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Physiological Reviews, Vol. 81, No. 2, April 2001, pp. 629-683
Copyright ©2001 by the American Physiological Society
Institut für Biochemie, Johannes Gutenberg Universität, Mainz, Germany
Gimpl, Gerald and
Falk Fahrenholz.
The Oxytocin Receptor System: Structure, Function, and
Regulation. Physiol. Rev. 81: 629-683, 2001.
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
Gq proteins to phospholipase C-
. The high-affinity
receptor state requires both Mg2+ 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 PGF2
. Experiments
with transgenic mice suggest that OT acts as a luteotrophic hormone
opposing the luteolytic action of PGF2. Thus, to
initiate labor, it might be essential to generate sufficient
PGF2 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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P. V. Nantermet, P. Masarachia, M. A. Gentile, B. Pennypacker, J. Xu, D. Holder, D. Gerhold, D. Towler, A. Schmidt, D. B. Kimmel, et al. Androgenic Induction of Growth and Differentiation in the Rodent Uterus Involves the Modulation of Estrogen-Regulated Genetic Pathways Endocrinology, February 1, 2005; 146(2): 564 - 578. [Abstract] [Full Text] [PDF]
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 L. Vignozzi, G. B. Vannelli, A. Morelli, R. Mancina, M. Marini, P. Ferruzzi, C. Crescioli, M. Luconi, S. Donati, A. D. Fisher, et al. Identification, characterization and biological activity of oxytocin receptor in the developing human penis Mol. Hum. Reprod., February 1, 2005; 11(2): 99 - 106. [Abstract] [Full Text] [PDF]
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A. Heydorn, B. P. Sondergaard, B. Ersboll, B. Holst, F. C. Nielsen, C. R. Haft, J. Whistler, and T. W. Schwartz A Library of 7TM Receptor C-terminal Tails: INTERACTIONS WITH THE PROPOSED POST-ENDOCYTIC SORTING PROTEINS ERM-BINDING PHOSPHOPROTEIN 50 (EBP50), N-ETHYLMALEIMIDE-SENSITIVE FACTOR (NSF), SORTING NEXIN 1 (SNX1), AND G PROTEIN-COUPLED RECEPTOR-ASSOCIATED SORTING PROTEIN (GASP) J. Biol. Chem., December 24, 2004; 279(52): 54291 - 54303. [Abstract] [Full Text] [PDF]
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S. Acharjee, J.-L. Do-Rego, D. Y. Oh, R. S. Ahn, H. Choe, H. Vaudry, K. Kim, J. Y. Seong, and H. B. Kwon Identification of Amino Acid Residues That Direct Differential Ligand Selectivity of Mammalian and Nonmammalian V1a Type Receptors for Arginine Vasopressin and Vasotocin: INSIGHTS INTO MOLECULAR COEVOLUTION OF V1a TYPE RECEPTORS AND THEIR LIGANDS J. Biol. Chem., December 24, 2004; 279(52): 54445 - 54453. [Abstract] [Full Text] [PDF]
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L. L. Collins, Y.-F. Lee, C. A. Heinlein, N.-C. Liu, Y.-T. Chen, C.-R. Shyr, C. K. Meshul, H. Uno, K. A. Platt, and C. Chang Growth retardation and abnormal maternal behavior in mice lacking testicular orphan nuclear receptor 4 PNAS, October 19, 2004; 101(42): 15058 - 15063. [Abstract] [Full Text] [PDF]
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N. Wettschureck, A. Moers, T. Hamalainen, T. Lemberger, G. Schutz, and S. Offermanns Heterotrimeric G Proteins of the Gq/11 Family Are Crucial for the Induction of Maternal Behavior in Mice Mol. Cell. Biol., September 15, 2004; 24(18): 8048 - 8054. [Abstract] [Full Text] [PDF]
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M. Jankowski, B. Danalache, D. Wang, P. Bhat, F. Hajjar, M. Marcinkiewicz, J. Paquin, S. M. McCann, and J. Gutkowska Oxytocin in cardiac ontogeny PNAS, August 31, 2004; 101(35): 13074 - 13079. [Abstract] [Full Text] [PDF]
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N. De Mota, A. Reaux-Le Goazigo, S. El Messari, N. Chartrel, D. Roesch, C. Dujardin, C. Kordon, H. Vaudry, F. Moos, and C. Llorens-Cortes Apelin, a potent diuretic neuropeptide counteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release PNAS, July 13, 2004; 101(28): 10464 - 10469. [Abstract] [Full Text] [PDF]
