Vasopressin and oxytocin receptors: Introduction

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing. » Email us

General

Arginine-vasopressin (AVP) and oxytocin (OT) are both neurohypophysial hormones and share a high sequence and structure homology. They are cyclic nonapeptides and only differ at residues 3 and 8. Four receptors exist in mammals, three for AVP and a unique receptor for OT, although AVP possesses a nanomolar affinity for all subtypes. AVP is also named the antidiuretic hormone (ADH) due to its effect on the regulation of water body balance whereas oxytocin is defined as the "quick birth" hormone because of its highly potent uterotonic activity

AVP

In 1895, the discovery by Oliver and Schäfer of the mammalian pressor effect of cow pituitary extracts constituted the starting point of more than a century of active research on the structure and function of vertebrate neurohypophysial hormones [51]. In the early 1950’s, Du Vigneaud and his team isolated two small peptides, AVP (displaying pressor and antidiuretic properties) and OT (with oxytocic and galactogenic activities), elucidated their chemical structure and chemically synthesized both hormones [16]. Since the discovery of these important landmarks in the field, AVP and OT have been the focus of intensive structure-activity and analogue design studies. This made available a series of most valuable pharmacological tools for the study of almost all aspects of AVP and OT physiological functions [44].

AVP is characterized by the presence of a disulfide bond between Cys1 and Cys6. This results in a peptide constituted of 6 amino-acid cyclic part and a COOH terminal α-aminated three residue tail. AVP contains a basic amino-acid arginine at position 8, and a phenylalanine at position 3. The presence of the glycinamide at the C-terminus is absolutely necessary for biological activity of the hormone.

AVP is primarily synthesized in the magnocellular neurons of the hypothalamic supraoptic nucleus, and in magnocellular and parvocellular neurons of the paraventricular and suprachismatic nuclei of the hypothalamus. In response to a variety of stimuli such as variations in plasma osmolality, arterial pressure and cardiac volume, the processed AVP peptide is released from the posterior pituitary into the systemic circulation. AVP is also released somatodendritically within the nuclei of its origin to regularize the phasic firing pattern of the neurons. AVP is secreted in peripheral tissues, like for instance thymus, testis, adrenal gland, vasculature.

Like many other neuropeptides, the bioactive form of AVP is generated from a large precurseur, preprovasopressin [60]. After removal of a signal peptide, preprovasopressin is further processed into three end products, neurophysin II, glycoprotein (copeptin) and mature AVP by intracellular processing. The neurophysin II is known as an important carrier protein which supports the axonal transport of AVP in the vasopressinergic neurons.

AVP has multiple physiological functions (see below), including body water regulation, control of blood pressure, platelet aggregation, release of coagulation factors, cell proliferation, and effects on body temperature, insulin release, corticotropin release, memory and social behaviour. All these actions are mediated through activation of three specific membrane-bound receptors present at the surface of the target cells. On the basis of pharmacological and functional studies, these receptors have been classified as V1A, V1B and V2 subtypes.

OT

The neurohypophysial hormone OT, together with AVP, was the first peptide hormone to have its structure determined and the first to be chemically synthesized in a biologically active form. Like AVP, OT is a disulfide-bridge cyclic nonapeptide but contains neutral amino-acids at position 3 and 8 (isoleucine and leucine, respectively). The difference in polarity of these residues, compared to AVP, is believed to enable OT to interact selectively with its specific receptor subtype. Like for AVP, the presence of the C-terminal glycinamide is absolutely necessary for biological activity of the hormone.

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, like uterus, placenta, amnion, corpus luteum, testis, and heart.

The OT prepropeptide precursor is subject to cleavage and other modifications as it is transported down the neuron axon to terminals located in the posterior pituitary [30]. The mature peptide products, OT and its carrier molecule neurophysin I, are stored in the axon terminals until neural inputs elicit their release. The main function of neurophysin I, a small disulfide-rich protein, appears to be related to the proper targeting, packaging, and storage of OT within the granula before release into the bloodstream.

In all species, OT and AVP genes are on the same chromosomal locus but are transcribed in opposite directions. The intergenic distance between these genes range from 3 to 12 kb in mouse, human, and rat. This type of genomic arrangement could result from the duplication of a common ancestral gene, which was followed by inversion of one of the genes. The human gene for OT-neurophysin I encoding the OT prepropeptide is mapped to chromosome 20p13 [56].

The neurohypophysial peptide OT facilitates reproduction in all vertebrates at several levels (see below).

