HGNC Approved Gene Symbol: AVPR1A
Cytogenetic location: 12q14.2 Genomic coordinates (GRCh38): 12:63,142,759-63,151,201 (from NCBI)
The antidiuretic hormone vasopressin (192340) is a cyclic nonapeptide involved in the control of body fluid osmolality, blood volume, blood pressure, and vascular tone. It acts by binding to G protein-coupled membrane receptors (see AVPR1B, 600264). One member of this receptor family is AVPR1A, which mediates cell contraction and proliferation, platelet aggregation, release of coagulation factor, and glycogenolysis. Arginine-vasopressin (AVP) action through the V1A receptor is mediated by activating phospholipase C, which in turn stimulates phosphatidylinositol turnover to increase intracellular calcium ion. Morel et al. (1992) cloned the rat hepatocyte VIA receptor. Based on that sequence, Thibonnier et al. (1994) screened a human liver cDNA library. The cDNA encodes a predicted protein of 418 amino acids with 7 putative transmembrane domains as seen in other G protein-coupled receptors. The protein was 72% identical to the rat sequence and 36% identical to the human V2 receptor (AVPR2; 300538). Human oxytocin receptor (167055) was 45% similar to AVPR1A. Recombinant V1A was expressed and localized to the cell surface.
Birnbaumer (2000) noted that the biologic effects of AVP are mediated by 3 receptor subtypes: the V1A and V1B receptors that activate phospholipases via Gq/11, and the V2 receptor that activates adenylyl cyclase by interacting with GS. Isolation of the cDNAs encoding the V1A and V1B receptor subtypes explained the tissue variability of V1 antagonist binding, whereas identification of the cDNA and gene encoding the V2 receptor provided the information to identify the mutations responsible for X-linked nephrogenic diabetes insipidus (304800). Mutations that abrogate the production and/or release of AVP from the pituitary have diabetes insipidus as their most dramatic manifestation, indicating that the maintenance of water homeostasis is the most important physiologic role of this neuropeptide.
By Northern blot analysis, Thibonnier et al. (1996) demonstrated a 5.5-kb mRNA transcript of the AVPR1A gene in liver and to a lesser degree in heart, kidney, and skeletal muscle.
Hawtin et al. (2002) showed that a single residue, arg46, is critical for AVP binding to the V1A receptor. Systematic substitution revealed that arg was required at this locus and could not be substituted by lys, glu, leu, or ala. Disruption of arg46 resulted in defective intracellular signaling. In addition to arg46, the residues leu42, gly43, and asp45 form a patch contributing to AVP binding.
Thibonnier et al. (1996) found that the AVPR1A gene is included entirely within a 6.4-kb EcoRI fragment and comprises 2 coding exons separated by a 2.2-kb intron located before the corresponding seventh transmembrane domain of the receptor sequence. The first exon also contains 2 kb of 5-prime untranslated region, and the second exon includes 1 kb of 3-prime untranslated region. The transcription start site was identified 1973 bp upstream of the translation initiation site.
Thibonnier et al. (1996) used specific oligonucleotides derived from the intron sequence as primers in PCR analysis of human/rodent somatic cell hybrids to localize the AVPR1A gene to chromosome 12. Thibonnier et al. (1996) used fluorescence in situ hybridization with a yeast artificial chromosome to map the AVPR1A gene to chromosome 12q14-q15.
Walum et al. (2008) genotyped 552 Swedish same-sex twin pairs and their spouses/partners, who had been in a relationship for at least 5 years, for the GT(25), RS1, and RS3 repeat polymorphisms in the 5-prime untranslated region of the AVPR1A gene. Using a questionnaire to assess relationship behavior, the authors found an association between the 334-bp allele of the RS3 polymorphism and traits reflecting decreased pair bonding in men, such as partner bonding, perceived marital status, and marital status. Men carrying 2 copies of allele 334 reported marital crisis at a higher frequency than men not carrying the allele (34% vs 15%). The frequency of nonmarried men was higher among allele 334 homozygotes (32%) compared to men with no allele 334 (17%). The cohort included 238 monozygotic and 314 dizygotic twin pairs. The findings suggested that the AVP system may influence pair-bonding behavior in humans, as had been observed in voles (see ANIMAL MODEL).
