity was compared by two-way ANOVA [37].
 

Other interactions of AVPR2

 

Analytical, diagnostic and therapeutic context of AVPR2

  • Besides clearly defined NDI symptoms caused by deletion of the AVPR2 gene, no major morphological abnormalities as determined by physical examination, radiography, ultrasound, and computed tomographic scan were detected [12].
  • In contrast, the W71X and R337X AVPR2 were retained inside the cell as determined by immunofluorescence [17].
  • Using an antibody directed to human AQP-2, a quantitative Western blot analysis was performed to determine the collecting duct responsiveness to an oral, nonpeptide, V2 receptor antagonist (VPA-985) in patients with chronic NYHA II and III heart failure [43].
  • These cells (but not HUVECs) express endogenous V2R, as shown by RT-PCR [34].
  • Truncation and site-directed mutagenesis of the V2R C terminus revealed an involvement of an RGR sequence in this interaction [44].

References

  1. Mutations in the vasopressin type 2 receptor gene (AVPR2) associated with nephrogenic diabetes insipidus. van den Ouweland, A.M., Dreesen, J.C., Verdijk, M., Knoers, N.V., Monnens, L.A., Rocchi, M., van Oost, B.A. Nat. Genet. (1992) [Pubmed]
  2. Identification and characterization of aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus with partial vasopressin response. Canfield, M.C., Tamarappoo, B.K., Moses, A.M., Verkman, A.S., Holtzman, E.J. Hum. Mol. Genet. (1997) [Pubmed]
  3. Diabetes insipidus. Hendy, G.N., Bichet, D.G. Baillieres Clin. Endocrinol. Metab. (1995) [Pubmed]
  4. Nephrogenic diabetes insipidus. Bichet, D.G. Advances in chronic kidney disease. (2006) [Pubmed]
  5. Nonpeptide vasopressin receptor antagonists: development of selective and orally active V1a, V2 and V1b receptor ligands. Serradeil-Le Gal, C., Wagnon, J., Valette, G., Garcia, G., Pascal, M., Maffrand, J.P., Le Fur, G. Prog. Brain Res. (2002) [Pubmed]
  6. Identification of mutations in the arginine vasopressin receptor 2 gene causing nephrogenic diabetes insipidus in Chinese patients. Chen, C.H., Chen, W.Y., Liu, H.L., Liu, T.T., Tsou, A.P., Lin, C.Y., Chao, T., Qi, Y., Hsiao, K.J. J. Hum. Genet. (2002) [Pubmed]
  7. Intrafamilial phenotype variability in nephrogenic diabetes insipidus. Kalenga, K., Persu, A., Goffin, E., Lavenne-Pardonge, E., van Cangh, P.J., Bichet, D.G., Devuyst, O. Am. J. Kidney Dis. (2002) [Pubmed]
  8. Antidiuretic hormone regulation in patients with primary nocturnal enuresis. Eggert, P., Kühn, B. Arch. Dis. Child. (1995) [Pubmed]
  9. Climbing the symbolic ladder in the DIR model through floor time/interactive play. Wieder, S., Greenspan, S.I. Autism : the international journal of research and practice. (2003) [Pubmed]
  10. Brief report: a molecular defect in the vasopressin V2-receptor gene causing nephrogenic diabetes insipidus. Holtzman, E.J., Harris, H.W., Kolakowski, L.F., Guay-Woodford, L.M., Botelho, B., Ausiello, D.A. N. Engl. J. Med. (1993) [Pubmed]
  11. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Gattone, V.H., Wang, X., Harris, P.C., Torres, V.E. Nat. Med. (2003) [Pubmed]
  12. Compound deletion of the rhoGAP C1 and V2 vasopressin receptor genes in a patient with nephrogenic diabetes insipidus. Schöneberg, T., Pasel, K., von Baehr, V., Schulz, A., Volk, H.D., Gudermann, T., Filler, G. Hum. Mutat. (1999) [Pubmed]
