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Oxytocin receptor

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Template:PBB 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.

Oxytocin receptors are also present in the central nervous system. These receptors modulate a variety of behaviors, including stress and anxiety, social memory and recognition, sexual and aggressive behaviors, bonding (affiliation) and maternal behavior.[9][10][11] (See the oxytocin article for more details.)

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

Polymorphism

The receptors for oxytocin (OXTR) have genetic differences with different 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. A-allele carrier individuals are associated with more sensitivity to stress, fewer social skills, and more mental health issues than the GG-carriers.[12]

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. A-allele carriers responded with more stress to stressful situations than GG-allele carriers.[13] 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] 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]

A study looking at facial recognition in British and Finnish families with a single high-functioning autistic child found that a single change in the DNA had a major impact on face memory,[15] with AA individuals having impaired SD scores.[16]

The frequency of the A allele varies among ethnic groups, being significantly more common among East Asians than Europeans.[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]

Agonists

Peptide
Non-peptide

Antagonists

Peptide
Non-peptide

References

  1. ^ a b Gimpl G, Fahrenholz F (2001). "The oxytocin receptor system: structure, function, and regulation". Physiological Reviews. 81 (2): 629–83. PMID 11274341.
  2. ^ Zingg HH, Laporte SA (2003). "The oxytocin receptor". Trends in Endocrinology and Metabolism. 14 (5): 222–7. doi:10.1016/S1043-2760(03)00080-8. PMID 12826328.
  3. ^ EntrezGene 5021
  4. ^ Kimura T, Tanizawa O, Mori K, Brownstein MJ, Okayama H (April 1992). "Structure and expression of a human oxytocin receptor". Nature. 356 (6369): 526–9. doi:10.1038/356526a0. PMID 1313946.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Simmons CF Jr, Clancy TE, Quan R, Knoll JH (19965). "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. {{cite journal}}: Check date values in: |year= (help)CS1 maint: multiple names: authors list (link)
  6. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1042/BST20120256, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1042/BST20120256 instead.
  7. ^ Devost D, Wrzal P, Zingg HH (2008). "Advances in Vasopressin and Oxytocin — from Genes to Behaviour to Disease". Progress in brain research. Progress in Brain Research. 170: 167–76. doi:10.1016/S0079-6123(08)00415-9. ISBN 978-0-444-53201-5. PMID 18655881. {{cite journal}}: |chapter= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Gimpl G, Reitz J, Brauer S, Trossen C (2008). "Advances in Vasopressin and Oxytocin — from Genes to Behaviour to Disease". Progress in brain research. Progress in Brain Research. 170: 193–204. doi:10.1016/S0079-6123(08)00417-2. ISBN 978-0-444-53201-5. PMID 18655883. {{cite journal}}: |chapter= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Caldwell HK, Young WS 3rd (2006). "Oxytocin and Vasopressin: Genetics and Behavioral Implications". In Lajtha, Abel; Ramon Lim (ed.). Handbook of Neurochemistry and Molecular Neurobiology (3rd ed.). Berlin: Springer. pp. 573–607. ISBN 0-387-30348-0.{{cite book}}: CS1 maint: multiple names: editors list (link) CS1 maint: numeric names: authors list (link)
  10. ^ Kiss A, Mikkelsen JD (September 2005). "Oxytocin--anatomy and functional assignments: a minireview" (PDF). Endocrine Regulations. 39 (3): 97–105. PMID 16468232.
  11. ^ Veenema AH, Neumann ID (2008). "Central vasopressin and oxytocin release: regulation of complex social behaviours". Progress in Brain Research. Progress in Brain Research. 170: 261–76. doi:10.1016/S0079-6123(08)00422-6. ISBN 978-0-444-53201-5. PMID 18655888.
  12. ^ a b Saphire-Bernstein S, Way BM, Kim HS, Sherman DK, Taylor SE (September 2011). "Oxytocin receptor gene (OXTR) is related to psychological resources". Proc. Natl. Acad. Sci. U.S.A. 108 (37): 15118–22. doi:10.1073/pnas.1113137108. PMC 3174632. PMID 21896752.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Rodrigues SM, Saslow LR, Garcia N, John OP, Keltner D (December 2009). "Oxytocin receptor genetic variation relates to empathy and stress reactivity in humans". Proc. Natl. Acad. Sci. U.S.A. 106 (50): 21437–41. doi:10.1073/pnas.0909579106. PMC 2795557. PMID 19934046.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ Tost H, Kolachana B, Hakimi S, Lemaitre H, Verchinski BA, Mattay VS, Weinberger DR, Meyer-Lindenberg A (August 2010). "A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function". Proc. Natl. Acad. Sci. U.S.A. 107 (31): 13936–41. doi:10.1073/pnas.1003296107. PMC 2922278. PMID 20647384.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ "Gene That Influences the Ability to Remember Faces Identified". Science Daily. 23 December 2013.
  16. ^ Skuse; et al. (19 December 2013). "Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills". Proceedings of the National Academy of Sciences. {{cite web}}: Explicit use of et al. in: |author= (help)
  17. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ 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.
  19. ^ 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". Progress in Brain Research. Progress in Brain Research. 170: 473–512. doi:10.1016/S0079-6123(08)00437-8. ISBN 978-0-444-53201-5. PMID 18655903.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ Borthwick AD (September 2010). "Oral Oxytocin Antagonists". Journal of Medicinal Chemistry. 53 (18): 6525–38. doi:10.1021/jm901812z. PMID 20550119.
  21. ^ 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 
  22. ^ Ring RH, Schechter LE, Leonard SK, Dwyer JM, Platt BJ, Graf R, Grauer S, Pulicicchio C, Resnick L, Rahman Z, Sukoff Rizzo SJ, Luo B, Beyer CE, Logue SF, Marquis KL, Hughes ZA, Rosenzweig-Lipson S (July 2009). "Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist". Neuropharmacology. 58 (1): 69–77. doi:10.1016/j.neuropharm.2009.07.016. PMID 19615387.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ Borthwick, A. D.; Liddle, J. (January 2013). "Retosiban and Epelsiban: Potent and Selective Orally available Oxytocin Antagonists". In Domling, A (ed.). Methods and Principles in Medicinal Chemistry: Protein-Protein Interactions in Drug Discovery. Weinheim: Wiley-VCH. pp. 225–256. ISBN 978-3-527-33107-9.
  24. ^ Williams PD, Anderson PS, Ball RG, Bock MG, Carroll L, Chiu SH, Clineschmidt BV, Culberson JC, Erb JM, Evans BE (March 1994). "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. doi:10.1021/jm00031a004. PMID 8126695.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  27. ^ Wyatt PG, Allen MJ, Chilcott J, Foster A, Livermore DG, Mordaunt JE, Scicinski J, Woollard PM (May 2002). "Identification of potent and selective oxytocin antagonists. Part 1: indole and benzofuran derivatives". Bioorganic & Medicinal Chemistry Letters. 12 (10): 1399–404. doi:10.1016/S0960-894X(02)00159-2. PMID 11992786.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ^ Ring RH, Malberg JE, Potestio L, Ping J, Boikess S, Luo B, Schechter LE, Rizzo S, Rahman Z, Rosenzweig-Lipson S (April 2006). "Anxiolytic-like activity of oxytocin in male mice: behavioral and autonomic evidence, therapeutic implications". Psychopharmacology (Berlin). 185 (2): 218–25. doi:10.1007/s00213-005-0293-z. PMID 16418825.{{cite journal}}: CS1 maint: multiple names: authors list (link)

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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