AVP/OT receptors

Based on pharmacological and functional studies, Michell and his collaborators proposed in 1979 that two types of AVP receptors can be distinguished [46]. Activation of the hepatic AVP receptor triggers a rise in cytosolic free calcium and an increase in phosphatidylinositol breakdown with production of inositol triphosphate and diacylglycerol leading to activation of proteine kinase C. They suggested the term V1 for this receptor. Renal AVP receptors involved in free water reabsorption by activation of adenylyl cyclase and production of cAMP were named V2. However, the AVP receptor present in anterior pituitary and involved in corticotropin release together with corticotropin-releasing factor CRF has a pharmacological profile different from that of the hepatic/vascular receptor [32]. Consequently, the V1 receptors were subdivided into V1A (the hepatic receptor) and V1B (the adenohypophysial receptor) subtypes by Jard and colleagues. The OT receptor displays unique pharmacological and tissue localization properties.

V1A receptor

In 1992, the V1A receptor subtype which responds to AVP was first isolated from rat liver, by cloning of its complementary DNA [47]. Two years later, the sequence of the human V1A receptor was published, after cloning of the corresponding cDNA from a liver cDNA library [65]. The V1A receptor is named the hepatic/vascular subtype. Human and rat receptors share 72% sequence identity. The V1A receptor is primarily coupled to an increase in phosphatidylinositol breakdown with production of inositol triphosphate and diacylglycerol leading to a rise in cytosolic free calcium concentration and activation of proteine kinase C, respectively. Production of inositol phosphates is generated through activation of Gq protein and phospholipase C. The V1A is widely distributed in peripheral tissues and different areas of the central nervous system, suggesting a neurotransmitter-like activity of AVP [66]. For instance, the V1A receptor is expressed in liver, vascular smooth muscles, heart, platelets, adrenal gland, testes, urinary bladder, and also in brainstem, cerebral cortex, hippocampus, hypothalamus, olfactory bulb, striatum. Selective V1A agonists and antagonists have been described [12]. Interestingly, OT is able to bind and activate V1A but with an affinity and potency which are much lower than those of AVP. As all other members of AVP/OT receptors, there are important differences between species in the pharmacology of the V1A.

V1B receptor

The V1B receptor which responds to AVP was first cloned in humans from a pituitary cDNA library in 1994 [62]. Evidence for an extra-pituitary expression of the V1B was demonstrated one year after cloning of the corresponding rat V1B receptor [59]. The V1B receptor is named the corticotrope AVP receptor. It displays a high percentage identity with all other AVP/OT receptors V1A, V2 and the OT receptor. Like the V1A subtype, the V1B is primarily coupled to an increase in phosphatidylinositol breakdown with production of inositol triphosphate and diacylglycerol leading to a rise in cytosolic free calcium concentration and activation of proteine kinase C, respectively. Production of inositol phosphates is generated through activation of Gq protein and phospholipase C. The V1B is also coupled to Gs and activation of adenylyl cyclase, although with a much lower potency [52]. The V1B is mostly expressed in the pituitary gland (corticotroph cells) and in beta cells of the pancreas islets, but also in multiple brain regions and other peripheral tissues, including kidney, thymus, heart, lung, spleen, uterus, adrenal gland and breast. This receptor can be distinguished from the vascular/hepatic V1A and renal V2 AVP receptors by its differential binding affinities for structural analogues of AVP. Selective V1B agonists and antagonists have been described [12]. Once again, like for the V1A, there are important differences between species in the pharmacology of the V1B.

V2 receptor

The human and rat V2 receptors were cloned concomitantly in 1992 from the isolation of the human AVP receptor gene using a genomic expression cloning approach and from a rat kidney cDNA library, respectively [7,41]. The human gene was then used to clone the complementary DNA from a human renal library. The V2 receptor is named the renal AVP receptor or the antidiuretic AVP receptor. The human V2 receptor gene has been localized to the long arm of the X chromosome and its mutations are responsible for congenital nephrogenic diabetes insipidus (cNDI), an X-linked recessive disorder characterized by renal resistance to the antidiuretic action of AVP [3,61]. The V2 receptor displays a high percentage identity with all other AVP/OT receptors. However, unlike the other receptors of the family, V1A, V1B and the OT receptor, it is primarily coupled to Gs, activation of adenylyl cyclase, production of cyclic AMP and activation of protein kinase A. The V2 receptor is secondarily coupled to Gq and a rise in cytosolic free calcium concentration, although with a much lower potency. The V2 receptor is exclusively expressed in the principal cells of the renal collecting duct, being responsible for the antidiuretic effect of AVP, but the existence of an extra-renal V2 receptor has been proposed [25,49]. For instance, the V2 receptor may also be expressed in the internal ear where it could regulate the hydraulic pressure of the endolymphatic system [39]. Selective V2 agonists and antagonists have been described [12]. Like for all other members of AVP/OT receptors, there are important differences between species in the pharmacology of the V2 receptor. For instance, the pig V2 receptor has a V1A-like ligand binding profile compared to the human V2, but interestingly the pig possesses a lysine-vasopressin as a natural ligand instead of the arginine-vasopressin that occurs in other placental mammals.

