Biology:Vasopressin receptor 1A

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Vasopressin receptor 1A (V1AR), or arginine vasopressin receptor 1A (officially called AVPR1A) is one of the three major receptor types for vasopressin (AVPR1B and AVPR2 being the others), and is present throughout the brain, as well as in the periphery in the liver, kidney, and vasculature.[1]

V1AR is also known as:

  • V1a vasopressin receptor
  • antidiuretic hormone receptor 1A
  • SCCL vasopressin subtype 1a receptor
  • V1-vascular vasopressin receptor AVPR1A
  • vascular/hepatic-type arginine vasopressin receptor

Structure and function

Human AVPR1A cDNA is 1472 bp long and encodes a 418 amino-acid long polypeptide which shares 72%, 36%, 37%, and 45% sequence identity with rat Avpr1a, human AVPR2, rat Avpr2, and human oxytocin receptor (OXTR), respectively. AVPR1A is a G-protein coupled receptor (GPCR) with 7 transmembrane domains that couples to Gaq/11 GTP binding proteins, which along with Gbl, activate phospholipase C activity.[1][2] Clinically, the V1A receptor is related to vasoconstriction compared to the V1B receptor that is more related to ACTH release or the V2 receptor that is linked to the antidiuretic function of ADH.

Ligand binding

In the N-terminal juxtamembrane segment of the AVPR1A, the glutamate residue at position 54 (E54) and the arginine residue at position 46 (R46) are critical for binding with AVP and AVP agonists, with E54 likely to interact with AVP and R46 to contribute to a conformational switch.[3]

Competitors of [125I]Tyr-Phaa-specific binding to AVPR1A include:[2]

  • Linear V1a antagonist phenylacetyl-D-Tyr(Et)-Phe-Gln-Asn-Lys-Pro-Arg-NH2 (Ki = 1.2 ± 0.2 nM)
  • Relcovaptan (SR-49059) (Ki = 1.3 ± 0.2 nM)
  • AVP (Ki = 1.8 ± 0.4 nM)
  • Linear V1a antagonist phenylacetyl-D-Tyr(Et)-Phe-Val-Asn-Lys-Pro-Tyr-NH2 (Ki = 3.0 ± 0.5 nM)
  • V2 antagonist d(CH2)5-[D-Ile2, Ile4, Ala-NH2]AVP (Ki = 68 ± 17 nM)
  • Oxytocin (Ki = 129 ± 22 nM)

The AVPR1A is endocytosed by binding to beta-arrestin, which dissociates rapidly from AVPR1A to allow it to return to the plasma membrane; however, upon activation, AVPR1A can heterodimerize with AVPR2 to increase beta-arrestin-mediated endocytosis (and intracellular accumulation) of AVPR1A, since AVPR2 is far less likely to dissociate from beta-arrestin.[4]

Role in behavior

The activity/genetic variants of the AVPR1A gene might be related to generosity and altruistic behavior.[5] Nature News has referred to AVPR1A as the "ruthlessness gene".[6]

Prairie vs. montane voles

The injection of oxytocin (OXT) vs. oxytocin antagonist (OTA) at birth has sexually dimorphic effects in prairie voles later on in life in various areas of the brain.[7]

Males treated with OXT showed increases in Avpr1a in the ventral pallidum, lateral septum, and cingulate cortex, while females showed decreases; males treated with an OTA showed decreases in AVPR1A in the bed nucleus of the stria terminalis, medial preoptic area of the hypothalamus, and lateral septum.[7]

Although the Avpr1a coding region is 99% identical between prairie and montane voles, and binding and second messenger activity does not differ, patterns of distribution of Avpr1a differ drastically.[8]

Mice

Male knockout mice in Avpr1a have reduced anxiety-like behavior and greatly impaired social recognition abilities, without any defects in spatial and nonsocial olfactory learning and memory tasks, as measured by the elevated plus maze, light/dark box, Morris water maze, forced swim, baseline acoustic startle and prepulse inhibition (PPI), and olfactory habituation tests.[9] Some studies have shown Avpr1a knockout mice to have deficits in their circadian rhythms[10][11] and olfaction.[10]