  13. Mutational analyses of AVPR2 gene in three Japanese families with X-linked nephrogenic diabetes insipidus: two recurrent mutations, R137H and deltaV278, caused by the hypermutability at CpG dinucleotides. Shoji, Y., Takahashi, T., Suzuki, Y., Suzuki, T., Komatsu, K., Hirono, H., Shoji, Y., Yokoyama, T., Kito, H., Takada, G. Hum. Mutat. (1998) [Pubmed]
  14. Functional studies of twelve mutant V2 vasopressin receptors related to nephrogenic diabetes insipidus: molecular basis of a mild clinical phenotype. Ala, Y., Morin, D., Mouillac, B., Sabatier, N., Vargas, R., Cotte, N., Déchaux, M., Antignac, C., Arthus, M.F., Lonergan, M., Turner, M.S., Balestre, M.N., Alonso, G., Hibert, M., Barberis, C., Hendy, G.N., Bichet, D.G., Jard, S. J. Am. Soc. Nephrol. (1998) [Pubmed]
  15. Epinephrine and dDAVP administration in patients with congenital nephrogenic diabetes insipidus. Evidence for a pre-cyclic AMP V2 receptor defective mechanism. Bichet, D.G., Razi, M., Arthus, M.F., Lonergan, M., Tittley, P., Smiley, R.K., Rock, G., Hirsch, D.J. Kidney Int. (1989) [Pubmed]
  16. Molecular biology of hereditary diabetes insipidus. Fujiwara, T.M., Bichet, D.G. J. Am. Soc. Nephrol. (2005) [Pubmed]
  17. Association of calnexin with wild type and mutant AVPR2 that causes nephrogenic diabetes insipidus. Morello, J.P., Salahpour, A., Petäjä-Repo, U.E., Laperrière, A., Lonergan, M., Arthus, M.F., Nabi, I.R., Bichet, D.G., Bouvier, M. Biochemistry (2001) [Pubmed]
  18. Clinical phenotype of nephrogenic diabetes insipidus in females heterozygous for a vasopressin type 2 receptor mutation. van Lieburg, A.F., Verdijk, M.A., Schoute, F., Ligtenberg, M.J., van Oost, B.A., Waldhauser, F., Dobner, M., Monnens, L.A., Knoers, N.V. Hum. Genet. (1995) [Pubmed]
  19. Novel mutations underlying nephrogenic diabetes insipidus in Arab families. Carroll, P., Al-Mojalli, H., Al-Abbad, A., Al-Hassoun, I., Al-Hamed, M., Al-Amr, R., Butt, A.I., Meyer, B.F. Genet. Med. (2006) [Pubmed]
  20. Impaired urinary water excretion in a three-generation family. Tanaka, Y., Sugita, K., Saito, T., Muroya, K., Ishikawa, S.E., Awazu, M., Ogata, T. Pediatr. Nephrol. (2001) [Pubmed]
  21. Nephrogenic diabetes insipidus. Morello, J.P., Bichet, D.G. Annu. Rev. Physiol. (2001) [Pubmed]
  22. V2 vasopressin receptor dysfunction in nephrogenic diabetes insipidus caused by different molecular mechanisms. Schöneberg, T., Schulz, A., Biebermann, H., Grüters, A., Grimm, T., Hübschmann, K., Filler, G., Gudermann, T., Schultz, G. Hum. Mutat. (1998) [Pubmed]
  23. Novel Vasopressin Type 2 (AVPR2) Gene Mutations in Brazilian Nephrogenic Diabetes Insipidus Patients. Boson, W.L., Manna, T.D., Damiani, D., Miranda, D.M., Gadelha, M.R., Liberman, B., Correa, H., Romano-Silva, M.A., Friedman, E., Silva, F.F., Ribeiro, P.A., Marco, L.D. Genet. Test. (2006) [Pubmed]
  24. Expression of all known vasopressin receptor subtypes by small cell tumors implies a multifaceted role for this neuropeptide. North, W.G., Fay, M.J., Longo, K.A., Du, J. Cancer Res. (1998) [Pubmed]
  25. Adenylate cyclase-coupled vasopressin receptor activates AQP2 promoter via a dual effect on CRE and AP1 elements. Yasui, M., Zelenin, S.M., Celsi, G., Aperia, A. Am. J. Physiol. (1997) [Pubmed]
  26. Aminoglycoside-mediated rescue of a disease-causing nonsense mutation in the V2 vasopressin receptor gene in vitro and in vivo. Sangkuhl, K., Schulz, A., Römpler, H., Yun, J., Wess, J., Schöneberg, T. Hum. Mol. Genet. (2004) [Pubmed]
  27. Mutations in the vasopressin V2 receptor and aquaporin-2 genes in 12 families with congenital nephrogenic diabetes insipidus. Vargas-Poussou, R., Forestier, L., Dautzenberg, M.D., Niaudet, P., Déchaux, M., Antignac, C. J. Am. Soc. Nephrol. (1997) [Pubmed]
