The oxytocin receptor, also known as OXTR, is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
which functions as
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
for the
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
and
neurotransmitter oxytocin
Oxytocin (Oxt or OT) is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. It plays a role in social bonding, reproduction, childbirth, and the period after childbirth. Oxytocin ...
.
In humans, the oxytocin receptor is encoded by the ''OXTR''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
which has been localized to human
chromosome 3p25.
Function and location
The OXTR protein belongs to the
G-protein coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of protein family, evolution ...
family, specifically
Gq,
and acts as a receptor for oxytocin. Its activity is mediated by
G protein
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...
s that activate several different
second messenger
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
systems.
Oxytocin receptors are expressed by the
myoepithelial cell
Myoepithelial cells (sometimes referred to as myoepithelium) are cells usually found in glandular epithelium as a thin layer above the basement membrane but generally beneath the luminal cells. These may be positive for alpha smooth muscle actin a ...
s of the
mammary gland
A mammary gland is an exocrine gland in humans and other mammals that produces milk to feed young offspring. Mammals get their name from the Latin word ''mamma'', "breast". The mammary glands are arranged in organs such as the breasts in primat ...
, and in both the
myometrium
The myometrium is the middle layer of the uterine wall, consisting mainly of uterine smooth muscle cells (also called uterine myocytes) but also of supporting stromal and vascular tissue. Its main function is to induce uterine contractions.
Struc ...
and
endometrium
The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional laye ...
of the
uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...
at the end of
pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ca ...
.
The oxytocin-oxytocin receptor system plays an important role as an inducer of uterine contractions during
parturition
Birth is the act or process of bearing or bringing forth offspring, also referred to in technical contexts as parturition. In mammals, the process is initiated by hormones which cause the muscular walls of the uterus to contract, expelling the f ...
and of milk ejection.
OXTR is also associated with the central nervous system. The gene is believed to play a major role in social, cognitive, and emotional behavior.
A decrease in OXTR expression by methylation of the ''OXTR'' gene is associated with
Callous and unemotional traits in adolescence, rigid thinking in
anorexia nervosa
Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gr ...
, problems with facial and emotional recognition, and difficulties in the
affect regulation. A reduction in this gene is believed to lead to prenatal stress, postnatal depression, and social anxiety.
Further research must be gathered before concluding these findings, however strong evidence is pointing in this direction. Studies on ''OXTR'' methylation—which downregulates oxytocin mechanisms—suggest this process is associated with increased gray matter density in the amygdala, implicating ''OXTR'' regulation in stress and parasympathetic regulation.
In some mammals, oxytocin receptors are also found in the
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
and
heart
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
.
Mesolimbic dopamine pathways
The oxytocinergic circuit projecting from the
paraventricular hypothalamic nucleus
The paraventricular nucleus (PVN, PVA, or PVH) is a nucleus in the hypothalamus. Anatomically, it is adjacent to the third ventricle and many of its neurons project to the posterior pituitary. These projecting neurons secrete oxytocin and a smaller ...
(PVN) innervates the
ventral tegmental area
The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the ...
(VTA) dopaminergic neurons that project to the
nucleus accumbens
The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for " nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypot ...
, i.e., the
mesolimbic pathway
The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmentum, ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the for ...
.
Activation of the PVN→VTA projection by oxytocin affects sexual, social, and addictive behavior via this link to the mesolimbic pathway;
specifically, oxytocin exerts a prosexual and prosocial effect in this region.
Polymorphism
The receptors for oxytocin (OXTR) have genetic differences with varied effects on individual behavior. The
polymorphism (rs53576) occurs on the third
intron
An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...
of OXTR in three types: GG, AG, AA. The GG allele is connected with oxytocin levels in people . A-allele carrier individuals are associated with more sensitivity to stress, fewer social skills, and more mental health issues than the GG-carriers.
In a study looking at
empathy
Empathy is the capacity to understand or feel what another person is experiencing from within their frame of reference, that is, the capacity to place oneself in another's position. Definitions of empathy encompass a broad range of social, co ...
and
stress
Stress may refer to:
Science and medicine
* Stress (biology), an organism's response to a stressor such as an environmental condition
* Stress (linguistics), relative emphasis or prominence given to a syllable in a word, or to a word in a phrase ...
, individuals with the allele GG scored higher than A-carrier individuals in a "Reading the Mind in the Eyes" test. GG carriers, with their naturally higher levels of oxytocin , were better able to distinguish between emotions. A-allele carriers responded with more stress to stressful situations than GG-allele carriers.
A-allele carriers had lower scores on psychological resources, like optimism, mastery, and self-esteem, than GG individuals when measured with factor analysis for depressive symptomology and psychological resources, along with the
Beck Depression Inventory
The Beck Depression Inventory (BDI, BDI-1A, BDI-II), created by Aaron T. Beck, is a 21-question multiple-choice self-report inventory, one of the most widely used psychometric tests for measuring the severity of depression. Its development mar ...
. A-allele carriers had higher depressive symptomology and lower psychological resources than GG individuals.
A-allele individuals scored lower in human sociality than GG people on a
Tridimensional Personality Questionnaire Tridimensional Personality Questionnaire (TPQ) is a personality test.