Avpr1a's role in social recognition is particularly important in the lateral septum, as using viral vectors to replace inactivated Avpr1a expression rescues social recognition and increases anxiety-related behavior.[12] However, conflicting results have been found in another study.[10] Also, unlike vasopressin 1b receptor and oxytocin knockout mice, Avpr1a KO mice have a normal Bruce effect (appropriate failure of pregnancy in presence of novel male).[13]

Although activation of Avpr1a is a major mediator of anxiogenesis in males, it is not in females.[14]

Rats

Avpr1a transcripts are diurnally expressed 12 hours out of phase from vasopressin expression in vasopressin and vasoactive intestinal polypeptide neurons of the suprachiasmatic nucleus in both vasopressin-normal Sprague-Dawley rats, as well as vasopressin-deficient Brattleboro rats.[15]

Rats with reduced Avpr1a in the bed nucleus of the stria terminalis have increased incidences[spelling?] of the isolation potentiated startle, a measure of isolation-induced anxiety.[16]

Subchronic phencyclidine (PCP) treatment (which induces symptoms similar to those of schizophrenia) reduces Avpr1a density in many brain regions, implying there might be a role for AVPR1A in schizophrenia.[17]

Avpr1a is present in the lateral septum, neocortical layer IV, hippocampal formation, amygdalostriatal area, bed nucleus of the stria terminalis, suprachiasmatic nucleus, ventral tegmental area, substantia nigra, superior colliculus, dorsal raphe, nucleus of the solitary tract, spinal cord, and inferior olive, while mRNA transcripts for Avpr1a are found in the olfactory bulb, hippocampal formation, lateral septum, suprachiasmatic nucleus, paraventricular nucleus, anterior hypothalamic area, arcuate nucleus, lateral habenula, ventral tegmental area, substantia nigra (pars compacta), superior colliculus, raphe nuclei, locus coeruleus, inferior olive, choroid plexus, endothelial cells, area postrema and nucleus of the solitary tract.[1]

Humans

Although vasopressin cell and fibre distribution patterns are highly conserved across species (with centrally projecting systems being sexually dimorphic), the vasopressin receptor AVPR1A distribution differs both between and within species; vasopressin production occurs in the hypothalamus, bed nucleus of the stria terminalis, and the medial amygdala (projecting to the lateral septum and ventral pallidum), while vasopressin binding sites in humans are in the lateral septum, thalamus, basal amygdaloid nucleus, and brainstem, but not cortex.[18]

Human AVPR1A is situated on chromosome 12q14-15, and the promoter region does not have repeat sequences homologous to those found in prairie voles. Three polymorphic repetitive sequences have been found in humans in the 5’ flanking region: RS3, RS1, and a (GT)25 dinucleotide repeat.

A 2015 study found a correlation between AVPR1A expression and predisposition to extra-pair mating in women but not in men.[19]

Polymorphisms

RS3

The AVPR1A repeat polymorphism RS3 is a complex (CT)4-TT-(CT)8-(GT)24 repeat that is 3625 bp upstream of the transcription start site.

Homozygosity in allele 334 of RS3 is associated in men (but not women) with problems with pair-bonding behavior, measured by traits such as partner bonding, perceived marital problems, marital status, as well as spousal perception of marital quality.[20]

In a study of 203 male and female university students, participants with short (308–325 bp) vs. long (327–343) versions of RS3 were less generous, as measured by lower scores on both money allocations in the dictator game, as well as by self-report with the Bardi-Schwartz Universalism and Benevolence Value-expressive Behavior Scales; although the precise functional significance of longer AVPR1A RS3 repeats is not known, they are associated with higher AVPR1A postmortem hippocampal mRNA levels.[5]

Relative to all other alleles, the 334 allele of RS3 shows overactivation of left amygdala (in response to fearful face stimuli), with longer variants of RS3 additionally associated with stronger amygdala activation.[18]

RS1

The AVPR1A repeat polymorphism RS1 is a (GATA)14 tetranucleotide repeat that is 553 bp upstream from the transcription start site. Allele 320 in RS1 is associated with increased novelty seeking and decreased harm avoidance; additionally, relative to all other alleles, the 320 allele of RS1 showed significantly less activity in the left amygdala, with shorter variants showing a trend of stronger activity.[18]

Other microsatellites

The AGAT polymorphism is associated with age of first intercourse in females, with those homozygous for long repeats more likely to have sex before age 15 than any other genotype.[21] However, there is no evidence of preferential transmission of AVPR1A microsatellite repeats to hypersexual or uninhibited people-seeking.[22]

