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      The Oxytocin Receptor System: Structure, Function, and Regulation

      1 , 1
      Physiological Reviews
      American Physiological Society

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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 . Experiments with transgenic mice suggest that OT acts as a luteotrophic hormone opposing the luteolytic action of PGF . Thus, to initiate labor, it might be essential to generate sufficient PGF 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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          Most cited references15

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          Induction of maternal behavior in virgin rats after intracerebroventricular administration of oxytocin.

          Oxytocin produces uterine contractions and milk ejection, functions related to parturition and nuturing. Studies were conducted to determine if this peptide, native to the brain and the posterior pituitary gland, plays a role in the induction of maternal behavior. Intact virgin female rats were given 0.4 mug of oxytocin, 0.4 mug of [Arg(8)]vasopressin, or saline through lateral ventricular cannulae. Forty-two percent of intact rats receiving oxytocin displayed full maternal behavior towards foster pups. None of the saline- or vasopressin-treated animals displayed full maternal behavior. Criteria in five behavioral categories had to be fulfilled by an animal within 2 hr of injection for its behavior to be considered fully maternal. When partial maternal responses were considered, oxytocin was significantly more effective than saline and marginally more effective than vasopressin. Five animals responding fully maternally after oxytocin injection were allowed to stay with pups for 10 days. All five continued to display full maternal behavior during this time. Nearly all animals that responded fully maternally to oxytocin injection were in the last day of diestrus or in proestrus or estrus. This suggested that elevated or recently elevated levels of estrogen may be necessary for the induction of full maternal behavior by oxytocin. Twenty-seven virgin female rats were ovariectomized and given either 100 mug of estradiol benzoate per kg in oil subcutaneously or oil alone immediately after operation. Forty-eight hours later, all animals received 0.4 mug of oxytocin intracerebroventricularly. Eleven of 13 estrogen-primed animals became fully maternal; none of 14 nonprimed animals became fully maternal.
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            Oxytocin receptors and human parturition: a dual role for oxytocin in the initiation of labor.

            The concentration of oxytocin receptors increased in the myometrium of pregnant women and reached maximum levels in early labor. Concentrations of oxytocin receptors were also high in the decidua and reached a maximum at parturition. In vitro, prostaglandin production by the decidua, but not by the myometrium, was increased by the addition of oxytocin. Oxytocin may therefore stimulate uterine contractions by acting both directly on the myometrium and indirectly on decidual prostaglandin production. Oxytocin receptors are probably crucial for the onset of human labor, and the stimulus for the increase in uterine prostaglandins may be oxytocin originating from the fetus.
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              Intracellular cholesterol transport.

                Author and article information

                Journal
                Physiological Reviews
                Physiological Reviews
                American Physiological Society
                0031-9333
                1522-1210
                April 01 2001
                April 01 2001
                : 81
                : 2
                : 629-683
                Affiliations
                [1 ]Institut für Biochemie, Johannes Gutenberg Universität, Mainz, Germany
                Article
                10.1152/physrev.2001.81.2.629
                11274341
                65c94521-ccbb-4789-9e6b-602d95d8691b
                © 2001
                History

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