OT receptor

The OT receptor (previously named OTR) which responds to OT but is able to bind AVP with an equivalent affinity, has been identified in 1992 through human complementary DNA isolated by expression cloning [35]. The human OT receptor mRNAs were found to be of two sizes, 3.6 kb in breast and 4.4 kb in ovary, uterine endometrium and myometrium [35,58]. The OT receptor is both coupled to Gq leading to a rise in cytosolic calcium concentration, and to Gi leading to inhibition of adenylyl cyclase and decrease in cAMP levels. The OT receptor is mostly expressed in the uterus and the mammary gland, but also in other peripheral organs such as ovaries, skin, adipose tissue, testes, adrenal gland, and in brain areas like cerebral cortex, hippocampus, hypothalamus, olfactory bulb or striatum, suggesting a neurotransmitter-like activity for OT. Selective OT agonists and antagonists have been described [12]. Like for all other members of AVP/OT receptors, there are important differences between species in the pharmacology of the OT receptor.

Receptor structure and activation

Molecular cloning of AVP/OT receptors confirmed that they are members of the G protein-coupled receptor superfamily. They are typical members of the rhodopsin-like class A receptors and are considered as prototypes of G protein-coupled receptors for which small peptides and hormones are endogenous ligands. They consist of seven hydrophobic transmembrane α-helices, joined by alternating intracellular and extracellular loops, an extracellular N-terminal domain and a cytoplasmic C-terminal end. V1A, V1B, V2 and the OT receptor display a high degree of sequence identity, showing about 102 invariant amino-acid residues among 370-420 amino-acids in the human receptors. They display all structural hallmarks characteristic of the class A receptors (many conserved amino-acid residues at specific positions, a disulfide bond linking the top of transmembrane helix 3 to the extracellular loop 2). In addition, V1A, V1B, V2 and the OT receptor also contain glycosylation sites in the extracellular parts and palmitoylation motifs in the C-terminal structural domain. No experimental three-dimensional structure has been described to date regarding the AVP/OT receptors.

Identification of the hormone binding sites of AVP/OT receptors has been undertaken at a molecular level. Receptor mutational analysis combined with receptor three-dimensional molecular modelling, but also direct receptor covalent photolabeling have led to very valuable information concerning peptide agonist and peptide and non-peptide antagonist binding domains of this receptor family [48]. Indeed, the AVP/OT receptor binding pocket is buried into a 15-20 Å deep central cavity defined by the transmembrane helices and surrounded by the extracellular loops. The hydrophobic part of the ligands dives deeply into the binding cavity for interacting with hydrophobic residue clusters, whereas the more hydrophilic part of the peptides bind to the transmembrane edge. Only the side-chain of residue 8 of the peptides is pointing towards the extracellular loops of the receptors and is potentially less constrained than all other parts of the ligands [13]. The N-terminal extracellular domain of AVP/OT receptors has also been shown to participate in the binding of agonists [71]. Interestingly, since the binding sites of AVP/OT receptors are conserved throughout the family and because AVP and OT are structurally similar, AVP can elicit OT responses and vice versa. The selectivity of the different AVP/OT receptors for their specific ligands is due to differences in the nature of some amino-acid residues located at very precise positions in the binding pockets.

The existence of different conformational states of these receptors, stabilized with different classes of ligands, is suggested. For instance, atosiban known as a competitive antagonist of OT, inhibits OTR-induced Gq activation pathway, but is also agonist for the receptor-mediated Gi pathway and the activation of MAP kinases [57]. Again, the SR121463 non-peptide ligand is defined as an antagonist of the V2 receptor subtype considering the Gs activation pathway, whereas this molecule is also able to recruit β-arrestin and stimulate MAP kinase activation [2]. Novel non-peptide pharmacochaperone agonists of the V2 receptor which activate the Gs pathway and inhibit the arrestin-related pathways such as receptor internalization and MAP kinase stimulation have been discovered recently [33]. Atosiban, SR121463 and these new pharmacochaperone agonists are thus functionally-selective ligands. Structural bases of functional selectivity of the V2 receptor have been recently studied by fluorescence spectroscopy [55]. Finally, AVP is a partial agonist of OTR [14], indicating that AVP and OT differ in the amplitude of the functional response that they elicit after maximal OTR receptor occupancy. Altogether, these results point to a multistate model of receptor activation in which ligand-specific conformations are capable of differentially activate distinct signaling partners.

Peripheral and central receptor functions

The distribution of AVP and OT and their receptors in the brain and in the periphery determines the physiological functions of the V1A, V1B, V2 and the OT receptor. Most of the peripheral activities of AVP and OT are well described. New roles in social behavior are now expanding. In addition, the availability of mutant mice lacking AVP, OT, or each of the different receptor subtypes, allowed to experimentally validate a number of physiological functions.

