Biology:Oxytocin receptor

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Short description: Genes on human chromosome 3


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

The oxytocin receptor, also known as OXTR, is a protein which functions as receptor for the hormone and neurotransmitter oxytocin.[1][2] In humans, the oxytocin receptor is encoded by the OXTR gene[3][4] which has been localized to human chromosome 3p25.[5]

Evolutionary tree of the oxytocin, vasotocin, mesotocin and isotocin receptors and their ligands. From Koechbach et al.[6]

Function and location

The OXTR protein belongs to the G-protein coupled receptor family, specifically Gq,[1] and acts as a receptor for oxytocin. Its activity is mediated by G proteins that activate several different second messenger systems.[7][8]

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.[9] 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.[9] 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.[10]

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

Mesolimbic dopamine pathways

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.[11] Activation of the PVN→VTA projection by oxytocin affects sexual, social, and addictive behavior via this link to the mesolimbic pathway;[11] specifically, oxytocin exerts a prosexual and prosocial effect in this region.[11]

Polymorphism

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.[12][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.[13][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.[12][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.[14] 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.[15]

The frequency of the A allele varies among ethnic groups, being significantly more common among East Asians than Europeans.[16][quantify][additional citation(s) needed]

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.[17]

Ligands

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.[18][19] However the search for a druggable, non-peptide template has led to several potent, highly selective, orally bioavailable oxytocin antagonists.[20] Oxytocin receptor agonists have also been developed.[21][22]

Agonists

Peptide
Non-peptide
  • LIT-001 — improved social deficits in mice; non-selective over vasopressin receptors
  • TC OT 39 – non-selective over vasopressin receptors
  • WAY-267,464 – anxiolytic in mice; possibly non-selective over vasopressin receptors[19][23][24]