Polymorphisms in AVPR1A have also been shown to be associated with social interaction skills, and have been linked to such diverse traits as dancing and musical ability, altruism and autism.[23][24][25][26]

Chimpanzee populations have individuals with single (only (GT)25 microsatellite) and duplicated (the (GT)25 microsatellite as well as the RS3) alleles, with allele frequencies of 0.795 and 0.205, respectively.[27]

References

  1. ↑ 1.0 1.1 1.2 "Vasopressin: behavioral roles of an "original" neuropeptide". Progress in Neurobiology 84 (1): 1–24. Jan 2008. doi:10.1016/j.pneurobio.2007.10.007. PMID 18053631. 
  2. ↑ 2.0 2.1 "Molecular cloning, sequencing, and functional expression of a cDNA encoding the human V1a vasopressin receptor". The Journal of Biological Chemistry 269 (5): 3304–10. Feb 1994. doi:10.1016/S0021-9258(17)41863-1. PMID 8106369. 
  3. ↑ "The N-terminal juxtamembrane segment of the V1a vasopressin receptor provides two independent epitopes required for high-affinity agonist binding and signaling". Molecular Endocrinology 19 (11): 2871–81. Nov 2005. doi:10.1210/me.2005-0148. PMID 15994199. 
  4. ↑ "Heterodimerization of V1a and V2 vasopressin receptors determines the interaction with beta-arrestin and their trafficking patterns". Proceedings of the National Academy of Sciences of the United States of America 101 (6): 1548–53. Feb 2004. doi:10.1073/pnas.0305322101. PMID 14757828. Bibcode: 2004PNAS..101.1548T. 
  5. ↑ 5.0 5.1 "Individual differences in allocation of funds in the dictator game associated with length of the arginine vasopressin 1a receptor RS3 promoter region and correlation between RS3 length and hippocampal mRNA". Genes, Brain and Behavior 7 (3): 266–75. Apr 2008. doi:10.1111/j.1601-183X.2007.00341.x. PMID 17696996. 
  6. ↑ Hopkin, Michael (April 2008). "'Ruthlessness gene' discovered". Nature News. doi:10.1038/news.2008.738. "Dictatorial behaviour may be partly genetic, study suggests". 
  7. ↑ 7.0 7.1 "Neonatal oxytocin manipulations have long-lasting, sexually dimorphic effects on vasopressin receptors". Neuroscience 144 (1): 38–45. Jan 2007. doi:10.1016/j.neuroscience.2006.09.009. PMID 17055176. 
  8. ↑ "Vasopressin and pair-bond formation: genes to brain to behavior". Physiology 21 (2): 146–52. Apr 2006. doi:10.1152/physiol.00049.2005. PMID 16565480. 
  9. ↑ "Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice". Neuropsychopharmacology 29 (3): 483–93. Mar 2004. doi:10.1038/sj.npp.1300360. PMID 14647484. 
  10. ↑ 10.0 10.1 10.2 "Vasopressin 1a receptor knockout mice have a subtle olfactory deficit but normal aggression". Genes, Brain and Behavior 6 (6): 540–51. Aug 2007. doi:10.1111/j.1601-183X.2006.00281.x. PMID 17083331. 
  11. ↑ "Vasopressin receptor V1a regulates circadian rhythms of locomotor activity and expression of clock-controlled genes in the suprachiasmatic nuclei". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 296 (3): R824–30. Mar 2009. doi:10.1152/ajpregu.90463.2008. PMID 19052319. 
  12. ↑ "The V1a vasopressin receptor is necessary and sufficient for normal social recognition: a gene replacement study". Neuron 47 (4): 503–13. Aug 2005. doi:10.1016/j.neuron.2005.06.031. PMID 16102534. 
  13. ↑ "Inactivation of the oxytocin and the vasopressin (Avp) 1b receptor genes, but not the Avp 1a receptor gene, differentially impairs the Bruce effect in laboratory mice (Mus musculus)". Endocrinology 149 (1): 116–21. Jan 2008. doi:10.1210/en.2007-1056. PMID 17947352. 