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A. Hasbi, D. Devost, S. A. Laporte, and H. H. Zingg Real-Time Detection of Interactions between the Human Oxytocin Receptor and G Protein-Coupled Receptor Kinase-2 Mol. Endocrinol., May 1, 2004; 18(5): 1277 - 1286. [Abstract] [Full Text] [PDF]
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O.N. Richter, K. Kubler, J. Schmolling, M. Kupka, J. Reinsberg, U. Ulrich, H. van derVen, E. Wardelmann, and K. van derVen Oxytocin receptor gene expression of estrogen-stimulated human myometrium in extracorporeally perfused non-pregnant uteri Mol. Hum. Reprod., May 1, 2004; 10(5): 339 - 346. [Abstract] [Full Text] [PDF]
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 R. P. Millar, Z.-L. Lu, A. J. Pawson, C. A. Flanagan, K. Morgan, and S. R. Maudsley Gonadotropin-Releasing Hormone Receptors Endocr. Rev., April 1, 2004; 25(2): 235 - 275. [Abstract] [Full Text] [PDF]
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 C. Serradeil-Le Gal, G. Valette, L. Foulon, G. Germain, C. Advenier, E. Naline, M. Bardou, J.-P. Martinolle, B. Pouzet, D. Raufaste, et al. SSR126768A (4-Chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)-benzamide, Hydrochloride): A New Selective and Orally Active Oxytocin Receptor Antagonist for the Prevention of Preterm Labor J. Pharmacol. Exp. Ther., April 1, 2004; 309(1): 414 - 424. [Abstract] [Full Text]
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L. Vignozzi, S. Filippi, M. Luconi, A. Morelli, R. Mancina, M. Marini, G. B. Vannelli, S. Granchi, C. Orlando, S. Gelmini, et al. Oxytocin Receptor Is Expressed in the Penis and Mediates an Estrogen-Dependent Smooth Muscle Contractility Endocrinology, April 1, 2004; 145(4): 1823 - 1834. [Abstract] [Full Text] [PDF]
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 J. ANTUNES-RODRIGUES, M. DE CASTRO, L. L. K. ELIAS, M. M. VALENCA, and S. M. McCANN Neuroendocrine Control of Body Fluid Metabolism Physiol Rev, January 1, 2004; 84(1): 169 - 208. [Abstract] [Full Text] [PDF]
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D. A. Fitts, S. N. Thornton, A. A. Ruhf, D. K. Zierath, A. K. Johnson, and R. L. Thunhorst Effects of central oxytocin receptor blockade on water and saline intake, mean arterial pressure, and c-Fos expression in rats Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2003; 285(6): R1331 - R1339. [Abstract] [Full Text] [PDF]
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 Y. Ueta, Y. Ozaki, J. Saito, and T. Onaka Involvement of Novel Feeding-Related Peptides in Neuroendocrine Response to Stress Experimental Biology and Medicine, November 1, 2003; 228(10): 1168 - 1174. [Abstract] [Full Text] [PDF]
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M. M. Byrne, C. Rolf, M. Depenbusch, T. G. Cooper, and E. Nieschlag Lack of effect of a single i.v. dose of oxytocin on sperm output in severely oligozoospermic men Hum. Reprod., October 1, 2003; 18(10): 2098 - 2102. [Abstract] [Full Text] [PDF]
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A. L. Siebel, H. M. Gehring, I. G. T. Reytomas, and L. J. Parry Inhibition of Oxytocin Receptor and Estrogen Receptor-{alpha} Expression, But Not Relaxin Receptors (LGR7), in the Myometrium of Late Pregnant Relaxin Gene Knockout Mice Endocrinology, October 1, 2003; 144(10): 4272 - 4275. [Abstract] [Full Text] [PDF]
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 K. Rigatto, R. Puryear, I. Bernatova, and M. Morris Salt Appetite and the Renin-Angiotensin System: Effect of Oxytocin Deficiency Hypertension, October 1, 2003; 42(4): 793 - 797. [Abstract] [Full Text] [PDF]
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R. Cirillo, E. Gillio Tos, M. K. Schwarz, A. Quattropani, A. Scheer, M. Missotten, J. Dorbais, A. Nichols, F. Borrelli, C. Giachetti, et al. Pharmacology of (2S,4Z)-N-[(2S)-2-Hydroxy-2-phenylethyl]-4-(methoxyimino) -1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide, a New Potent and Selective Nonpeptide Antagonist of the Oxytocin Receptor J. Pharmacol. Exp. Ther., July 1, 2003; 306(1): 253 - 261. [Abstract] [Full Text] [PDF]