  28. Aminoglycoside pretreatment partially restores the function of truncated V(2) vasopressin receptors found in patients with nephrogenic diabetes insipidus. Schulz, A., Sangkuhl, K., Lennert, T., Wigger, M., Price, D.A., Nuuja, A., Grüters, A., Schultz, G., Schöneberg, T. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  29. Minireview: aquaporin 2 trafficking. Valenti, G., Procino, G., Tamma, G., Carmosino, M., Svelto, M. Endocrinology (2005) [Pubmed]
  30. A role for K268 in V2R folding. Gouill, C.L., Darden, T., Madziva, M.T., Birnbaumer, M. FEBS Lett. (2005) [Pubmed]
  31. Autosomal recessive familial neurohypophyseal diabetes insipidus with continued secretion of mutant weakly active vasopressin. Willcutts, M.D., Felner, E., White, P.C. Hum. Mol. Genet. (1999) [Pubmed]
  32. C112R, W323S, N317K mutations in the vasopressin V2 receptor gene in patients with nephrogenic diabetes insipidus. Mutations in brief no. 165. Online. Szalai, C., Triga, D., Czinner, A. Hum. Mutat. (1998) [Pubmed]
  33. Pathophysiology of renal fluid retention. Schrier, R.W., Fassett, R.G., Ohara, M., Martin, P.Y. Kidney Int. Suppl. (1998) [Pubmed]
  34. Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP. Kaufmann, J.E., Oksche, A., Wollheim, C.B., Günther, G., Rosenthal, W., Vischer, U.M. J. Clin. Invest. (2000) [Pubmed]
  35. Biochemical basis of partial nephrogenic diabetes insipidus phenotypes. Sadeghi, H., Robertson, G.L., Bichet, D.G., Innamorati, G., Birnbaumer, M. Mol. Endocrinol. (1997) [Pubmed]
  36. Physiological effects of vasopressin and atrial natriuretic peptide in the collecting duct. Inoue, T., Nonoguchi, H., Tomita, K. Cardiovasc. Res. (2001) [Pubmed]
  37. Loss of biological activity of arginine vasopressin during its degradation by vasopressinase from pregnancy serum. Gordge, M.P., Williams, D.J., Huggett, N.J., Payne, N.N., Neild, G.H. Clin. Endocrinol. (Oxf) (1995) [Pubmed]
  38. Urinary content of aquaporin 1 and 2 in nephrogenic diabetes insipidus. Deen, P.M., van Aubel, R.A., van Lieburg, A.F., van Os, C.H. J. Am. Soc. Nephrol. (1996) [Pubmed]
  39. Hereditary vasopressin resistance in man and mouse. Moses, A.M., Scheinman, S.J. Ann. N. Y. Acad. Sci. (1993) [Pubmed]
  40. Molecular pharmacology and modeling of vasopressin receptors. Thibonnier, M., Coles, P., Thibonnier, A., Shoham, M. Prog. Brain Res. (2002) [Pubmed]
  41. Two novel types of contiguous gene deletion of the AVPR2 and ARHGAP4 genes in unrelated Japanese kindreds with nephrogenic diabetes insipidus. Demura, M., Takeda, Y., Yoneda, T., Furukawa, K., Usukura, M., Itoh, Y., Mabuchi, H. Hum. Mutat. (2002) [Pubmed]
  42. AVPR2 variants and V2 vasopressin receptor function in nephrogenic diabetes insipidus. Wildin, R.S., Cogdell, D.E., Valadez, V. Kidney Int. (1998) [Pubmed]
  43. Selective V2-receptor vasopressin antagonism decreases urinary aquaporin-2 excretion in patients with chronic heart failure. Martin, P.Y., Abraham, W.T., Lieming, X., Olson, B.R., Oren, R.M., Ohara, M., Schrier, R.W. J. Am. Soc. Nephrol. (1999) [Pubmed]
  44. Calmodulin interacts with the V2 vasopressin receptor: elimination of binding to the C terminus also eliminates arginine vasopressin-stimulated elevation of intracellular calcium. Nickols, H.H., Shah, V.N., Chazin, W.J., Limbird, L.E. J. Biol. Chem. (2004) [Pubmed]
 
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