The Oxytocin Receptor System: Structure, Function, and Regulation

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Abstract

The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation. Such stimuli also lead to an intranuclear release of OT. Moreover, oxytocinergic neurons display widespread projections throughout the central nervous system. However, OT is also synthesized in peripheral tissues, e.g., uterus, placenta, amnion, corpus luteum, testis, and heart. The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via G _q proteins to phospholipase C-β. The high-affinity receptor state requires both Mg ²⁺ and cholesterol, which probably function as allosteric modulators. The agonist-binding region of the receptor has been characterized by mutagenesis and molecular modeling and is different from the antagonist binding site. The function and physiological regulation of the OT system is strongly steroid dependent. However, this is, unexpectedly, only partially reflected by the promoter sequences in the OT receptor gene. The classical actions of OT are stimulation of uterine smooth muscle contraction during labor and milk ejection during lactation. While the essential role of OT for the milk let-down reflex has been confirmed in OT-deficient mice, OT's role in parturition is obviously more complex. Before the onset of labor, uterine sensitivity to OT markedly increases concomitant with a strong upregulation of OT receptors in the myometrium and, to a lesser extent, in the decidua where OT stimulates the release of PGF _2α. Experiments with transgenic mice suggest that OT acts as a luteotrophic hormone opposing the luteolytic action of PGF _2α. Thus, to initiate labor, it might be essential to generate sufficient PGF _2α to overcome the luteotrophic action of OT in late gestation. OT also plays an important role in many other reproduction-related functions, such as control of the estrous cycle length, follicle luteinization in the ovary, and ovarian steroidogenesis. In the male, OT is a potent stimulator of spontaneous erections in rats and is involved in ejaculation. OT receptors have also been identified in other tissues, including the kidney, heart, thymus, pancreas, and adipocytes. For example, in the rat, OT is a cardiovascular hormone acting in concert with atrial natriuretic peptide to induce natriuresis and kaliuresis. The central actions of OT range from the modulation of the neuroendocrine reflexes to the establishment of complex social and bonding behaviors related to the reproduction and care of the offspring. OT exerts potent antistress effects that may facilitate pair bonds. Overall, the regulation by gonadal and adrenal steroids is one of the most remarkable features of the OT system and is, unfortunately, the least understood. One has to conclude that the physiological regulation of the OT system will remain puzzling as long as the molecular mechanisms of genomic and nongenomic actions of steroids have not been clarified.

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The purpose of this paper is to review existing behavioral and neuroendocrine perspectives on social attachment and love. Both love and social attachments function to facilitate reproduction, provide a sense of safety, and reduce anxiety or stress. Because social attachment is an essential component of love, understanding attachment formation is an important step toward identifying the neurobiological substrates of love. Studies of pair bonding in monogamous rodents, such as prairie voles, and maternal attachment in precocial ungulates offer the most accessible animal models for the study of mechanisms underlying selective social attachments and the propensity to develop social bonds. Parental behavior and sexual behavior, even in the absence of selective social behaviors, are associated with the concept of love; the analysis of reproductive behaviors, which is far more extensive than our understanding of social attachment, also suggests neuroendocrine substrates for love. A review of these literatures reveals a recurrent association between high levels of activity in the hypothalamic pituitary adrenal (HPA) axis and the subsequent expression of social behaviors and attachments. Positive social behaviors, including social bonds, may reduce HPA axis activity, while in some cases negative social interactions can have the opposite effect. Central neuropeptides, and especially oxytocin and vasopressin have been implicated both in social bonding and in the central control of the HPA axis. In prairie voles, which show clear evidence of pair bonds, oxytocin is capable of increasing positive social behaviors and both oxytocin and social interactions reduce activity in the HPA axis. Social interactions and attachment involve endocrine systems capable of decreasing HPA reactivity and modulating the autonomic nervous system, perhaps accounting for health benefits that are attributed to loving relationships.

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Among membrane-bound receptors, the G protein-coupled receptors (GPCRs) are certainly the most diverse. They have been very successful during evolution, being capable of transducing messages as different as photons, organic odorants, nucleotides, nucleosides, peptides, lipids and proteins. Indirect studies, as well as two-dimensional crystallization of rhodopsin, have led to a useful model of a common 'central core', composed of seven transmembrane helical domains, and its structural modifications during activation. There are at least six families of GPCRs showing no sequence similarity. They use an amazing number of different domains both to bind their ligands and to activate G proteins. The fine-tuning of their coupling to G proteins is regulated by splicing, RNA editing and phosphorylation. Some GPCRs have been found to form either homo- or heterodimers with a structurally different GPCR, but also with membrane-bound proteins having one transmembrane domain such as nina-A, odr-4 or RAMP, the latter being involved in their targeting, function and pharmacology. Finally, some GPCRs are unfaithful to G proteins and interact directly, via their C-terminal domain, with proteins containing PDZ and Enabled/VASP homology (EVH)-like domains.

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Author and article information

Journal

Title: Physiological Reviews

Abbreviated Title: Physiological Reviews

Publisher: American Physiological Society

ISSN (Print): 0031-9333

ISSN (Electronic): 1522-1210

Publication date Created: April 01 2001

Publication date (Print): April 01 2001

Volume: 81

Issue: 2

Pages: 629-683

Affiliations

[1 ]Institut für Biochemie, Johannes Gutenberg Universität, Mainz, Germany

DOI: 10.1152/physrev.2001.81.2.629

PubMed ID: 11274341

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Self URI (article page): https://www.physiology.org/doi/10.1152/physrev.2001.81.2.629

The Oxytocin Receptor System: Structure, Function, and Regulation

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Most cited references 571

Neuroendocrine perspectives on social attachment and love.

The development of human benign prostatic hyperplasia with age.

Molecular tinkering of G protein-coupled receptors: an evolutionary success.

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