It was devised by C. Robert Cloninger.
A newer version of the questionnaire is called Temperament and Character Inventory.
As the name indicates TPQ seeks to measure three dimen ...
. AA individuals had the lowest amygdala activation while processing emotionally salient information and those with GG had the highest activity when tested using BOLD during an
fMRI
Functional magnetic resonance imaging or functional MRI (fMRI) measures brain activity by detecting changes associated with blood flow. This technique relies on the fact that cerebral blood flow and neuronal activation are coupled. When an area ...
.
On the other hand, variations at the CD38 rs3796863 and OXTR rs53576 loci were not associated with psychosocial characteristics of adolescents assessed with the
Strengths and Difficulties Questionnaire (SDQ); in studies with a similar design, authors recommend replication with larger samples and greater power to detect small effects, especially in age–sex subgroups of adolescents.
The frequency of the A allele varies among ethnic groups, being significantly more common among East Asians than Europeans.
Some evidence suggests an association between OXTR gene polymorphism and Autism Spectrum Disorder (ASD). Studies have done research focusing on variants in the third intron of the gene, a region that is strongly correlated with personality traits and ASD. OXTR knockout mice have shown abnormal behaviors such as social impairments and aggressiveness. These abnormalities can be reduced with oxytocin or oxytocin agonist administration. Overall, the study suggests that rare variants are considerably more abundant in individuals with ASD compared to that of a normal individual, however further research with larger sample sizes must be completed before concluding any information.
Ligands
Several selective
ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
s for the oxytocin receptor have recently been developed, but close similarity between the oxytocin and related
vasopressin
Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then trave ...
receptors make it difficult to achieve high selectivity with peptide derivatives.
However the search for a druggable, non-peptide template has led to several potent, highly selective, orally bioavailable oxytocin antagonists.
Agonists
;Peptide
*
Carbetocin
Carbetocin, sold under the brand names Pabal among others, is a medication used to prevent excessive bleeding after childbirth, particularly following Cesarean section. It appears to work as well as oxytocin. Due to it being less economical than ...
*
Demoxytocin
Demoxytocin ( INN) (brand names Sandopart, Odeax, Sandopral), also known as desaminooxytocin or deaminooxytocin, as well as 1-(3-mercaptopropanoic acid)oxytocin ( Mpa1.html" ;"title="/nowiki>Mpa1">/nowiki>Mpa1/nowiki>OT), is an oxytocic peptide dr ...
*
Lipo-oxytocin-1
*
Merotocin
Merotocin (INN) (developmental code name FE-202767), also known as carba-1-(4-FBzlGly7)dOT, is a peptidic agonist of the oxytocin receptor that was derived from oxytocin. It is under development by Ferring Pharmaceuticals for the treatment of p ...
*
Oxytocin
Oxytocin (Oxt or OT) is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. It plays a role in social bonding, reproduction, childbirth, and the period after childbirth. Oxytocin ...
;Non-peptide
*
TC OT 39
TC OT 39 is a non-peptide partial agonist
In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligand ...
– non-selective over vasopressin receptors
*
WAY-267,464
WAY-267464 is a potent, selective, non-peptide agonist for the oxytocin receptor, with negligible affinity for the vasopressin receptors. Contradictorily however, though originally described as selective for the oxytocin receptor and lacking aff ...
–
anxiolytic
An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxi ...
in mice; possibly non-selective over vasopressin receptors
Antagonists
;Peptide
*
Atosiban
Atosiban, sold under the brand name Tractocile among others, is an inhibitor of the hormones oxytocin and vasopressin. It is used as an intravenous medication as a labour repressant (tocolytic) to halt premature labor. It was developed by Ferri ...
*
Barusiban
;Non-peptide
*
Epelsiban
Epelsiban ( INN, USAN, code name GSK-557,296-B) is an orally bioavailable drug which acts as a selective and potent oxytocin receptor antagonist ( Ki = 0.13 nM). It was initially developed by GlaxoSmithKline (GSK) for the treatment of premature ...
*
L-368,899
L-368,899 is a drug used in scientific research which acts as a selective antagonist of the oxytocin receptor, with good selectivity over the related vasopressin receptors. Unlike related drugs such as the peripherally selective L-371,257, the ora ...
(CAS# 148927-60-0)
*
L-371,257
L-371,257 is a compound used in scientific research which acts as a selective antagonist of the oxytocin receptor with over 800x selectivity over the related vasopressin receptors. It was one of the first non-peptide oxytocin antagonists develope ...
(CAS# 162042-44-6)
– peripherally selective (i.e. poor
blood brain barrier
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...
penetration, few central effects)
*
L-372,662
*
Retosiban
Retosiban also known as GSK-221,149-A is an oral drug which acts as an oxytocin receptor antagonist. It is being developed by GlaxoSmithKline for the treatment of preterm labour. Retosiban has high affinity for the oxytocin receptor (Ki = 0.65 ...
(GSK-221,149)
*
SSR-126,768
*
WAY-162,720 – centrally active following peripheral administration
References
External links
*
*
*
{{Oxytocin and vasopressin receptor modulators
G protein-coupled receptors
Genes on human chromosome 3