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Are there sex differences in oxytocin and vasopressin V1a receptors ligand binding affinities?

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Abstract

Background

There is substantial evidence for sex differences in the functioning of one of the most common receptor systems; G protein-coupled receptors (GPCRs). There are many points along the GPCR-mediated molecular signaling pathway at which males and females may differ, one of the first of which, chronologically, is in the stability of the interaction between the ligand and the receptor, or its binding affinity. Here we investigate the binding affinities of oxytocin (OT) and vasopressin (AVP) at the oxytocin receptor (OTR) and the vasopressin V1a receptor (V1aR), both of which are present in numerous in brain regions associated with social behavior.

Method

In order to investigate sex- and estrous cycle-dependent differences in ligand-receptor binding affinity, male (n = 6) Syrian hamsters (Mesocricetus auratus), females on the day of estrus (E females, n = 6), and females on the second day of diestrus (D2 females n = 6) were chosen for study. Brains from hamsters were mounted on slides and competition and saturation binding assays were conducted.

Results

We report a remarkable similarity in the binding affinities of OT and AVP in males and females. Small differences were detected, however, in receptor and ligand specificity in females depending on whether they were in the estrous or diestrous stage of their ovulatory cycle.

Conclusion

These data suggest that sex differences in binding affinity are not a likely source of the many sex differences that have been observed in the effects of OT and AVP in hamsters and other species.

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Fig. 1
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Fig. 3

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

GPCR:

G protein-coupled receptor

OT:

Oxytocin

OTR:

Oxytocin receptor

AVP:

Arginine vasopressin

V1aR:

Vasopressin V1a receptor

NSB:

Nonspecific binding

D2:

Diestrus day 2

E:

Estrus

CRFr:

Corticotrophin releasing factor receptor

DPM:

Disintegrations per minute

[125I]OVTA:

[125I] ornithine vasotocin analogue

[125I]LVA:

[125I] linear vasopressin antagonist

References

  1. Caldwell JD, Walker CH, Pedersen CA, Baraka AS, Mason GA. Estrogen increases affinity of oxytocin receptors in the medial preoptic area-anterior hypothalamus. Peptides. 1994;15:1079–84.

    Article  CAS  PubMed  Google Scholar 

  2. Gimpl G, Burger K, Fahrenholz F. Cholesterol as modulator of receptor function. Biochemistry. 1997;36:10959–74. https://doi.org/10.1021/bi963138w.

    Article  CAS  PubMed  Google Scholar 

  3. Gimpl G, Klein U, Reilaender H, Fahrenholz F. Expression of the human oxytocin receptor in baculovirus-infected insect cells: high-affinity binding is induced by a cholesterol-cyclodextrin complex. Biochemistry. 1995;34:13794–801. https://doi.org/10.1021/bi00042a010.

    Article  CAS  PubMed  Google Scholar 

  4. Gimpl G, Fahrenholz F. Cholesterol as stabilizer of the oxytocin receptor. Biochimica et Biophysica Acta (BBA) Biomembranes. 2002;1564:384–92. https://doi.org/10.1016/S0005-2736(02)00475-3.

    Article  CAS  PubMed  Google Scholar 

  5. Klein U, Gimpl G, Fahrenholz F. Alteration of the myometrial plasma membrane cholesterol content with beta-cyclodextrin modulates the binding affinity of the oxytocin receptor. Biochemistry. 1995;34:13784–93. https://doi.org/10.1021/bi00042a009.

    Article  CAS  PubMed  Google Scholar 

  6. Soloff MS. Uterine receptor for oxytocin: effects of estrogen. Biochem Biophys Res Commun. 1975;65:205–12. https://doi.org/10.1016/S0006-291X(75)80080-5.

    Article  CAS  PubMed  Google Scholar 

  7. Ruprecht JJ, Mielke T, Vogel R, Villa C, Schertler GF. Electron crystallography reveals the structure of metarhodopsin I. EMBO J. 2004;23:3609–20. https://doi.org/10.1038/sj.emboj.7600374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chini B, Parenti M. G-protein-coupled receptors, cholesterol and palmitoylation: facts about fats. J Mol Endocrinol. 2009;42:371–9. https://doi.org/10.1677/JME-08-0114.

    Article  CAS  PubMed  Google Scholar 

  9. Fullerton EF, Karom MC, Streicher JM, Young LJ, Murphy AZ. Age-induced changes in µ-opioid receptor signaling in the midbrain periaqueductal gray of male and female rats. J Neurosci. 2022;42:6232–42. https://doi.org/10.1523/JNEUROSCI.0355-22.2022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang Y-J, Huang P, Blendy JA, Liu-Chen L-Y. Brain region- and sex-specific alterations in DAMGO-stimulated [(35) S]GTPγS binding in mice with Oprm1 A112G. Addict Biol. 2014;19:354–61. https://doi.org/10.1111/j.1369-1600.2012.00484.x.

    Article  CAS  PubMed  Google Scholar 

  11. Wang Y-J, Rasakham K, Huang P, Chudnovskaya D, Cowan A, Liu-Chen L-Y. Sex difference in κ-opioid receptor (KOPR)-mediated behaviors, brain region KOPR level and KOPR-mediated guanosine 5′-O-(3-[35S]Thiotriphosphate) binding in the Guinea Pig. J Pharmacol Exp Ther. 2011;339:438–50. https://doi.org/10.1124/jpet.111.183905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bangasser DA, Curtis A, Reyes BAS, Bethea TT, Parastatidis I, Ischiropoulos H, et al. Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology. Mol Psychiatry. 2010;15:896–904. https://doi.org/10.1038/mp.2010.66.

