User:Gotogo272y/Sandbox

Arginine vasopressin receptor 1A. Avpr1a is one of the three major receptor types for AVP (Avpr1b and Avpr2 being the others), and is present throughout the brain, as well as in the periphery in the liver, kidney, and vasculature.

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

= Structure & Function =

Human V1aR cDNA is 1472 bp long and encodes a 418 amino-acid long polypeptide which shares 72%, 36%, 37%, and 45% sequence identity with rat V1aR, human V2R, rat V2R, and human OXTR. V1aR 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.

= Receptor ligand binding =

In the N-terminal juxtamembrane segment of the V1a receptor, the glutamine 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.

Competitors of [125 I]TyrPhaa-specific binding :
 * 1) linear V1a antagonist phenylacetyl-D-Tyr(Et)-Phe-Gln-Asn-Lys-Pro-Arg-NH2 (Ki = 1.24+/-0.16 nM)
 * 2) linear V1a non-peptide antagonist SR 49059 (Ki = 1.29+/-0.17 nM)
 * 3) AVP (Ki=1.79+/-0.36 nM)
 * 4) Linear V1a antagonist phenylacetyl-D-Tyr(Et)-Phe-Val-Asn-Lys-Pro-Tyr-NH2 (Ki = 2.96+/-0.52 nM)
 * 5) V2 antagonist d(CH2)5-[D-Ile^2, Ile^4, Ala-NH2]AVP (Ki=67.71+/-16.91 nM)
 * 6) Oxytocin (Ki=67.91+/-16.91 nM)

The V1aR receptor is endocytosed by binding to beta arrestin, which dissociates rapidly from V1aR to allow it to return to the plasma membrane; however, upon activation, V1aR can heterodimerize with V2R to increase beta-arrestin-mediated endocytosis (and intracellular accumulation) of V1aR, since V2R is far less likely to dissociate from beta-arrestin.

= Animal Models =

Prairie Voles vs. Montane voles
The injection of oxytocin (OT) vs. oxytocin antagonist (OTA) at birth has sexually dimorphic effects in prairie voles later on in life in various areas of the brain.

Males treated with OT showed increases in V1aR in the ventral palladium, lateral septum, and cingulated cortex, while females showed decreases; males treated with an OTA showed decreases in V1aR in the bed nucleus of the stria terminalis, medial preoptic area of the hypothalamus, and lateral septum.

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.

Mice
Male knockout mice in V1aR 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), social recognition, and olfactory habituation tests.

V1aR’s role in social recognition is particularly important in the lateral septum, as using viral vectors to reexpress and then overexpress V1aR expression rescues social recognition and increases anxiety-related behavior, respectively. However, conflicting results have been found in other studies.

Although activation of V1aR is a major mediator of anxiogenesis in males, it is not in females.

Rats
V1aR 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.

Rats with reduced V1aR in the bed nucleus of the stria terminalis have increased incidences of the isolation potentiated startle, a measure of isolation-induced anxiety.

Interestingly, subchronic phencyclidine (PCP) treatment reduces AVPR1a receptor density in many brain regions.

AVPR1a is present in the lateral septum, neocortical layer IV, hippocampal formation, amygdalostriatal area, BNST, suprachiasmatic nucleus, ventral tegmental area, substantia nigra, superior colliculus, dorsal raphe, nucleus of the solitary tract and inferior olive, spinal cord, while mRNA transcripts for Avpr1a are found in the olfactory bulb, hippocampal formation, LS, SCN, PVN, 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.

Humans
Although vasopressin cell and fibre distribution patterns are highly conserved across species (with centrally projecting systems being sexually dimorphic), the vasopressin receptor V1aR 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.

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.

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.

Allele 334
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.

In a study of 203 male and female university students, participants with short (308-325 bp) vs. long (327-342) 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.

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.

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.

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.

However, there is no evidence of preferential transmission of AVPR1a microsattelite repeats to hypersexual or uninhibited people-seeking.

Chimpanzees
Chimpanzees populations have individuals with single (only (GT)25 microsattelite) and duplicated (the (GT)25 microsattelite as well as the RS3) alleles, with allele frequencies of 0.795 and 0.205, respectively.