UDC

612.1/.8

Authors

Viktor I. Tsirkin*/**, Svetlana I. Trukhina*, Andrey N. Trukhin*
*Vyatka State University (Kirov, Russian Federation)
**Kazan State Medical University (Kazan, Russian Federation)
Corresponding author: Viktor Tsirkin, address: ul. Moskovskaya 36, Kirov, 610000, Russian Federation; e-mail: tsirkin@list.ru

Abstract

Contemporary scientists have reported new findings on the physiological effects of oxytocin, its role in the development of the “social brain” and in the formation of prosocial behaviour, as well as on the contribution of oxytocin deficit to the pathogenesis of autism, schizophrenia, anxiety, and other syndromes. This article presents data on the synthesis of oxytocin in the central nervous system and beyond, including the male and female reproductive systems as well as the cardiovascular and digestive systems. Further, it generalizes the findings about the regulation of the synthesis of oxytocin in the central nervous system and on the periphery, including the role of oestradiol, progesterone, testosterone, glucocorticoids, and tri- and tetraiodothyronines. Further, the paper covers the data on the regulation of oxytocin release in the central nervous system, in particular, the key role in this process of such proteins as CD38/ADP-ribosyl cyclase and CD157, which are involved in the formation of cyclic ADP-ribose (cADPR). Serving as a secondary mediator, cADPR promotes the activation of a TRPM2 Ca channel (transient receptor potential cation channel, subfamily M, member 2), or melastatin-related channel, which contributes to the release of Ca2+ ions from the endoplasmic reticulum, thereby inducing the release of oxytocin. Deficiency of CD38, CD157 and TRPM2 proteins is, probably, related to the formation of autism and other mental disorders. It is reported that oxytocin release in neurons of the central nervous system is inhibited by glucocorticoids, catecholamines (at beta-adrenoceptor activation), nitric oxide, GABA, and testosterone and increases under the influence of oestrogens, serotonin, oxytocin (autoregulation) and the ecstasy drug. In addition, data are provided on the metabolism of oxytocin, including the role of oxytocinase in this process.

Keywords

oxytocin, oestrogens, progesterone, testosterone, glucocorticoids, cyclic ADP-ribose, CD38/ADP-ribosyl cyclase, CD157

References

1. Dale H.H. The Action of Extracts of the Pituitary Body. Biochem. J., 1909, vol. 4, no. 9, pp. 427–447. [PMID: 16742120; PMCID: PMC: 1276314; DOI: 10.1042/bj0040427]
2. Grigor’eva M.E., Golubeva M.G. Oxytocin: Structure, Synthesis, Receptors, and Basic Effects. Neurochem. J., 2010, vol. 4, no. 2, pp. 75–83.
3. Du Vigneaud V., Ressler C., Trippett S. The Sequence of Amino Acids in Oxytocin, with a Proposal for the Structure of Oxytocin. J. Biol. Chem., 1953, vol. 205, no. 2, pp. 949–957. [PMID: 13129273]
4. Arrowsmith S., Wray S. Oxytocin: Its Mechanism of Action and Receptor Signalling in the Myometrium. J. Neuroendocrinol., 2014, vol. 26, no. 6, pp. 356–369. [PMID: 24888645; DOI: 10.1111/jne.12154]
5. Tsirkin V.I., Dvoryanskiy S.A. Sokratitel’naya deyatel’nost’ matki (mekhanizmy regulyatsii) [Uterine Activity (Regulation Mechanisms)]. Kirov, 1997. 270 p.
6. Chernysheva M.P., Nozdrachev A.D. Nonapeptid oksitotsin: somaticheskie i vistseral’nye funktsii pri nekotorykh psikhopatologiyakh [Nonapeptide Oxytocin: Somatic and Visceral Functions in Some Psychopathologies]. Psikhofarmakologiya i biologicheskaya narkologiya, 2009, vol. 9, no. 3–4, pp. 2574–2590.