Arginine vasopressin influences male reproductive and social behaviors in several vertebrate taxa through its actions at the V1A receptor in the brain. The neuroanatomic distribution of vasopressin V1A receptors varies greatly between species with different forms of social organization. Young et al. (1999) demonstrated that centrally administered arginine vasopressin increases affiliative behavior in the highly social, monogamous prairie vole, but not in the relatively asocial, promiscuous montane vole. While no significant differences were found in the coding regions of the V1A receptor of the 2 species, the 5-prime flanking region of the V1A gene displayed marked differences between the species. In the prairie vole V1A receptor gene, the 5-prime flanking region contains a 428-bp sequence that is rich in microsatellite DNA. This sequence was not found in the montane vole V1A gene, and sequences on either side of the expansion were contiguous in the montane vole gene. Another monogamous vole, the pine vole, was found to have the same 428-bp sequence in the 5-prime flanking region. Young et al. (1999) generated mice that were transgenic for the prairie vole receptor gene and found that they had a neuroanatomic pattern of receptor binding that was similar to that of the prairie vole and exhibited increased affiliative behavior after injection with arginine vasopressin. Young et al. (1999) concluded that the pattern of V1A receptor gene expression in the brain may be functionally associated with species-typical social behaviors in male vertebrates.
Using viral vector AVPR1A gene transfer into the ventral forebrain, Lim et al. (2004) substantially increased partner preference formation in the socially promiscuous meadow vole. They showed that a change in the expression of a single gene in the larger context of preexisting genetic and neural circuits can profoundly alter social behavior, providing a potential molecular mechanism for the rapid evolution of complex social behavior.
Hammock and Young (2005) showed that individual alleles of a repetitive polymorphic microsatellite in the 5-prime region of the prairie vole Avpr1a gene modify gene expression in vitro. In vivo, they observed that this regulatory polymorphism predicted both individual differences in receptor distribution patterns and sociobehavioral traits. Hammock and Young (2005) concluded that individual differences in gene expression patterns may be conferred via polymorphic microsatellites in the cis-regulatory regions of genes and may contribute to normal variation in behavioral traits.
Koshimizu et al. (2006) generated Avpr1a-null mice and found that they had significantly lower basal blood pressure than wildtype mice, with no change in heart rate. There was no significant change in cardiac function as assessed by echocardiogram in the mutant mice. AVP-induced vasopressor responses were abolished, and arterial baroreceptor reflexes markedly impaired in the mutant mice, which also showed a significant 9% reduction in circulating blood volume. Avpr1a-null mice had normal plasma AVP levels and a normal AVP secretory response but significantly lower adrenocortical responsiveness to adrenocorticotropic hormone. Koshimizu et al. (2006) concluded that AVPR1A maintains normal resting blood pressure by regulating circulating blood volume and baroreflex sensitivity.
Yamaguchi et al. (2013) found that circadian rhythms of behavior (locomotor activity), clock gene expression, and body temperature immediately reentrained to phase-shifted light-dark cycles in mice lacking Avpr1a (V1a) and Avpr1b (V1b; 600264). Nevertheless, the behavior of V1a-V1b double-knockout mice was still coupled to the internal clock, which oscillated normally under standard conditions. Experiments with suprachiasmatic nucleus (SCN) slices in culture suggested that interneuronal communication mediated by V1a and V1b confers on the SCN an intrinsic resistance to external perturbation. Pharmacologic blockade of V1a and V1b in the SCN of wildtype mice resulted in accelerated recovery from jet lag.