    Article  CAS  Google Scholar 

  13. Valentino RJ, Bangasser DA. Sex-biased cellular signaling: molecular basis for sex differences in neuropsychiatric diseases. Dialogues Clin Neurosci. 2016;18:385–93.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Shah K, McCormack CE, Bradbury NA. Do you know the sex of your cells? Am J Physiol Cell Physiol. 2014;306:C3-18. https://doi.org/10.1152/ajpcell.00281.2013.

    Article  CAS  PubMed  Google Scholar 

  15. Taylor JH, McCann KE, Ross AP, Albers HE. Binding affinities of oxytocin, vasopressin and Manning compound at oxytocin and V1a receptors in male Syrian hamster brains. J Neuroendocrinol. 2020. https://doi.org/10.1111/jne.12882.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Bylund DB, Toews ML. Radioligand binding methods: practical guide and tips. Am J Physiol. 1993;265:L421-429. https://doi.org/10.1152/ajplung.1993.265.5.L421.

    Article  CAS  PubMed  Google Scholar 

  17. Chini B, Manning M, Guillon G. Affinity and efficacy of selective agonists and antagonists for vasopressin and oxytocin receptors: an “easy guide” to receptor pharmacology. In: Neumann ID, Landgraf R, editors. Progress in brain research, vol. 170. Elsevier; 2008. p. 513–7. https://doi.org/10.1016/S0079-6123(08)00438-X.

    Chapter  Google Scholar 

  18. Caldwell HK. Oxytocin and sex differences in behavior. Curr Opin Behav Sci. 2018;23:13–20. https://doi.org/10.1016/j.cobeha.2018.02.002.

    Article  Google Scholar 

  19. Albizu L, Cottet M, Kralikova M, Stoev S, Seyer R, Brabet I, et al. Time-resolved FRET between GPCR ligands reveals oligomers in native tissues. Nat Chem Biol. 2010;6:587–94. https://doi.org/10.1038/nchembio.396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Devost D, Zingg HH. Homo- and hetero-dimeric complex formations of the human oxytocin receptor. J Neuroendocrinol. 2004;16:372–7. https://doi.org/10.1111/j.0953-8194.2004.01188.x.

    Article  CAS  PubMed  Google Scholar 

  21. Terrillon S, Barberis C, Bouvier M. Heterodimerization of V1a and V2 vasopressin receptors determines the interaction with β-arrestin and their trafficking patterns. Proc Natl Acad Sci U S A. 2004;101:1548–53. https://doi.org/10.1073/pnas.0305322101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Terrillon S, Durroux T, Mouillac B, Breit A, Ayoub MA, Taulan M, et al. Oxytocin and vasopressin V1a and V2 receptors form constitutive homo- and heterodimers during biosynthesis. Mol Endocrinol. 2003;17:677–91. https://doi.org/10.1210/me.2002-0222.

    Article  CAS  PubMed  Google Scholar 

  23. Wallace Fitzsimons SE, Chruścicka B, Druelle C, Stamou P, Nally K, Dinan TG, et al. A ghrelin receptor and oxytocin receptor heterocomplex impairs oxytocin mediated signalling. Neuropharmacology. 2018. https://doi.org/10.1016/j.neuropharm.2018.12.022.

    Article  PubMed  Google Scholar 

  24. Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov. 2017;16:829–42. https://doi.org/10.1038/nrd.2017.178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Alberich S, Fernández-Sevillano J, González-Ortega I, Usall J, Sáenz M, González-Fraile E, et al. A systematic review of sex-based differences in effectiveness and adverse effects of clozapine. Psychiatry Res. 2019;280: 112506. https://doi.org/10.1016/j.psychres.2019.112506.

    Article  PubMed  Google Scholar 

  26. Bartok RE, Craft RM. Sex differences in opioid antinociception. J Pharmacol Exp Ther. 1997;282:769–78.

    CAS  PubMed  Google Scholar 

  27. Freedman RR, Sabharwal SC, Desai N. Sex differences in peripheral vascular adrenergic receptors. Circ Res. 1987;61:581–5.

    Article  CAS  PubMed  Google Scholar 

  28. Gear RW, Gordon NC, Heller PH, Paul S, Miaskowski C, Levine JD. Gender difference in analgesic response to the kappa-opioid pentazocine. Neurosci Lett. 1996;205:207–9. https://doi.org/10.1016/0304-3940(96)12402-2.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by NIH grant R01MH122622 to HEA.

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Authors and Affiliations

Authors

Contributions

JHT designed and conducted all experiments, analyzed the data, and wrote the first draft of this manuscript. HEA supervised all aspects of the study, especially experimental design, data analysis, and preparation of the final submission.

Corresponding author

Correspondence to H. Elliott Albers.

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Conflict of interest

The authors declare no conflicts of interest.

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Taylor, J.H., Elliott Albers, H. Are there sex differences in oxytocin and vasopressin V1a receptors ligand binding affinities?. Pharmacol. Rep 76, 416–423 (2024). https://doi.org/10.1007/s43440-024-00577-6

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  • DOI: https://doi.org/10.1007/s43440-024-00577-6

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