Arginine vasopressin receptor 1A
Encyclopedia
Arginine vasopressin receptor 1A (officially called AVPR1A) is one of the three major receptor types for arginine 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.
Arginine vasopressin receptor 1A is also known as:
, respectfully. 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.
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 [125I]Tyr-Phaa-specific binding to AVPR1A include:
Synthetic antagonists of AVPR1A include Relcovaptan
and PF-184563
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.
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 OXT showed increases in Avpr1a in the ventral palladium, 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.
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.
, light/dark box, Morris water maze
, forced swim, baseline acoustic startle and prepulse inhibition (PPI)
, and olfactory habituation tests. Some studies have shown Avpr1a knockout mice to have deficits in their circadian rhythms and olfaction.
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, respectively. However, conflicting results have been found in another study. Also, unlike vasopressin 1b receptor and oxytcoin knockout mice, Avpr1a KO mice have a normal Bruce effect
(appropriate failure of pregnancy in presence of novel male).
Although activation of Avpr1a is a major mediator of anxiogenesis
in males, it is not in females.
in both vasopressin-normal Sprague-Dawley rats, as well as vasopressin-deficient Brattleboro rat
s.
Rats with reduced Avpr1a 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 (which induces schizophrenic
symptoms) reduces Avpr1a density in many brain regions, implying there might be a role for AVPR1A in schizophrenia.
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.
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.
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.
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.
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
.
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.
Vasopressin
Arginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...
(AVPR1B
Arginine vasopressin receptor 1B
Arginine vasopressin receptor 1B is a protein that acts as receptor for arginine vasopressin. AVPR1B belongs to the subfamily of G-protein coupled receptors...
and AVPR2
Arginine vasopressin receptor 2
Arginine vasopressin receptor 2 is a protein that acts as receptor for arginine vasopressin. AVPR2 belongs to the subfamily of G-protein-coupled receptors...
being the others), and is present throughout the brain, as well as in the periphery in the liver, kidney, and vasculature.
Arginine vasopressin receptor 1A 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)Oxytocin receptor
The oxytocin receptor, also known as OXTR, is a protein which functions as receptor for the hormone and neurotransmitter oxytocin. In humans, the oxytocin receptor is encoded by the OXTR gene., which has been localized to human chromosome 3p25....
, respectfully. AVPR1A is a G-protein coupled receptor (GPCR)
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
with 7 transmembrane domains that couples to Gaq/11
Gq alpha subunit
Gq protein or Gq/11 is a heterotrimeric G protein subunit that activates phospholipase C . PLC in turn hydrolyzes Phosphatidylinositol 4,5-bisphosphate to diacyl glycerol and inositol triphosphate signal transduction pathway...
GTP binding proteins, which along with Gbl, activate phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
activity.
Ligand binding
In the N-terminal juxtamembrane segment of the AVPR1A, the glutamate residue at position 54 (E54) and the arginineArginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
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 [125I]Tyr-Phaa-specific binding to AVPR1A include:
- linear V1a antagonist phenylacetyl-D-Tyr(Et)-Phe-Gln-Asn-Lys-Pro-Arg-NH2 (Ki = 1.2 ± 0.2 nM)
- linear V1a non-peptide antagonist 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 = 68 ± 17 nM)
Synthetic antagonists of AVPR1A include Relcovaptan
Relcovaptan
Relcovaptan is a non-peptide vasopressin receptor antagonist, selective for the V1a subtype. It has shown positive initial results in tests against Raynaud's disease, dysmenorrhoea, and tocolysis, although it is not yet approved for clinical use.-References:...
and PF-184563
PF-184563
PF-184563 is a potent, selective non-peptidic antagonist of the V1a receptor.. The compound was discovered by Pfizer in its Sandwich, Kent research center, as a potential treatment for dysmenorrhoea, an indication for which V1a antagonists have shown efficacy..-References:...
The AVPR1A is endocytosed
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
by binding to beta arrestin
Arrestin
Arrestins are a small family of proteins important for regulating signal transduction.-Function:Arrestins were first discovered as a part of a conserved two-step mechanism for regulating the activity of G protein-coupled receptors in the visual rhodopsin system by Hermann Kühn and co-workers and...
, 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.
Role in behavior
The activity / genetic variants of the AVPR1A gene might be related to generosity and altruistic behavior. NatureNews has referred to AVPR1A as the "ruthlessness gene".Prairie vs. montane voles
The injection of oxytocin (OXT)Oxytocin
Oxytocin is a mammalian hormone that acts primarily as a neuromodulator in the brain.Oxytocin is best known for its roles in sexual reproduction, in particular during and after childbirth...
vs. oxytocin antagonist (OTA) at birth has sexually dimorphic
Sexual dimorphism
Sexual dimorphism is a phenotypic difference between males and females of the same species. Examples of such differences include differences in morphology, ornamentation, and behavior.-Examples:-Ornamentation / coloration:...
effects in prairie voles
Prairie Vole
The Prairie Vole is a small vole found in central North America. The vole has long, coarse grayish-brown fur on the upper portion of the body and yellowish fur on the lower portion of the body...
later on in life in various areas of the brain.
Males treated with OXT showed increases in Avpr1a in the ventral palladium, lateral septum, and cingulate cortex
Cingulate cortex
The cingulate cortex is a part of the brain situated in the medial aspect of the cortex. It includes the cortex of the cingulate gyrus, which lies immediately above the corpus callosum, and the continuation of this in the cingulate sulcus...
, while females showed decreases; males treated with an OTA showed decreases in AVPR1A in the bed nucleus of the stria terminalis
Terminal stria
The stria terminalis is a structure in the brain consisting of a band of fibers running along the lateral margin of the ventricular surface of the thalamus...