Antidiuresis is the most important physiological role of AVP [9]. Prevention of body fluid loss is regulated by reabsorption of water in the kidney. This activity is achieved through the V2 subtype which is expressed at the basolateral membrane of the tubule and the collecting duct principal cells of the kidney. AVP synthesis is stringently regulated by plasma osmolality (sensed by osmoreceptors), and is released in the general circulation in response to hyperosmotic changes. As a result, AVP causes a decrease in plasma osmololity. AVP also controls the cardiovascular system in response to hemodynamic stress [34]. Hypotension or hypovolemia initiates the secretion of the hormone from the posterior pituitary through baroreceptor sensing. AVP increases the arterial blood pressure by acting on the V1A subtype which is present in the vessel walls. The name "vasopressin" comes from the its vasoconstriction activity. Like other stress hormones, AVP enhances blood coagulation [11]. In particular, AVP increases factor VIII and von Willebrand factor (vWF) plasma concentration. However, the wide range of physiological actions evoked by AVP limits its use for treatment of bleeding disorders. Desmopressin (dDAVP), an analogue of AVP, described first as a selective V2 agonist but is not in human, also increases factor VIII and vWF, has few side effects than AVP and is widely used to treat bleeding disorders [45]. However, neither the receptor site nor the mechanisms by which desmopressin enhances platelet adhesion and increases factor VIII and vWF concentrations have been elucidated to date. AVP and CRH (corticoptropin-releasing hormone) activate the HPA (hypothalamus-pituitary-adrenal gland) axis playing a principal role in stress and immune response [73]. CRH and AVP act as ACTH (adrenocorticotropic hormone) secretagogues from the corticotroph cells, then ACTH stimulates the glucocorticoid synthesis and secretion from the adrenal cortex. The AVP receptor present at the surface of corticotroph cells is the V1B subtype. Compared with CRH, AVP itself has a weak ability of upregulating the ACTH secretion ; however it markedly potentiates the effects of CRH. Altogether, CRH and AVP are characterized as upstream regulators of the HPA axis. Among the plethora of physiological processes regulated by AVP is the homeostatic control of blood glucose levels. Indeed, AVP is involved in insulin release from pancreatic beta cells and this activity is mediated via the V1B subtype [53]. The activation of the V1B subtype of islet cells decreases blood glucose level, but AVP is also able to increase the blood glucose level by promoting the release of glucagon and by enhancing glycogenolysis in the liver [36]. The hepatic glycogenolysis is mediated predominantly by the V1A AVP receptor. The effect of AVP on islet cells has been demonstrated by combined pharmacological and knockout approaches. The AVP effect on insulin release is entirely lost in mice lacking the V1B subtype but was preserved in mice lacking the V1A receptor subtype.

The classical actions of OT are stimulation of uterine smooth muscle contraction during labor and milk ejection during lactation [23]. 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 the OT receptor in the myometrium and, to a lesser extent, in the decidua where OT stimulates the release of prostaglandine PGF2α. Experiments with transgenic mice suggest that OT acts as a luteotrophic hormone opposing the luteolytic action of PGF2α. 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. 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.

More relevant to social neuroscience, OT- and AVP-expressing neurons in the hypothalamus also project centrally and OT, V1A and V1B receptors are found in the brain. Today, apart from their well-known peripheral effects, OT and AVP may be best known for their contribution to the regulation of social behaviors [74]. The first evidence linking OT and AVP to social behavior came in the late 1970’s and 1980’s when it was found that centrally administered OT promoted maternal nurturing in virgin, steroid-primed female rats suggesting that this hormone coordinates not only the peripheral physiology of reproduction, but also transforms the mother’s brain to ensure the survival of the offspring [54]. There is now compelling evidence that OT modulates maternal behavior in several species. The behavioral role of AVP and OT expanded in the mid 1990’s as it was reported that these peptides play important roles in regulating pair bonding, mate guarding and paternal care in monogamous prairie voles [72]. The prominence of these peptides in the public’s attention has been further elevated in the past few years by a plethora of studies in humans suggesting that OT and AVP modulate human social behavior and cognition. In 2005, a landmark paper suggested that OT enhanced trust in humans [37]. OT has even been shown to enhance some aspects of social function in psychiatric disorders like autism [40]. Polymorphisms in the OT and AVP receptor genes have been linked to attachment, generosity, and even pair bonding behaviors in humans [17]. Once known almost exclusively for their role in birth, milk ejection, and water balance, it is not uncommon for OT and AVP peptides or their receptors to be referred to as the "trust" hormone, the "monogamy gene", the "cheating gene" and very recently the "moral molecule".

V1A receptor knockout mice exhibit altered glucose homeostasis, a decrease in blood pressure and circulating blood volume, impaired aldosterone secretion, impaired spatial memory, subtle olfactory deficit but normal aggression, a decrease in anxiety-like behaviour and impaired social recognition [1,4-6,8,10,19-20,26-28,38,50,68].