7. Vrachnis N., Malamas F.M., Sifakis S., Deligeoroglou E., Iliodromiti Z. The Oxytocin-Oxytocin Receptor System and Its Antagonists as Tocolytic Agents. Int. J. Endocrinol., 2011, vol. 2011. Art. no. 350546. [PMID: 22190926; PMCID: PMC: 3235456; DOI: 10.1155/2011/350546]
8. Szukiewicz D., Bilska A., Mittal T.K., Stangret A., Wejman J., Szewczyk G., Pyzlak M., Zamlynski J. Myometrial Contractility Influences Oxytocin Receptor (OXTR) Expression in Term Trophoblast Cells Obtained from the Maternal Surface of the Human Placenta. BMC Pregnancy Childbirth, 2015, vol. 15. Art. no. 220. [PMID: 26377392; DOI: 10.1186/s12884-015-0656-3]
9. Zeeman G.G., Khan-Dawood F.S., Dawood M.Y. Oxytocin and Its Receptor in Pregnancy and Parturition: Current Concepts and Clinical Implications. Obstet. Gynecol., 1997, vol. 89, no. 5, pt. 2, pp. 873–883. [PMID: 9166360; DOI: 10.1016/s0029-7844(97)00056-2]
10. Lopatina O., Inzhutova A., Salmina A.B., Higashida H. The Roles of Oxytocin and CD38 in Social or Parental Behaviors. Front. Neurosci., 2013, vol. 6. Art. no. 182. [PMID: 23335873; DOI: 10.3389/fnins.2012.00182]
11. Gimpl G., Fahrenholz F. The Oxytocin Receptor System: Structure, Function, and Regulation. Physiol. Rev., 2001, vol. 81, no. 2, pp. 629–683. [PMID: 11274341; DOI: 10.1152/physrev.2001.81.2.629]
12. Yamashita K., Kitano T. Molecular Evolution of the Oxytocin-Oxytocin Receptor System in Eutherians. Mol. Phylogenet. Evol., 2013, vol. 67, no. 2, pp. 520–528. [PMID: 23485918; DOI: 10.1016/j.ympev.2013.02.017]
13. Zingg H.H., Rozen F., Breton C., Larcher A., Neculcea J., Chu K., Russo C., Arslan A. Gonadal Steroid Regulation of Oxytocin and Oxytocin Receptor Gene Expression. Adv. Exp. Med. Biol., 1995, vol. 395, pp. 395–404. [PMID: 8713994]
14. Teplyashina E.A., Lopatina O.L., Ekimova M.V., Pozhilenkova E.A., Salmina A.B. Rol’ oksitotsina i oksitotsinovykh retseptorov v regulyatsii reproduktivnykh funktsiy i follikulogeneza [Role of Oxytocin and Oxytocin Receptors in the Regulation of the Reproductive Function and Folliculogenesis]. Sibirskiy meditsinskiy zhurnal, 2013, no. 8, pp. 21–26.