Antagonists

Peptide
Non-peptide

References

  1. ↑ 1.0 1.1 "The oxytocin receptor system: structure, function, and regulation". Physiological Reviews 81 (2): 629–83. April 2001. doi:10.1152/physrev.2001.81.2.629. PMID 11274341. 
  2. ↑ "The oxytocin receptor". Trends in Endocrinology and Metabolism 14 (5): 222–7. July 2003. doi:10.1016/S1043-2760(03)00080-8. PMID 12826328. 
  3. ↑ EntrezGene 5021
  4. ↑ "Structure and expression of a human oxytocin receptor". Nature 356 (6369): 526–9. April 1992. doi:10.1038/356526a0. PMID 1313946. Bibcode: 1992Natur.356..526K. http://ir.library.osaka-u.ac.jp/dspace/bitstream/11094/38708/1/10817_%e8%a6%81%e6%97%a8.pdf. 
  5. ↑ "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. April 1995. doi:10.1016/0888-7543(95)80188-R. PMID 7607693. 
  6. ↑ "Insights into the molecular evolution of oxytocin receptor ligand binding". Biochemical Society Transactions 41 (1): 197–204. February 2013. doi:10.1042/BST20120256. PMID 23356283. 
  7. ↑ "Oxytocin receptor signalling". Advances in Vasopressin and Oxytocin — from Genes to Behaviour to Disease. Progress in Brain Research. 170. 2008. pp. 167–76. doi:10.1016/S0079-6123(08)00415-9. ISBN 978-0-444-53201-5. 
  8. ↑ "Oxytocin receptors: ligand binding, signalling and cholesterol dependence". Advances in Vasopressin and Oxytocin — from Genes to Behaviour to Disease. Progress in Brain Research. 170. 2008. pp. 193–204. doi:10.1016/S0079-6123(08)00417-2. ISBN 978-0-444-53201-5. 
  9. ↑ 9.0 9.1 "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. May 2018. doi:10.1186/s12888-018-1740-9. PMID 29843655. 
  10. ↑ "DNA methylation of OXTR is associated with parasympathetic nervous system activity and amygdala morphology". Social Cognitive and Affective Neuroscience 13 (11): 1155–1162. November 2018. doi:10.1093/scan/nsy086. PMID 30257007. 
  11. ↑ 11.0 11.1 11.2 "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. May 2008. doi:10.1038/bjp.2008.132. 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).". 
  12. ↑ 12.0 12.1 "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. September 2011. doi:10.1073/pnas.1113137108. PMID 21896752. Bibcode: 2011PNAS..10815118S. 
  13. ↑ "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. December 2009. doi:10.1073/pnas.0909579106. PMID 19934046. Bibcode: 2009PNAS..10621437R. 
  14. ↑ "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. August 2010. doi:10.1073/pnas.1003296107. PMID 20647384. Bibcode: 2010PNAS..10713936T. 
  15. ↑ "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. 2021. doi:10.3389/fpsyt.2021.714093. PMID 34434131. 
  16. ↑ "Religion and Well-being: The Moderating Role of Culture and the Oxytocin Receptor (OXTR) Gene". Journal of Cross-Cultural Psychology 42 (8): 1394–1405. July 2011. doi:10.1177/0022022111412526. https://labs.psych.ucsb.edu/kim/heejung/sasakikimxu.pdf. 
  17. ↑ "Evidence for Association Between OXTR Gene and ASD Clinical Phenotypes". Journal of Molecular Neuroscience 65 (2): 213–221. June 2018. doi:10.1007/s12031-018-1088-0. PMID 29858823. 
  18. ↑ "Agonist selectivity in the oxytocin/vasopressin receptor family: new insights and challenges". Biochemical Society Transactions 35 (Pt 4): 737–41. August 2007. doi:10.1042/BST0350737. PMID 17635137. 
  19. ↑ 19.0 19.1 "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. 170. 2008. pp. 473–512. doi:10.1016/S0079-6123(08)00437-8. ISBN 978-0-444-53201-5. 
  20. ↑ "Oral oxytocin antagonists". Journal of Medicinal Chemistry 53 (18): 6525–38. September 2010. doi:10.1021/jm901812z. PMID 20550119. 
  21. ↑ "The Current Status of Drug Discovery for the Oxytocin Receptor". Oxytocin. Methods Mol Biol. 2384. 2022. pp. 153–174. doi:10.1007/978-1-0716-1759-5_10. ISBN 978-1-0716-1758-8. 
  22. ↑ "Targeting the Oxytocin System: New Pharmacotherapeutic Approaches". Trends Pharmacol Sci 40 (1): 22–37. January 2019. doi:10.1016/j.tips.2018.11.001. PMID 30509888. 
  23. ↑ Rahman Z, Resnick L, Rosenzweig-Lipson SJ, Ring RH,"Methods of treatment using oxytocin receptor agonists", US patent application 2007/0117794, published 2007-05-24 , assigned to Wyeth Corp 
  24. ↑ "Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist". Neuropharmacology 58 (1): 69–77. January 2010. doi:10.1016/j.neuropharm.2009.07.016. PMID 19615387. 
  25. ↑ 25.0 25.1 "Retosiban and Epelsiban: Potent and Selective Orally available Oxytocin Antagonists". Methods and Principles in Medicinal Chemistry: Protein-Protein Interactions in Drug Discovery. Weinheim: Wiley-VCH. January 2013. pp. 225–256. doi:10.1002/9783527648207.ch10. ISBN 978-3-527-33107-9. 
  26. ↑ "1-((7,7-Dimethyl-2(S)-(2(S)-amino-4-(methylsulfonyl)butyramido)bicyclo [2.2.1]-heptan-1(S)-yl)methyl)sulfonyl)-4-(2-methylphenyl)piperaz ine (L-368,899): an orally bioavailable, non-peptide oxytocin antagonist with potential utility for managing preterm labor". Journal of Medicinal Chemistry 37 (5): 565–71. March 1994. doi:10.1021/jm00031a004. PMID 8126695. 
  27. ↑ "Peripherally administered non-peptide oxytocin antagonist, L368,899, accumulates in limbic brain areas: a new pharmacological tool for the study of social motivation in non-human primates". Hormones and Behavior 52 (3): 344–51. September 2007. doi:10.1016/j.yhbeh.2007.05.009. PMID 17583705. 
  28. ↑ "1-(1-[4-[(N-acetyl-4-piperidinyl)oxy]-2-methoxybenzoyl]piperidin-4- yl)-4H-3,1-benzoxazin-2(1H)-one (L-371,257): a new, orally bioavailable, non-peptide oxytocin antagonist". Journal of Medicinal Chemistry 38 (23): 4634–6. November 1995. doi:10.1021/jm00023a002. PMID 7473590. 
  29. ↑ "Identification of potent and selective oxytocin antagonists. Part 1: indole and benzofuran derivatives". Bioorganic & Medicinal Chemistry Letters 12 (10): 1399–404. May 2002. doi:10.1016/S0960-894X(02)00159-2. PMID 11992786. 
  30. ↑ "Anxiolytic-like activity of oxytocin in male mice: behavioral and autonomic evidence, therapeutic implications". Psychopharmacology 185 (2): 218–25. April 2006. doi:10.1007/s00213-005-0293-z. PMID 16418825. 

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