Birnbaumer, M. Vasopressin receptors. Trends Endocr. Metab. 11: 406-410, 2000. [PubMed: 11091117] [Full Text: https://doi.org/10.1016/s1043-2760(00)00304-0]
Hammock, E. A. D., Young, L. J. Microsatellite instability generates diversity in brain and sociobehavioral traits. Science 308: 1630-1634, 2005. [PubMed: 15947188] [Full Text: https://doi.org/10.1126/science.1111427]
Hawtin, S. R., Wesley, V. J., Parslow, R. A., Simms, J., Miles, A., McEwan, K., Wheatley, M. A single residue (arg46) located within the N-terminus of the V(1a) vasopressin receptor is critical for binding vasopressin but not peptide or nonpeptide antagonists. Molec. Endocr. 16: 600-609, 2002. [PubMed: 11875119] [Full Text: https://doi.org/10.1210/mend.16.3.0795]
Koshimizu, T., Nasa, Y., Tanoue, A., Oikawa, R., Kawahara, Y., Kiyono, Y., Adachi, T., Tanaka, T., Kuwaki, T., Mori, T., Takeo, S., Okamura, H., Tsujimoto, G. V1a vasopressin receptors maintain normal blood pressure by regulating circulating blood volume and baroreflex sensitivity. Proc. Nat. Acad. Sci. 103: 7807-7812, 2006. [PubMed: 16682631] [Full Text: https://doi.org/10.1073/pnas.0600875103]
Lim, M. M., Wang, Z., Olazabal, D. E., Ren, X., Terwilliger, E. F., Young, L. J. Enhanced partner preference in a promiscuous species by manipulating the expression of a single gene. Nature 429: 754-757, 2004. [PubMed: 15201909] [Full Text: https://doi.org/10.1038/nature02539]
Morel, A., O'Carroll, A.-M., Brownstein, M. J., Lolait, S. J. Molecular cloning and expression of a rat V1a arginine vasopressin receptor. Nature 356: 523-526, 1992. [PubMed: 1560825] [Full Text: https://doi.org/10.1038/356523a0]
Thibonnier, M., Auzan, C., Madhun, Z., Wilkins, P., Berti-Mattera, L., Clauser, E. Molecular cloning, sequencing, and functional expression of a cDNA encoding the human V1a vasopressin receptor. J. Biol. Chem. 269: 3304-3310, 1994. [PubMed: 8106369]
Thibonnier, M., Graves, M. K., Wagner, M. S., Auzan, C., Clauser, E., Willard, H. F. Structure, sequence, expression, and chromosomal localization of the human V(1a) vasopressin receptor gene. Genomics 31: 327-334, 1996. [PubMed: 8838314] [Full Text: https://doi.org/10.1006/geno.1996.0055]
Walum, H., Westberg, L., Henningsson, S., Neiderhiser, J. M., Reiss, D., Igl, W., Ganiban, J. M., Spotts, E. L., Pedersen, N. L., Eriksson, E., Lichtenstein, P. Genetic variation in the vasopressin receptor 1a gene (AVPR1A) associates with pair-bonding behavior in humans. Proc. Nat. Acad. Sci. 105: 14153-14156, 2008. [PubMed: 18765804] [Full Text: https://doi.org/10.1073/pnas.0803081105]
Yamaguchi, Y., Suzuki, T., Mizoro, Y., Kori, H., Okada, K., Chen, Y., Fustin, J.-M., Yamazaki, F., Mizuguchi, N., Zhang, J., Dong, X., Tsujimoto, G., Okuno, Y., Doi, M., Okamura, H. Mice genetically deficient in vasopressin V1a and V1b receptors are resistant to jet lag. Science 342: 85-90, 2013. [PubMed: 24092737] [Full Text: https://doi.org/10.1126/science.1238599]
Young, L. J., Nilsen, R., Waymire, K. G., MacGregor, G. R., Insel, T. R. Increased affiliative response to vasopressin in mice expressing the V(1A) receptor from a monogamous vole. Nature 400: 766-768, 1999. [PubMed: 10466725] [Full Text: https://doi.org/10.1038/23475]