15. Hoge E.A., Lawson E.A., Metcalf C.A., Keshaviah A., Zak P.J., Pollack M.H., Simon N.M. Plasma Oxytocin Immunoreactive Products and Response to Trust in Patients with Social Anxiety Disorder. Depress. Anxiety, 2012, vol. 29, no. 11, pp. 924–930. [PMID: 22807189; PMCID: PMC: 3751166; DOI: 10.1002/da.21973]
16. Thackare H., Nicholson H.D., Whittington K. Oxytocin – Its Role in Male Reproduction and New Potential Therapeutic Uses. Hum. Reprod. Update, 2006, vol. 12, no. 4, pp. 437–448. [PMID: 16436468; DOI: 10.1093/humupd/ dmk002]
17. Thompson M.R., Callaghan P.D., Hunt G.E., Cornish J.L., McGregor I.S. A Role for Oxytocin and 5-HT(1A) Receptors in the Prosocial Effects of 3,4 Methylenedioxymethamphetamine (“Ecstasy”). Neuroscience, 2007, vol. 146, no. 2, pp. 509–514. [PMID: 17383105; DOI: 10.1016/j.neuroscience.2007.02.032]
18. Parrott A.C. Oxytocin, Cortisol and 3,4-Methylenedioxymethamphetamine: Neurohormonal Aspects of Recreational ‘Ecstasy’. Behav. Pharmacol., 2016, vol. 27, no. 8, pp. 649–658. [PMID: 27681116; DOI: 10.1097/ FBP.0000000000000262]
19. Higashida H., Bowden S.E., Yokoyama S., Salmina A., Hashii M., Hoshi N., Zhang J.S., Knijnik R., Noda M., Zhong Z.G., Jin D., Higashida K., Takeda H., Akita T., Kuba K., Yamagishi S., Shimizu N., Takasawa S., Okamoto H., Robbins J. Overexpression of Human CD38/ADP-Ribosyl Cyclase Enhances Acetylcholine-Induced Ca2+ Signalling in Rodent NG108-15 Neuroblastoma Cells. Neurosci. Res., 2007, vol. 57, no. 3, pp. 339–346. [PMID: 17173996; DOI: 10.1016/j.neures.2006.11.008]
20. Lee H.C. Cyclic ADP-Ribose and NAADP: Fraternal Twin Messengers for Calcium Signaling. Sci. China Life Sci., 2011, vol. 54, no. 8, pp. 699–711. [PMID: 21786193; DOI: 10.1007/s11427-011-4197-3]
21. Salmina A.B., Komleva Yu.K., Kuvacheva N.V., Lopatina O.L., Inzhutova A.I., Cherepanov S.M., Yauzina N.A., Morozova G.A., Malinovskaya N.A., Pozhilenkova E.A., Morgun A.V., Taranushenko T.E., Petrova M.M. Molekulyarnye mekhanizmy narusheniya razvitiya mozga v pre- i neonatal’nom periode [Molecular Mechanisms of Neurodevelopmental Alterations in Prenatal and Neonatal Periods]. Voprosy sovremennoy pediatrii, 2012, vol. 11, no. 6, pp. 15–20.
22. Zhong J., Amina S., Liang M., Akther S., Yuhi T., Nishimura T., Tsuji C., Tsuji T., Liu H.X., Hashii M., Furuhara K., Yokoyama S., Yamamoto Y., Okamoto H., Zhao Y.J., Lee H.C., Tominaga M., Lopatina O., Higashida H. Cyclic ADPRibose and Heat Regulate Oxytocin Release via CD38 and TRPM2 in the Hypothalamus During Social or Psychological Stress in Mice. Front. Neurosci., 2016, vol. 10. Art. no. 304. [PMID: 27499729; DOI: 10.3389/fnins.2016.00304]
23. Deaglio S., Mallone R., Baj G., Arnulfo A., Surico N., Dianzani U., Mehta K., Malavasi F. CD38/CD31, a Receptor/Ligand System Ruling Adhesion and Signaling in Human Leukocytes. Chem. Immunol., 2000, vol. 75, pp. 99–120. [PMID: 10851781]
24. Salmina A.B., Okuneva O.S., Malinovskaya N.A., Taranushenko T.E., Morgun A.V., Mantorova N.S., Mikhutkina S.V. NAD+-Dependent Mechanisms of Disturbances of Viability of Brain Cells During the Acute Period of Hypoxic-Ischemic Perinatal Injury. Neurochem. J., 2008, vol. 25, no. 3, pp. 247–254.
25. Uspenskaya Yu.A., Gorina Ya.V., Lopatina O.L., Olovyannikova R.Ya., Endrzheevskaya-Shurygina V.Yu., Trufanova L.V., Salmina A.B. Mindalina golovnogo mozga: kontrol’ emotsiy i osobennosti metabolizma glyukozy [The Amygdala: Emotion Control and Glucose Metabolism Features]. Uspekhi fiziologicheskikh nauk, 2017, vol. 48, no. 3, pp. 45–55.