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 V. Simonneaux and C. Ribelayga Generation of the Melatonin Endocrine Message in Mammals: A Review of the Complex Regulation of Melatonin Synthesis by Norepinephrine, Peptides, and Other Pineal Transmitters Pharmacol. Rev., June 1, 2003; 55(2): 325 - 395. [Abstract] [Full Text] [PDF]
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 L. C. Michelini, M. C. Marcelo, J. Amico, and M. Morris Oxytocinergic regulation of cardiovascular function: studies in oxytocin-deficient mice Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2269 - H2276. [Abstract] [Full Text] [PDF]
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E. Choleris, J.-A. Gustafsson, K. S. Korach, L. J. Muglia, D. W. Pfaff, and S. Ogawa An estrogen-dependent four-gene micronet regulating social recognition: A study with oxytocin and estrogen receptor-alpha and -beta knockout mice PNAS, May 13, 2003; 100(10): 6192 - 6197. [Abstract] [Full Text] [PDF]
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 M. A.G. van der Heyden and L. H.K. Defize Twenty one years of P19 cells: what an embryonal carcinoma cell line taught us about cardiomyocyte differentiation Cardiovasc Res, May 1, 2003; 58(2): 292 - 302. [Abstract] [Full Text] [PDF]
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 S. R. Wesolowski, M. F. Allan, M. K. Nielsen, and D. Pomp Evaluation of hypothalamic gene expression in mice divergently selected for heat loss Physiol Genomics, April 16, 2003; 13(2): 129 - 137. [Abstract] [Full Text] [PDF]
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D. Wang, J. Gutkowska, M. Marcinkiewicz, G. Rachelska, and M. Jankowski Genistein supplementation stimulates the oxytocin system in the aorta of ovariectomized rats Cardiovasc Res, January 1, 2003; 57(1): 186 - 194. [Abstract] [Full Text] [PDF]
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L. Kunz, A. Thalhammer, F. D. Berg, U. Berg, D. M. Duffy, R. L. Stouffer, G. A. Dissen, S. R. Ojeda, and A. Mayerhofer Ca2+-Activated, Large Conductance K+ Channel in the Ovary: Identification, Characterization, and Functional Involvement in Steroidogenesis J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5566 - 5574. [Abstract] [Full Text] [PDF]
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S. Filippi, M. Luconi, S. Granchi, L. Vignozzi, S. Bettuzzi, P. Tozzi, F. Ledda, G. Forti, and M. Maggi Estrogens, But Not Androgens, Regulate Expression and Functional Activity of Oxytocin Receptor in Rabbit Epididymis Endocrinology, November 1, 2002; 143(11): 4271 - 4280. [Abstract] [Full Text] [PDF]
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N. Vasudevan, S. Ogawa, and D. Pfaff Estrogen and Thyroid Hormone Receptor Interactions: Physiological Flexibility by Molecular Specificity Physiol Rev, October 1, 2002; 82(4): 923 - 944. [Abstract] [Full Text] [PDF]
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J. Paquin, B. A. Danalache, M. Jankowski, S. M. McCann, and J. Gutkowska Oxytocin induces differentiation of P19 embryonic stem cells to cardiomyocytes PNAS, July 9, 2002; 99(14): 9550 - 9555. [Abstract] [Full Text] [PDF]
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F. Staubli, T. J. D. Jorgensen, G. Cazzamali, M. Williamson, C. Lenz, L. Sondergaard, P. Roepstorff, and C. J. P. Grimmelikhuijzen Molecular identification of the insect adipokinetic hormone receptors PNAS, March 19, 2002; 99(6): 3446 - 3451. [Abstract] [Full Text] [PDF]
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S. Toda, H. Ando, T. Nagasaka, S.-I. Tsukahara, M. Nomura, Y. Kotani, S. Nomura, F. Kikkawa, M. Tsujimoto, and S. Mizutani Existence of Placental Leucine Aminopeptidase/Oxytocinase/Insulin-Regulated Membrane Aminopeptidase in Human Endometrial Epithelial Cells J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1384 - 1389. [Abstract] [Full Text] [PDF]
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