V1B receptor knockout mice exhibit reduced basal adrenocorticotropin and corticosterone levels, an impaired rise in adrenocorticotropin in response to AVP, altered stress-induced catecholamine release, reduced aggressive behaviour, enhanced sensitivity to insulin [15,18,21-22,29,42-43,64,67,69-70].

Many natural mutations of the V2 receptor gene result in loss of function receptors leading to the X-linked congenital nephrogenic diabetes insipidus [3]. People suffering from this disease do not concentrate urine and are characterized by polyuria. Other natural mutations of the V2 gene lead to constitutive activation of the receptor, characterized by hyponatremia [24]. This disease is named nephrogenic syndrome of inappropriate antidiuresis (NSIAD).

Female OT receptor knockout exhibit defects in lactation and maternal nurturing, male OT receptor knockout mice have deficits in social discrimination and elevated aggressive behaviour [63]. Polymorphism in the OT receptor gene may be linked to autism [31].

References

Show »

1. Aoyagi T, Birumachi J, Hiroyama M, Fujiwara Y, Sanbe A, Yamauchi J, Tanoue A. (2007) Alteration of glucose homeostasis in V1a vasopressin receptor-deficient mice. Endocrinology, 148 (5): 2075-84. [PMID:17303660]

2. Azzi M, Charest PG, Angers S, Rousseau G, Kohout T, Bouvier M, Piñeyro G. (2003) Beta-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors. Proc. Natl. Acad. Sci. U.S.A., 100 (20): 11406-11. [PMID:13679574]

3. Bichet DG. (2006) Nephrogenic diabetes insipidus. Adv Chronic Kidney Dis, 13 (2): 96-104. [PMID:16580609]

4. Bielsky IF, Hu SB, Ren X, Terwilliger EF, Young LJ. (2005) The V1a vasopressin receptor is necessary and sufficient for normal social recognition: a gene replacement study. Neuron, 47: 503-513. [PMID:16102534]

5. Bielsky IF, Hu SB, Szegda KL, Westphal H, Young LJ. (2004) Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice. Neuropsychopharmacology, 29 (3): 483-93. [PMID:14647484]

6. Bielsky IF, Hu SB, Young LJ. (2005) Sexual dimorphism in the vasopressin system: lack of an altered behavioral phenotype in female V1a receptor knockout mice. Behav. Brain Res., 164 (1): 132-6. [PMID:16046007]

7. Birnbaumer M, Seibold A, Gilbert S, Ishido M, Barberis C, Antaramian A, Brabet P, Rosenthal W. (1992) Molecular cloning of the receptor for human antidiuretic hormone. Nature, 357 (6376): 333-5. [PMID:1534149]

8. Birumachi J, Hiroyama M, Fujiwara Y, Aoyagi T, Sanbe A, Tanoue A. (2007) Impaired arginine-vasopressin-induced aldosterone release from adrenal gland cells in mice lacking the vasopressin V1A receptor. Eur. J. Pharmacol., 566 (1-3): 226-30. [PMID:17449028]

9. Boone M, Deen PM. (2008) Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption. Pflugers Arch., 456 (6): 1005-24. [PMID:18431594]

10. Caldwell HK, Stewart J, Wiedholz LM, Millstein RA, Iacangelo A, Holmes A, Young 3rd WS, Wersinger SR. (2006) The acute intoxicating effects of ethanol are not dependent on the vasopressin 1a or 1b receptors. Neuropeptides, 40 (5): 325-37. [PMID:17049983]

11. Cash JD, Gader AM, da Costa J. (1974) Proceedings: The release of plasminogen activator and factor VIII to lysine vasopressin, arginine vasopressin, I-desamino-8-d-arginine vasopressin, angiotensin and oxytocin in man. Br. J. Haematol., 27 (2): 363-4. [PMID:4367720]

12. Chini B, Manning M, Guillon G. (2008) Affinity and efficacy of selective agonists and antagonists for vasopressin and oxytocin receptors: an "easy guide" to receptor pharmacology. Prog. Brain Res., 170: 513-7. [PMID:18655904]

13. Chini B, Mouillac B, Ala Y, Balestre MN, Trumpp-Kallmeyer S, Hoflack J, Elands J, Hibert M, Manning M, Jard S et al.. (1995) Tyr115 is the key residue for determining agonist selectivity in the V1a vasopressin receptor. EMBO J., 14 (10): 2176-82. [PMID:7774575]

14. Chini B, Mouillac B, Balestre MN, Trumpp-Kallmeyer S, Hoflack J, Hibert M, Andriolo M, Pupier S, Jard S, Barberis C. (1996) Two aromatic residues regulate the response of the human oxytocin receptor to the partial agonist arginine vasopressin. FEBS Lett., 397 (2-3): 201-6. [PMID:8955347]