26. Higashida H., Hashii M., Yokoyama S., Hoshi N., Chen X.L., Egorova A., Noda M., Zhang J.S. Cyclic ADP-Ribose as a Second Messenger Revisited from a New Aspect of Signal Transduction from Receptors to ADP-Ribosyl Cyclase. Pharmacol. Ther., 2001, vol. 90, no. 2-3, pp. 283–296. [PMID: 11578661; DOI: 10.1016/s0163-7258(01)00142-5]
27. Perraud A.L., Fleig A., Dunn C.A., Bagley L.A., Launay P., Schmitz C., Stokes A.J., Zhu Q., Bessman M.J., Penner R., Kinet J.P., Scharenberg A.M. ADP-Ribose Gating of the Calcium-Permeable LTRPC2 Channel Revealed by Nudix Motif Homology. Nature, 2001, vol. 411, no. 6837, pp. 595–599. [PMID: 11385575; DOI: 10.1038/35079100]
28. Moos F., Freund-Mercier M.J., Guerné Y., Guerné J.M., Stoeckel M.E., Richard P. Release of Oxytocin and Vasopressin by Magnocellular Nuclei in vitro: Specific Facilitatory Effect of Oxytocin on Its Own Release. J. Endocrinol., 1984, vol. 102, no. 1, pp. 63–72. [PMID: 6539805; DOI: 10.1677/joe.0.1020063]
29. Moos F., Poulain D.A., Rodriguez F., Guerné Y., Vincent J.D., Richard P. Release of Oxytocin Within the Supraoptic Nucleus During the Milk Ejection Reflex in Rats. Exp. Brain Res., 1989, vol. 76, no. 3, pp. 593–602. [PMID: 2792248; DOI: 10.1007/bf00248916]
30. Ferguson J.K.W. A Study of the Motility of the Intact Uterus at Term. Surg. Gynecol. Obstet., 1941, vol. 73, no. 3, pp. 359–366.
31. Richard P., Moos F., Freund-Mercier M.J. Central Effects of Oxytocin. Physiol. Rev., 1991, vol. 71, no. 2, pp. 331–370. [PMID: 1672455; DOI: 10.1152/physrev.1991.71.2.331]
32. Lambert R.C., Dayanithi G., Moos F.C., Richard P. A Rise in the Intracellular Ca2+ Concentration of Isolated Rat Supraoptic Cells in Response to Oxytocin. J. Physiol., 1994, vol. 478, no. 2, pp. 275–287. [PMID: 7525943; DOI: 10.1113/jphysiol.1994.sp020249]
33. Tasker J.G., Di S., Malcher-Lopes R. Minireview: Rapid Glucocorticoid Signaling via Membrane-Associated Receptors. Endocrinology, 2006, vol. 147, no. 12, pp. 5549–5556. [PMID: 16946006; DOI: 10.1210/en.20060981]
34. Di S., Tasker J.G. Rapid Synapse-Specific Regulation of Hypothalamic Magnocellular Neurons by Glucocorticoids. Prog. Brain Res., 2008, vol. 170, pp. 379–388. [PMID: 18655897; DOI: 10.1016/S0079-6123(08)00431-7]
35. Scantamburlo G., Ansseau M., Legros J.J. Role of the Neurohypophysis in Psychological Stress. Encephale, 2001, vol. 27, no. 3, pp. 245–259. [PMID: 11488255]
36. Kirilov G., Lang R.E., Kraft K., Ganten D. The Effects of Orchidectomy and Testosterone Replacement Therapy on Plasma and Brain Oxytocin in Normal Rats. Acta Physiol. Pharmacol. Bulg., 1987, vol. 13, no. 2, pp. 30–35. [PMID: 3673599]
37. Hollander E., Novotny S., Hanratty M., Yaffe R., DeCaria C.M., Aronowitz B.R., Mosovich S. Oxytocin Infusion Reduces Repetitive Behaviors in Adults with Autistic and Asperger’s Disorders. Neuropsychopharmacology, 2003, vol. 28, no. 1, pp. 193–198. [PMID: 12496956; DOI: 10.1038/sj.npp.1300021]
