The Oxytocin Receptor System: Structure, Function, and Regulation

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-beta. 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(2 alpha). Experiments with transgenic mice suggest that OT acts as a luteotrophic hormone opposing the luteolytic action of PGF(2 alpha). Thus, to initiate labor, it might be essential to generate sufficient PGF(2 alpha) 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, unfor...

Oxytocin pathways in the intergenerational transmission of maternal early life stress

“…Second, it has been shown that in the rodent (Knobloch et al, 2012) and human brain (Boccia et al, 2013) there is a variety of “hard-wired” oxytocinergic nerve fibers from the hypothalamus to limbic, mesencephalic, and cortical brain regions that allow fine-tuned and fast modulation of target structures (Knobloch et al, 2012; Landgraf and Neumann, 2004; Stoop, 2012; Strathearn, 2011). Effects of OT in the CNS and in the periphery (e.g., heart and cardiovascular system, kidney, reproductive organs) are critically dependent on presence of OT receptors (OTR) (Gimpl and Fahrenholz, 2001). The OTR is a 389-amino acid polypeptide and belongs to the G-protein coupled receptor superfamily (Gimpl and Fahrenholz, 2001; Kimura et al, 1992).…”

“…Effects of OT in the CNS and in the periphery (e.g., heart and cardiovascular system, kidney, reproductive organs) are critically dependent on presence of OT receptors (OTR) (Gimpl and Fahrenholz, 2001). The OTR is a 389-amino acid polypeptide and belongs to the G-protein coupled receptor superfamily (Gimpl and Fahrenholz, 2001; Kimura et al, 1992). The OTR expressing gene ( OXTR ) is located on chromosomal region 3p25–3p26.2, spans 17 kb, and consists of 3 introns and 4 exons (Gimpl and Fahrenholz, 2001).…”

“…The OTR is a 389-amino acid polypeptide and belongs to the G-protein coupled receptor superfamily (Gimpl and Fahrenholz, 2001; Kimura et al, 1992). The OTR expressing gene ( OXTR ) is located on chromosomal region 3p25–3p26.2, spans 17 kb, and consists of 3 introns and 4 exons (Gimpl and Fahrenholz, 2001). Studies on distribution patterns of OTRs in human post mortem brains found high OTR expression in amygadaloid nuclei, cingulate cortex, the hypothalamic medial preoptic area (MPOA), PVN, ventromedial nucleus, the solitary nucleus, and the spinal trigeminal nucleus (Boccia et al, 2013; Freeman et al, 2016).…”

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“…Das Nonapeptid Oxytocin ist nach den altgriechischen Wörtern "ὀξύς" und "τόκος" benannt, was "schnelle Geburt" bedeutet, da es mit der uteruskontrahierenden Wirkung von Oxytocin zunächst in Verbindung gebracht wurde [29]. Oxytocin wird vornehmlich in den hypothalamischen Kernen PVN und Nucleus supraopticus (SON) produziert [29].…”

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