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Oxytocin receptor

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OXTR
Identifiers
AliasesOXTR, OT-R, oxytocin receptor
External IDsOMIM: 167055; MGI: 109147; HomoloGene: 20255; GeneCards: OXTR; OMA:OXTR - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5021

18430

Ensembl

ENSG00000180914

ENSMUSG00000049112

UniProt

P30559

P97926

RefSeq (mRNA)

NM_000916

NM_001081147

RefSeq (protein)

NP_000907
NP_001341582
NP_001341583
NP_001341584
NP_001341585

NP_001074616

Location (UCSC)n/aChr 6: 112.45 – 112.47 Mb
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

The oxytocin receptor, also known as OXTR, is a protein which functions as receptor for the hormone and neurotransmitter oxytocin.[4][5] In humans, the oxytocin receptor is encoded by the OXTR gene[6][7] which has been localized to human chromosome 3p25.[8]

Evolutionary tree of the oxytocin, vasotocin, mesotocin and isotocin receptors and their ligands. From Koechbach et al.[9]

Function and location

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The OXTR protein belongs to the G-protein coupled receptor family, specifically Gq,[4] and acts as a receptor for oxytocin. Its activity is mediated by G proteins that activate several different second messenger systems.[10][11]

Oxytocin receptors are expressed by the myoepithelial cells of the mammary gland, and in both the myometrium and endometrium of the uterus at the end of pregnancy. The oxytocin-oxytocin receptor system plays an important role as an inducer of uterine contractions during parturition 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.[12] 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, 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.[12] 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.[13]

In some mammals, oxytocin receptors are also found in the kidney and heart.

Mesolimbic dopamine pathways

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The oxytocinergic circuit projecting from the paraventricular hypothalamic nucleus (PVN) innervates the ventral tegmental area (VTA) dopaminergic neurons that project to the nucleus accumbens, i.e., the mesolimbic pathway.[14] Activation of the PVN→VTA projection by oxytocin affects sexual, social, and addictive behavior via this link to the mesolimbic pathway;[14] specifically, oxytocin exerts a prosexual and prosocial effect in this region.[14]

Polymorphism

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The receptors for oxytocin (OXTR) have genetic differences with varied effects on individual behavior. The polymorphism (rs53576) occurs on the third intron of OXTR in three types: GG, AG, AA. The GG allele is connected with oxytocin levels in people [citation needed]. A-allele carrier individuals are associated with more sensitivity to stress, fewer social skills, and more mental health issues than the GG-carriers.[15][qualify evidence]

In a study looking at empathy and stress, 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.[citation needed] A-allele carriers responded with more stress to stressful situations than GG-allele carriers.[16][further explanation needed] 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. A-allele carriers had higher depressive symptomology and lower psychological resources than GG individuals.[15][qualify evidence] A-allele individuals scored lower in human sociality than GG people on a Tridimensional Personality Questionnaire. 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.[17] 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.[18]

The frequency of the A allele varies among ethnic groups, being significantly more common among East Asians than Europeans.[19][quantify][additional citation(s) needed]

Some evidence suggests an association between OXTR gene polymorphism, IQ, and autism spectrum disorder (ASD).[20] 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.[21]

Ligands

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Several selective ligands for the oxytocin receptor have recently been developed, but close similarity between the oxytocin and related vasopressin receptors make it difficult to achieve high selectivity with peptide derivatives.[22][23] However the search for a druggable, non-peptide template has led to several potent, highly selective, orally bioavailable oxytocin antagonists.[24] Oxytocin receptor agonists have also been developed.[25][26]