38. Douglas A.J., Ludwig M. Quo vadis Neurohypophysial Hormone Research? Exp. Physiol., 2000, vol. 85S, pp. 267S–272S. [PMID: 10795931]
39. Neumann I.D., Maloumby R., Beiderbeck D.I., Lukas M., Landgraf R. Increased Brain and Plasma Oxytocin After Nasal and Peripheral Administration in Rats and Mice. Psychoneuroendocrinology, 2013, vol. 38, no. 10, pp. 1985–1993. [PMID: 23579082; DOI: 10.1016/j.psyneuen.2013.03.003]
40. Gordon I., Vander Wyk B.C., Bennett R.H., Cordeaux C., Lucas M.V., Eilbott J.A., Zagoory-Sharon O., Leckman J.F., Feldman R., Pelphrey K.A. Oxytocin Enhances Brain Function in Children with Autism. Proc. Natl. Acad. Sci. U.S.A., 2013, vol. 110, no. 52, pp. 20953–20958. [PMID: 24297883; DOI: 10.1073/pnas.1312857110]
41. Watanabe T., Abe O., Kuwabara H., Yahata N., Takano Y., Iwashiro N., Natsubori T., Aoki Y., Takao H., Kawakubo Y., Kamio Y., Kato N., Miyashita Y., Kasai K., Yamasue H. Mitigation of Sociocommunicational Deficits of Autism Through Oxytocin-Induced Recovery of Medial Prefrontal Activity: A Randomized Trial. JAMA Psychiatry, 2014, vol. 71, no. 2, pp. 166–175. [PMID: 24352377; DOI: 10.1001/jamapsychiatry.2013.3181]
42. Ring R.H., Schechter L.E., Leonard S.K., Dwyer J.M., Platt B.J., Graf R., Grauer S., Pulicicchio C., Resnick L., Rahman Z., Sukoff Rizzo S.J., Luo B., Beyer C.E., Logue S.F., Marquis K.L., Hughes Z.A., Rosenzweig-Lipson S. Receptor and Behavioral Pharmacology of WAY-267464, a Non-Peptide Oxytocin Receptor Agonist. Neuropharmacology, 2010, vol. 58, no. 1, pp. 69–77. [PMID: 19615387; DOI: 10.1016/j.neuropharm.2009.07.016]
43. Chibbar R., Miller F.D., Mitchell B.F. Synthesis of Oxytocin in Amnion, Chorion, and Decidua May Influence the Timing of Human Parturition. J. Clin. Invest., 1993, vol. 91, no. 1, pp. 185–192. [PMID: 8423217; PMCID: PMC: 330013; DOI: 10.1172/JCI116169]
44. Shojo H., Kaneko Y. Characterization and Expression of Oxytocin and the Oxytocin Receptor. Mol. Genet. Metab., 2000, vol. 71, no. 4, pp. 552–558. [PMID: 11136546; DOI: 10.1006/mgme.2000.3094]
45. Blanks A.M., Vatish M., Allen M.J., Ladds G., de Wit N.C., Slater D.M., Thornton S. Paracrine Oxytocin and Estradiol Demonstrate a Spatial Increase in Human Intrauterine Tissues with Labor. J. Clin. Endocrinol. Metab., 2003, vol. 88, no. 7, pp. 3392–3400. [PMID: 12843193; DOI: 10.1210/jc.2002-021212]
46. Friebe-Hoffmann U., Baston D.M., Hoffmann T.K., Chiao J.P., Rauk P.N. The Influence of Interleukin-1β on Oxytocin Signalling in Primary Cells of Human Deciduas. Regul. Pept., 2007, vol. 142, no. 3, pp. 78–85. [PMID: 17428554; DOI: 10.1016/j.regpep.2007.01.012]