, medial preoptic area of the hypothalamus
Preoptic area
The preoptic area is a region of the hypothalamus. According to the MeSH classification, it is considered part of the anterior hypothalamus. There are four nuclei in this region, according to Terminologia Anatomica .-Functions:The preoptic area is responsible for thermoregulation and receives...
, and lateral septum.
Although the Avpr1a coding region is 99% identical between prairie and montane voles
Montane Vole
The Montane Vole is a species of rodent in the family Cricetidae.It is found in the western United States and British Columbia in Canada.-References:...
, and binding and second messenger activity does not differ, patterns of distribution of Avpr1a differ drastically.
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 mazeElevated plus maze
The elevated plus maze is a rodent model of anxiety that is used as a screening test for putative anxiolytic or anxiogenic compounds and as a general research tool in neurobiological anxiety research.-Method:...
, light/dark box, Morris water maze
Morris water maze
The Morris water navigation task is a behavioral procedure widely used in behavioral neuroscience to study spatial learning and memory. It was developed by neuroscientist Richard G...
, forced swim, baseline acoustic startle and prepulse inhibition (PPI)
Prepulse inhibition
Prepulse Inhibition is a neurological phenomenon in which a weaker prestimulus inhibits the reaction of an organism to a subsequent strong startling stimulus . The stimuli are usually acoustic, but tactile stimuli Prepulse Inhibition (PPI) is a neurological phenomenon in which a weaker...
, and olfactory habituation tests. Some studies have shown Avpr1a knockout mice to have deficits in their circadian rhythms and olfaction.
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, respectively. However, conflicting results have been found in another study. Also, unlike vasopressin 1b receptor and oxytcoin knockout mice, Avpr1a KO mice have a normal Bruce effect
Bruce effect
The Bruce effect, or pregnancy block, refers to the tendency for female rodents to terminate their pregnancies following exposure to the scent of an unfamiliar male. The effect has primarily been studied in laboratory mice , but is also observed in deer-mice, meadow voles, and collared lemmings...
(appropriate failure of pregnancy in presence of novel male).
Although activation of Avpr1a is a major mediator of anxiogenesis
Anxiogenic
An anxiogenic substance is one that causes anxiety. Anxiogenic effects can be measured by, for example, the hole-board test in rats and mice. A number of agents are used to provoke anxiety or panic in experimental models...
in males, it is not in females.
Rats
Avpr1a transcripts are diurnally expressed 12 hours out of phase from vasopressin expression in vasopressin and vasoactive intestinal polypeptide neurons of the suprachiasmatic nucleusSuprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms...
in both vasopressin-normal Sprague-Dawley rats, as well as vasopressin-deficient Brattleboro rat
Brattleboro rat
The Brattleboro rat is a strain of laboratory rat descended from a litter born in West Brattleboro, Vermont in 1961 without the ability to produce the hormone vasopressin, which helps control kidney function. The rats' lack of vasopressin was the result of a naturally occurring genetic mutation.The...
s.
Rats with reduced Avpr1a 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)
Phencyclidine
Phencyclidine , commonly initialized as PCP and known colloquially as angel dust, is a recreational dissociative drug...
treatment (which induces schizophrenic
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
symptoms) reduces Avpr1a density in many brain regions, implying there might be a role for AVPR1A in schizophrenia.
Avpr1a is present in the lateral septum, neocortical layer IV
Neocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
, hippocampal formation
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, amygdalostriatal area, bed nucleus of the stria terminalis, suprachiasmatic nucleus, ventral tegmental area
Ventral tegmentum
The ventral tegmentum , better known as the ventral tegmental area , is a group of neurons located close to the midline on the floor of the midbrain...
, substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
, superior colliculus
Superior colliculus
The optic tectum or simply tectum is a paired structure that forms a major component of the vertebrate midbrain. In mammals this structure is more commonly called the superior colliculus , but, even in mammals, the adjective tectal is commonly used. The tectum is a layered structure, with a...
, dorsal raphe, nucleus of the solitary tract
Solitary nucleus
The solitary tract and nucleus are structures in the brainstem that carry and receive visceral sensation and taste from the facial , glossopharyngeal and vagus cranial nerves.-Anatomy:...
, spinal cord, and inferior olive
Inferior olivary nucleus
The inferior olivary nucleus is the largest nucleus situated in the olivary body, part of the medulla oblongata.-Function:It is closely associated with the cerebellum, meaning that it is involved in control and coordination of movements, sensory processing and cognitive tasks likely by encoding the...
, while mRNA transcripts for Avpr1a are found in the olfactory bulb
Olfactory bulb
The olfactory bulb is a structure of the vertebrate forebrain involved in olfaction, the perception of odors.-Anatomy:In most vertebrates, the olfactory bulb is the most rostral part of the brain. In humans, however, the olfactory bulb is on the inferior side of the brain...
, 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.
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.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.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 seekingNovelty seeking
In psychology, novelty seeking is a personality trait.It is measured in the Tridimensional Personality Questionnaire as well as the later version Temperament and Character Inventory.NS has been suggested to be related to low dopaminergic activity....
and decreased harm avoidance
Harm avoidance
In psychology, harm avoidance is a personality trait characterized by excessive worrying; pessimism; shyness; and being fearful, doubtful, and easily fatigued...
; 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.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
Altruism
Altruism is a concern for the welfare of others. It is a traditional virtue in many cultures, and a core aspect of various religious traditions, though the concept of 'others' toward whom concern should be directed can vary among cultures and religions. Altruism is the opposite of...
and autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
.
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.