15. Daikoku R, Kunitake T, Kato K, Tanoue A, Tsujimoto G, Kannan H. (2007) Body water balance and body temperature in vasopressin V1b receptor knockout mice. Auton Neurosci, 136 (1-2): 58-62. [PMID:17512263]

16. Du Vigneaud V, Ressler C, Trippett S. (1953) The sequence of amino acids in oxytocin, with a proposal for the structure of oxytocin. J Biol Chem, 205: 949-957. [PMID:13129273]

17. Ebstein RP, Knafo A, Mankuta D, Chew SH, Lai PS. (2012) The contributions of oxytocin and vasopressin pathway genes to human behavior. Horm Behav, 61 (3): 359-79. [PMID:22245314]

18. Egashira N, Tanoue A, Higashihara F, Fuchigami H, Sano K, Mishima K, Fukue Y, Nagai H, Takano Y, Tsujimoto G et al.. (2005) Disruption of the prepulse inhibition of the startle reflex in vasopressin V1b receptor knockout mice: reversal by antipsychotic drugs. Neuropsychopharmacology, 30 (11): 1996-2005. [PMID:15956991]

19. Egashira N, Tanoue A, Higashihara F, Mishima K, Fukue Y, Takano Y, Tsujimoto G, Iwasaki K, Fujiwara M. (2004) V1a receptor knockout mice exhibit impairment of spatial memory in an eight-arm radial maze. Neurosci. Lett., 356 (3): 195-8. [PMID:15036628]

20. Egashira N, Tanoue A, Matsuda T, Koushi E, Harada S, Takano Y, Tsujimoto G, Mishima K, Iwasaki K, Fujiwara M. (2007) Impaired social interaction and reduced anxiety-related behavior in vasopressin V1a receptor knockout mice. Behav. Brain Res., 178 (1): 123-7. [PMID:17227684]

21. Fujiwara Y, Hiroyama M, Sanbe A, Aoyagi T, Birumachi J, Yamauchi J, Tsujimoto G, Tanoue A. (2007) Insulin hypersensitivity in mice lacking the V1b vasopressin receptor. J. Physiol. (Lond.), 584 (Pt 1): 235-44. [PMID:17673508]

22. Fujiwara Y, Hiroyama M, Sanbe A, Yamauchi J, Tsujimoto G, Tanoue A. (2007) Mutual regulation of vasopressin- and oxytocin-induced glucagon secretion in V1b vasopressin receptor knockout mice. J. Endocrinol., 192 (2): 361-9. [PMID:17283236]

23. Gimpl G, Fahrenholz F. (2001) The oxytocin receptor system: structure, function, and regulation. Physiol. Rev., 81 (2): 629-83. [PMID:11274341]

24. Gitelman SE, Feldman BJ, Rosenthal SM. (2006) Nephrogenic syndrome of inappropriate antidiuresis: a novel disorder in water balance in pediatric patients. Am J Med, 119: S54-S58. [PMID:16843086]

25. Hirasawa A, Nakayama Y, Ishiharada N, Honda K, Saito R, Tsujimoto G, Takano Y, Kamiya H. (1994) Evidence for the existence of vasopressin V2 receptor mRNA in rat hippocampus. Biochem. Biophys. Res. Commun., 205 (3): 1702-6. [PMID:7811254]

26. Hiroyama M, Aoyagi T, Fujiwara Y, Birumachi J, Shigematsu Y, Kiwaki K, Tasaki R, Endo F, Tanoue A. (2007) Hypermetabolism of fat in V1a vasopressin receptor knockout mice. Mol Endocrinol, 21: 247-258. [PMID:17021052]

27. Hiroyama M, Aoyagi T, Fujiwara Y, Oshikawa S, Sanbe A, Endo F, Tanoue A. (2007) Hyperammonaemia in V1a vasopressin receptor knockout mice caused by the promoted proteolysis and reduced intrahepatic blood volume. J. Physiol. (Lond.), 581 (Pt 3): 1183-92. [PMID:17379633]

28. Hiroyama M, Wang S, Aoyagi T, Oikawa R, Sanbe A, Takeo S, Tanoue A. (2007) Vasopressin promotes cardiomyocyte hypertrophy via the vasopressin V1A receptor in neonatal mice. Eur. J. Pharmacol., 559 (2-3): 89-97. [PMID:17275806]

29. Itoh S, Yamada S, Mori T, Miwa T, Tottori K, Uwahodo Y, Yamamura Y, Fukuda M, Yamamoto K, Tanoue A et al.. (2006) Attenuated stress-induced catecholamine release in mice lacking the vasopressin V1b receptor. Am. J. Physiol. Endocrinol. Metab., 291 (1): E147-51. [PMID:16464910]

30. Ivell R, Richter D. (1984) Structure and comparison of the oxytocin and vasopressin genes from rat. Proc. Natl. Acad. Sci. U.S.A., 81 (7): 2006-10. [PMID:6326097]