  14. ↑ "Sexual dimorphism in the vasopressin system: lack of an altered behavioral phenotype in female V1a receptor knockout mice". Behavioural Brain Research 164 (1): 132–6. Oct 2005. doi:10.1016/j.bbr.2005.06.005. PMID 16046007. 
  15. ↑ "The diurnal rhythm in vasopressin V1a receptor expression in the suprachiasmatic nucleus is not dependent on vasopressin". Endocrinology 133 (2): 585–90. Aug 1993. doi:10.1210/en.133.2.585. PMID 8344200. 
  16. ↑ "Central oxytocin, vasopressin, and corticotropin-releasing factor receptor densities in the basal forebrain predict isolation potentiated startle in rats". The Journal of Neuroscience 25 (49): 11479–88. Dec 2005. doi:10.1523/JNEUROSCI.2524-05.2005. PMID 16339041. 
  17. ↑ "Subchronic phencyclidine administration alters central vasopressin receptor binding and social interaction in the rat". Brain Research 992 (2): 239–45. Dec 2003. doi:10.1016/j.brainres.2003.08.050. PMID 14625062. 
  18. ↑ 18.0 18.1 18.2 "Genetic variants in AVPR1A linked to autism predict amygdala activation and personality traits in healthy humans". Molecular Psychiatry 14 (10): 968–75. Oct 2009. doi:10.1038/mp.2008.54. PMID 18490926. 
  19. ↑ Zietsch, Brendan P.; Westberg, Lars; Santtila, Pekka; Jern, Patrick (2015). "Genetic analysis of human extrapair mating: heritability, between-sex correlation, and receptor genes for vasopressin and oxytocin". Evolution & Human Behavior 36 (2): 130–136. doi:10.1016/j.evolhumbehav.2014.10.001. http://espace.library.uq.edu.au/view/UQ:352859/UQ352859_OA.pdf. 
  20. ↑ "Genetic variation in the vasopressin receptor 1a gene (AVPR1A) associates with pair-bonding behavior in humans". Proceedings of the National Academy of Sciences of the United States of America 105 (37): 14153–6. Sep 2008. doi:10.1073/pnas.0803081105. PMID 18765804. Bibcode: 2008PNAS..10514153W. 
  21. ↑ "AVPR1A and OXTR polymorphisms are associated with sexual and reproductive behavioral phenotypes in humans. Mutation in brief no. 981. Online". Human Mutation 28 (11): 1150. Nov 2007. doi:10.1002/humu.9510. PMID 17939166. 
  22. ↑ "Are the arginine vasopressin V1a receptor microsatellites related to hypersexuality in children with a prepubertal and early adolescent bipolar disorder phenotype?". Bipolar Disorders 7 (6): 610–6. Dec 2005. doi:10.1111/j.1399-5618.2005.00259.x. PMID 16403186. 
  23. ↑ "AVPR1a and SLC6A4 gene polymorphisms are associated with creative dance performance". PLOS Genetics 1 (3): e42. Sep 2005. doi:10.1371/journal.pgen.0010042. PMID 16205790.  open access
  24. ↑ "Association between the arginine vasopressin 1a receptor (AVPR1a) gene and autism in a family-based study: mediation by socialization skills". Molecular Psychiatry 11 (5): 488–94. May 2006. doi:10.1038/sj.mp.4001812. PMID 16520824. 
  25. ↑ "Molecular genetic studies of the arginine vasopressin 1a receptor (AVPR1a) and the oxytocin receptor (OXTR) in human behaviour: from autism to altruism with some notes in between". Advances in Vasopressin and Oxytocin — from Genes to Behaviour to Disease. Progress in Brain Research. 170. 2008. pp. 435–49. doi:10.1016/S0079-6123(08)00434-2. ISBN 9780444532015. 
  26. ↑ Reif, Andreas, ed (2009). "Musical aptitude is associated with AVPR1A-haplotypes". PLOS ONE 4 (5): e5534. doi:10.1371/journal.pone.0005534. PMID 19461995. Bibcode: 2009PLoSO...4.5534U.  open access
  27. ↑ "Evolution of a behavior-linked microsatellite-containing element in the 5' flanking region of the primate AVPR1A gene". BMC Evolutionary Biology 8: 180. Jun 2008. doi:10.1186/1471-2148-8-180. PMID 18573213. 

Further reading

External links



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