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.[5]
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.[5][6] 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.[7]
Competitors of [125I]Tyr-Phaa-specific binding to AVPR1A include:[6]
Linear V1a antagonist phenylacetyl-D-Tyr(Et)-Phe-Gln-Asn-Lys-Pro-Arg-NH2 (Ki = 1.2 ± 0.2 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.[8]
Role in behavior
The activity/genetic variants of the AVPR1A gene might be related to generosity and altruistic behavior.[9] Nature News has referred to AVPR1A as the "ruthlessness gene".[10]
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.[12]
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.[13] Some studies have shown Avpr1a knockout mice to have deficits in their circadian rhythms[14][15] and olfaction.[14]
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.[16] However, conflicting results have been found in another study.[14] 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).[17]
Although activation of Avpr1a is a major mediator of
anxiogenesis in males, it is not in females.[18]
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.[19]
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.[20]
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.[21]
Although vasopressin cell and fiber 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.[22]
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.[23]
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.[24]
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.[9]
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.[22]
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.[22]
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.[25] However, there is no evidence of preferential transmission of AVPR1A microsatellite repeats to hypersexual or uninhibited people-seeking.[26]
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.[27][28][29][30]
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.[31]
^Hopkin, Michael (April 2008). "'Ruthlessness gene' discovered". Nature News.
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10.1038/news.2008.738. Dictatorial behaviour may be partly genetic, study suggests
^Bielsky IF, Hu SB, Young LJ (Oct 2005). "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.
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^Young WS, Kovács K, Lolait SJ (Aug 1993). "The diurnal rhythm in vasopressin V1a receptor expression in the suprachiasmatic nucleus is not dependent on vasopressin". Endocrinology. 133 (2): 585–90.
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^Tanaka K, Suzuki M, Sumiyoshi T, Murata M, Tsunoda M, Kurachi M (Dec 2003). "Subchronic phencyclidine administration alters central vasopressin receptor binding and social interaction in the rat". Brain Research. 992 (2): 239–45.
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^Geller B, Tillman R, Badner JA, Cook EH (Dec 2005). "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.
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^Israel S, Lerer E, Shalev I, Uzefovsky F, Reibold M, Bachner-Melman R, Granot R, Bornstein G, Knafo A, Yirmiya N, Ebstein RP (2008). "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. Vol. 170. pp. 435–49.
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