31. Jacob S, Brune CW, Carter CS, Leventhal BL, Lord C, Cook Jr EH. (2007) Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism. Neurosci. Lett., 417 (1): 6-9. [PMID:17383819]

32. Jard S, Gaillard RC, Guillon G, Marie J, Schoenenberg P, Muller AF, Manning M, Sawyer WH. (1986) Vasopressin antagonists allow demonstration of a novel type of vasopressin receptor in the rat adenohypophysis. Mol. Pharmacol., 30 (2): 171-7. [PMID:3016500]

33. Jean-Alphonse F, Perkovska S, Frantz MC, Durroux T, Méjean C, Morin D, Loison S, Bonnet D, Hibert M, Mouillac B et al.. (2009) Biased agonist pharmacochaperones of the AVP V2 receptor may treat congenital nephrogenic diabetes insipidus. J. Am. Soc. Nephrol., 20 (10): 2190-203. [PMID:19729439]

34. Johnston CI. (1985) Vasopressin in circulatory control and hypertension. J. Hypertens., 3 (6): 557-69. [PMID:2935570]

35. Kimura T, Tanizawa O, Mori K, Brownstein MJ, Okayama H. (1992) Structure and expression of a human oxytocin receptor. Nature, 356 (6369): 526-9. [PMID:1313946]

36. Kirk CJ, Rodrigues LM, Hems DA. (1979) The influence of vasopressin and related peptides on glycogen phosphorylase activity and phosphatidylinositol metabolism in hepatocytes. Biochem. J., 178 (2): 493-6. [PMID:444224]

37. Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. (2005) Oxytocin increases trust in humans. Nature, 435 (7042): 673-6. [PMID:15931222]

38. Koshimizu TA, Nasa Y, Tanoue A, Oikawa R, Kawahara Y, Kiyono Y, Adachi T, Tanaka T, Kuwaki T, Mori T, Takeo S, Okamura H, Tsujimoto G. (2006) V1a vasopressin receptors maintain normal blood pressure by regulating circulating blood volume and baroreflex sensitivity. Proc Natl Acad Sci U S A, 103: 7807-7812. [PMID:16682631]

39. Kumagami H, Loewenheim H, Beitz E, Wild K, Schwartz H, Yamashita K, Schultz J, Paysan J, Zenner HP, Ruppersberg JP. (1998) The effect of anti-diuretic hormone on the endolymphatic sac of the inner ear. Pflugers Arch., 436 (6): 970-5. [PMID:9799415]

40. Lim MM, Bielsky IF, Young LJ. (2005) Neuropeptides and the social brain: potential rodent models of autism. Int. J. Dev. Neurosci., 23 (2-3): 235-43. [PMID:15749248]

41. Lolait SJ, O'Carroll AM, McBride OW, Konig M, Morel A, Brownstein MJ. (1992) Cloning and characterization of a vasopressin V2 receptor and possible link to nephrogenic diabetes insipidus. Nature., 357: 336-339. [PMID:1534150]

42. Lolait SJ, Stewart LQ, Jessop DS, Young 3rd WS, O'Carroll AM. (2007) The hypothalamic-pituitary-adrenal axis response to stress in mice lacking functional vasopressin V1b receptors. Endocrinology, 148 (2): 849-56. [PMID:17122081]

43. Lolait SJ, Stewart LQ, Roper JA, Harrison G, Jessop DS, Young 3rd WS, O'Carroll AM. (2007) Attenuated stress response to acute lipopolysaccharide challenge and ethanol administration in vasopressin V1b receptor knockout mice. J. Neuroendocrinol., 19 (7): 543-51. [PMID:17561882]

44. Manning M, Stoev S, Chini B, Durroux T, Mouillac B, Guillon G. (2008) Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents. Prog. Brain Res., 170: 473-512. [PMID:18655903]

45. Mannucci PM. (1997) Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood, 90 (7): 2515-21. [PMID:9326215]

46. Michell RH, Kirk CJ, Billah MM. (1979) Hormonal stimulation of phosphatidylinositol breakdown with particular reference to the hepatic effects of vasopressin. Biochem. Soc. Trans., 7 (5): 861-5. [PMID:510730]

47. Morel A, O'Carroll AM, Brownstein MJ, Lolait SJ. (1992) Molecular cloning and expression of a rat V1a arginine vasopressin receptor. Nature, 356 (6369): 523-6. [PMID:1560825]

48. Mouillac B, Chini B, Balestre MN, Elands J, Trumpp-Kallmeyer S, Hoflack J, Hibert M, Jard S, Barberis C. (1995) The binding site of neuropeptide vasopressin V1a receptor. Evidence for a major localization within transmembrane regions. J. Biol. Chem., 270 (43): 25771-7. [PMID:7592759]