Agonists

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Peptide
Non-peptide

Antagonists

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Peptide
Non-peptide

References

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  1. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000049112 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ a b Gimpl G, Fahrenholz F (April 2001). "The oxytocin receptor system: structure, function, and regulation". Physiological Reviews. 81 (2): 629–83. doi:10.1152/physrev.2001.81.2.629. PMID 11274341. S2CID 13265083.
  5. ^ Zingg HH, Laporte SA (July 2003). "The oxytocin receptor". Trends in Endocrinology and Metabolism. 14 (5): 222–7. doi:10.1016/S1043-2760(03)00080-8. PMID 12826328. S2CID 21540056.
  6. ^ EntrezGene 5021
  7. ^ Kimura T, Tanizawa O, Mori K, Brownstein MJ, Okayama H (April 1992). "Structure and expression of a human oxytocin receptor" (PDF). Nature. 356 (6369): 526–9. Bibcode:1992Natur.356..526K. doi:10.1038/356526a0. PMID 1313946. S2CID 4273722. Archived from the original (PDF) on 2017-09-21. Retrieved 2021-05-29.
  8. ^ Simmons CF, Clancy TE, Quan R, Knoll JH (April 1995). "The oxytocin receptor gene (OXTR) localizes to human chromosome 3p25 by fluorescence in situ hybridization and PCR analysis of somatic cell hybrids". Genomics. 26 (3): 623–5. doi:10.1016/0888-7543(95)80188-R. PMID 7607693.
  9. ^ Koehbach J, Stockner T, Bergmayr C, Muttenthaler M, Gruber CW (February 2013). "Insights into the molecular evolution of oxytocin receptor ligand binding". Biochemical Society Transactions. 41 (1): 197–204. doi:10.1042/BST20120256. PMC 3634130. PMID 23356283.
  10. ^ Devost D, Wrzal P, Zingg HH (2008). "Oxytocin receptor signalling". Advances in Vasopressin and Oxytocin — from Genes to Behaviour to Disease. Progress in Brain Research. Vol. 170. pp. 167–76. doi:10.1016/S0079-6123(08)00415-9. ISBN 978-0-444-53201-5. PMID 18655881.
  11. ^ Gimpl G, Reitz J, Brauer S, Trossen C (2008). "Oxytocin receptors: ligand binding, signalling and cholesterol dependence". Advances in Vasopressin and Oxytocin — from Genes to Behaviour to Disease. Progress in Brain Research. Vol. 170. pp. 193–204. doi:10.1016/S0079-6123(08)00417-2. ISBN 978-0-444-53201-5. PMID 18655883.
  12. ^ a b Maud C, Ryan J, McIntosh JE, Olsson CA (May 2018). "The role of oxytocin receptor gene (OXTR) DNA methylation (DNAm) in human social and emotional functioning: a systematic narrative review". BMC Psychiatry. 18 (1): 154. doi:10.1186/s12888-018-1740-9. PMC 5975530. PMID 29843655.
  13. ^ Lancaster K, Goldbeck L, Puglia MH, Morris JP, Connelly JJ (November 2018). "DNA methylation of OXTR is associated with parasympathetic nervous system activity and amygdala morphology". Social Cognitive and Affective Neuroscience. 13 (11): 1155–1162. doi:10.1093/scan/nsy086. PMC 6234329. PMID 30257007.
  14. ^ a b c McGregor IS, Callaghan PD, Hunt GE (May 2008). "From ultrasocial to antisocial: a role for oxytocin in the acute reinforcing effects and long-term adverse consequences of drug use?". British Journal of Pharmacology. 154 (2): 358–68. doi:10.1038/bjp.2008.132. PMC 2442436. PMID 18475254. Recent studies also highlight remarkable anxiolytic and prosocial effects of intranasally administered OT in humans, including increased 'trust', decreased amygdala activation towards fear-inducing stimuli, improved recognition of social cues and increased gaze directed towards the eye regions of others (Kirsch et al., 2005; Kosfeld et al., 2005; Domes et al., 2006; Guastella et al., 2008).
  15. ^ a b Saphire-Bernstein S, Way BM, Kim HS, Sherman DK, Taylor SE (September 2011). "Oxytocin receptor gene (OXTR) is related to psychological resources". Proceedings of the National Academy of Sciences of the United States of America. 108 (37): 15118–22. Bibcode:2011PNAS..10815118S. doi:10.1073/pnas.1113137108. PMC 3174632. PMID 21896752.
  16. ^ Rodrigues SM, Saslow LR, Garcia N, John OP, Keltner D (December 2009). "Oxytocin receptor genetic variation relates to empathy and stress reactivity in humans". Proceedings of the National Academy of Sciences of the United States of America. 106 (50): 21437–41. Bibcode:2009PNAS..10621437R. doi:10.1073/pnas.0909579106. PMC 2795557. PMID 19934046.
  17. ^ Tost H, Kolachana B, Hakimi S, Lemaitre H, Verchinski BA, Mattay VS, et al. (August 2010). "A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function". Proceedings of the National Academy of Sciences of the United States of America. 107 (31): 13936–41. Bibcode:2010PNAS..10713936T. doi:10.1073/pnas.1003296107. PMC 2922278. PMID 20647384.
  18. ^ Tereshchenko S, Kasparov E, Zobova S, Smolnikova M, Evert L, Semenova N, et al. (2021). "Oxytocin Pathway Gene (CD38, OXTR) Variants Are Not Related to Psychosocial Characteristics Defined by Strengths and Difficulties Questionnaire in Adolescents: A Field School-Based Study". Frontiers in Psychiatry. 12: 714093. doi:10.3389/fpsyt.2021.714093. PMC 8380924. PMID 34434131.
  19. ^ Sasaki JY, Kim HS, Xu J (July 2011). "Religion and Well-being: The Moderating Role of Culture and the Oxytocin Receptor (OXTR) Gene" (PDF). Journal of Cross-Cultural Psychology. 42 (8): 1394–1405. doi:10.1177/0022022111412526. S2CID 145567198.
  20. ^ Lerer, E., Levi, S., Salomon, S. et al. Association between the oxytocin receptor (OXTR) gene and autism: relationship to Vineland Adaptive Behavior Scales and cognition. Mol Psychiatry 13, 980–988 (2008). https://doi.org/10.1038/sj.mp.4002087
  21. ^ de Oliveira Pereira Ribeiro L, Vargas-Pinilla P, Kappel DB, Longo D, Ranzan J, Becker MM, et al. (June 2018). "Evidence for Association Between OXTR Gene and ASD Clinical Phenotypes". Journal of Molecular Neuroscience. 65 (2): 213–221. doi:10.1007/s12031-018-1088-0. PMID 29858823. S2CID 46924606.
  22. ^ Chini B, Manning M (August 2007). "Agonist selectivity in the oxytocin/vasopressin receptor family: new insights and challenges". Biochemical Society Transactions. 35 (Pt 4): 737–41. doi:10.1042/BST0350737. PMID 17635137.
  23. ^ a b Manning M, Stoev S, Chini B, Durroux T, Mouillac B, Guillon G (2008). "Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: Research tools and potential therapeutic agents☆". Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents. Progress in Brain Research. Vol. 170. pp. 473–512. doi:10.1016/S0079-6123(08)00437-8. ISBN 978-0-444-53201-5. PMID 18655903.
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