The Oxytocin Receptor System: Structure, function, and regulation

The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gen e expression is the magnocellular neurons of the hypothalamic paraventricul ar and supraoptic nuclei. In response to a variety of stimuli such as suckl ing, parturition, or certain kinds of stress, the processed OT peptide is r eleased from the posterior pituitary into the systemic circulation. Such st imuli also lead to an intranuclear release of OT. Moreover, oxytocinergic n eurons display widespread projections throughout the central nervous system . However, OT is also synthesized in peripheral tissues, e.g., uterus, plac enta, amnion, corpus luteum, testis, and heart. The OT receptor is a typica l class I G protein-coupled receptor that is primarily coupled via G, prote ins to phospholipase C-P. The high-affinity receptor state requires both Mg 2+ and cholesterol, which probably function as allosteric modulators. The a gonist-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 ster oid 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 parturit ion is obviously more complex. Before the onset of labor, uterine sensitivi ty to OT markedly increases concomitant with a strong upregulation of OT re ceptors in the myometrium and, to a lesser extent, in the decidua where OT stimulates the release of PGF(2 alpha). Experiments with transgenic mice su ggest that OT acts as a luteotrophic hormone opposing the luteolytic action of PGF(2 alpha). Thus, to initiate labor, it might be essential to generat e sufficient PGF(2 alpha) to overcome the luteotrophic action of OT in late gestation. OT also plays an important role in many other reproduction-rela ted functions, such as control of the estrous cycle length, follicle lutein ization in the ovary, and ovarian steroidogenesis. In the male, OT is a pot ent stimulator of spontaneous erections in rats and is involved in ejaculat ion. 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 pe ptide 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 p air bonds. Overall, the regulation by gonadal and adrenal steroids is one o f 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 g enomic and nongenomic actions of steroids have not been clarified.