47. Edwards D., Good D.M., Granger S.E., Hollingsworth M., Robson A., Small R.C., Weston A.H. The Spasmogenic Action of Oxytocin in the Rat Uterus – Comparison with Other Agonists. Br. J. Pharmacol., 1986, vol. 88, no. 4, pp. 899–908. [PMID: 3742162; PMCID: PMC: 1917071; DOI: 10.1111/j.1476-5381.1986.tb16264.x]
48. Gutkowska J., Jankowski M., Lambert C., Mukaddam-Daher S., Zingg H.H., McCann S.M. Oxytocin Releases Atrial Natriuretic Peptide by Combining with Oxytocin Receptors in the Heart. Proc. Natl. Acad. Sci. U.S.A., 1997, vol. 94, no. 21, pp. 11704–11709. [PMID: 9326674; PMCID: PMC: 23602; DOI: 10.1073/pnas.94.21.11704]
49. Jankowski M., Danalache B., Wang D., Bhat P., Hajjar F., Marcinkiewicz M., Paquin J., McCann S.M., Gutkowska J. Oxytocin in Cardiac Ontogeny. Proc. Natl. Acad. Sci. U.S.A., 2004, vol. 101, no. 35, pp. 13074–13079. [PMID: 15316117; DOI: 10.1073/pnas.0405324101]
50. Konstatinova M.S., Natochin Yu.V. Gormony neyrogipofiza vazopressin i oksitotsin [Neurohypophysial Hormones Vasopressin and Oxytocin]. Fiziologiya endokrinnoy sistemy [Physiology of the Endocrine System]. Leningrad, 1979, pp. 90–119.
51. Mizutani S., Hayakawa H., Akiyama H., Sakura H., Yoshino M., Oya M., Kawashima Y. Simultaneous Determinations of Plasma Oxytocin and Serum Placental Leucine Aminopeptidase (P-LAP) During Late Pregnancy. Clin. Biochem., 1982, vol. 15, no. 3, pp. 141–145. [PMID: 7116622; DOI: 10.1016/s0009-9120(82)90582-3]
52. Golumb S.B. Aktivnost’ oksitotsinazy v krovi pri normal’noy beremennosti i v rodakh [Oxytocinase Activity in the Blood During Normal Pregnancy and in Labour]. Voprosy okhrany materinstva i detstva, 1976, vol. 21, no. 7, pp. 70–72.
53. Schumann K., Fährmann M., Schneider J. The Activity of L-Cysteine Aminopeptidase (Oxytocinase) During Premature Labour and Tocolytic Treatment (Author’s Transl.). Geburtshilfe Frauenheilkd., 1977, vol. 37, no. 2, pp. 156–160. [PMID: 838265]
54. Roy A.C., Karim S.M. Review: Significance of the Inhibition by Prostaglandins and Cyclic GMP of Oxytocinase Activity in Human Pregnancy and Labour. Prostaglandins, 1983, vol. 25, no. 1, pp. 55–70. [PMID: 6302740; DOI: 10.1016/0090-6980(83)90135-1]
55. Blum M., Shabtay F., Halbrecht I. Relationship Between Postpartum Serum Oxytocinase Levels and Afterpains. Harefuah, 1975, vol. 88, no. 7, p. 316. [PMID: 1132837]
56. Roy A.C., Yeang M., Karim S.M. Inhibition of Serum Oxytocinase Activity by Prostaglandins. Prostaglandins Med., 1981, vol. 6, no. 6, pp. 577–587. [PMID: 6267639; DOI: 10.1016/0161-4630(81)90119-1]
57. Rydén G., Sjöholm I. Half-Life of Oxytocin in Blood of Pregnant and Non-Pregnant Women. Acta Endocrinol. (Copenh.), 1969, vol. 61, no. 3, pp. 425–431. [PMID: 5820054; DOI: 10.1530/acta.0.0610425]
58. Gonser M. Labor Induction and Augmentation with Oxytocin: Pharmacokinetic Considerations. Arch. Gynecol. Obstet., 1995, vol. 256, no. 2, pp. 63–66. [PMID: 7611820; DOI: 10.1007/bf00634710]