49. Nonoguchi H, Owada A, Kobayashi N, Takayama M, Terada Y, Koike J, Ujiie K, Marumo F, Sakai T, Tomita K. (1995) Immunohistochemical localization of V2 vasopressin receptor along the nephron and functional role of luminal V2 receptor in terminal inner medullary collecting ducts. J Clin Invest, 96: 1768-1778. [PMID:7560068]

50. Oikawa R, Nasa Y, Ishii R, Kuwaki T, Tanoue A, Tsujimoto G, Takeo S. (2007) Vasopressin V1A receptor enhances baroreflex via the central component of the reflex arc. Eur. J. Pharmacol., 558 (1-3): 144-50. [PMID:17224142]

51. Oliver G, Schäfer EA. (1895) On the Physiological Action of Extracts of Pituitary Body and certain other Glandular Organs: Preliminary Communication. J. Physiol. (Lond.), 18 (3): 277-9. [PMID:16992253]

52. Orcel H, Albizu L, Perkovska S, Durroux T, Mendre C, Ansanay H, Mouillac B, Rabié A. (2009) Differential coupling of the vasopressin V1b receptor through compartmentalization within the plasma membrane. Mol. Pharmacol., 75 (3): 637-47. [PMID:19047484]

53. Oshikawa S, Tanoue A, Koshimizu TA, Kitagawa Y, Tsujimoto G. (2004) Vasopressin stimulates insulin release from islet cells through V1b receptors: a combined pharmacological/knockout approach. Mol. Pharmacol., 65 (3): 623-9. [PMID:14978240]

54. Pedersen CA, Prange AJ. (1979) Induction of maternal behavior in virgin rats after intracerebroventricular administration of oxytocin. Proc. Natl. Acad. Sci. U.S.A., 76 (12): 6661-5. [PMID:293752]

55. Rahmeh R, Damian M, Cottet M, Orcel H, Mendre C, Durroux T, Sharma KS, Durand G, Pucci B, Trinquet E et al.. (2012) Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy. Proc. Natl. Acad. Sci. U.S.A., 109 (17): 6733-8. [PMID:22493271]

56. Rao VV, Löffler C, Battey J, Hansmann I. (1992) The human gene for oxytocin-neurophysin I (OXT) is physically mapped to chromosome 20p13 by in situ hybridization. Cytogenet. Cell Genet., 61 (4): 271-3. [PMID:1486803]

57. Reversi A, Rimoldi V, Marrocco T, Cassoni P, Bussolati G, Parenti M, Chini B. (2005) The oxytocin receptor antagonist atosiban inhibits cell growth via a "biased agonist" mechanism. J. Biol. Chem., 280 (16): 16311-8. [PMID:15705593]

58. Rozen F, Russo C, Banville D, Zingg HH. (1995) Structure, characterization, and expression of the rat oxytocin receptor gene. Proc. Natl. Acad. Sci. U.S.A., 92 (1): 200-4. [PMID:7816817]

59. Saito M, Sugimoto T, Tahara A, Kawashima H. (1995) Molecular cloning and characterization of rat V1b vasopressin receptor: evidence for its expression in extra-pituitary tissues. Biochem. Biophys. Res. Commun., 212 (3): 751-7. [PMID:7626108]

60. Schmale H, Heinsohn S, Richter D. (1983) Structural organization of the rat gene for the arginine vasopressin-neurophysin precursor. EMBO J., 2 (5): 763-7. [PMID:6315416]

61. Seibold A, Brabet P, Rosenthal W, Birnbaumer M. (1992) Structure and chromosomal localization of the human antidiuretic hormone receptor gene. Am. J. Hum. Genet., 51 (5): 1078-83. [PMID:1415251]

62. Sugimoto T, Saito M, Mochizuki S, Watanabe Y, Hashimoto S, Kawashima H. (1994) Molecular cloning and functional expression of a cDNA encoding the human V1b vasopressin receptor. J. Biol. Chem., 269 (43): 27088-92. [PMID:7929452]

63. Takayanagi Y, Yoshida M, Bielsky IF, Ross HE, Kawamata M, Onaka T, Yanagisawa T, Kimura T, Matzuk MM, Young LJ et al.. (2005) Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice. Proc. Natl. Acad. Sci. U.S.A., 102 (44): 16096-101. [PMID:16249339]

64. Tanoue A, Ito S, Honda K, Oshikawa S, Kitagawa Y, Koshimizu TA, Mori T, Tsujimoto G. (2004) The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions. J. Clin. Invest., 113 (2): 302-9. [PMID:14722621]

65. Thibonnier M, Auzan C, Madhun Z, Wilkins P, Berti-Mattera L, Clauser E. (1994) Molecular cloning, sequencing, and functional expression of a cDNA encoding the human V1a vasopressin receptor. J. Biol. Chem., 269 (5): 3304-10. [PMID:8106369]

66. Thibonnier M, Graves MK, Wagner MS, Auzan C, Clauser E, Willard HF. (1996) Structure, sequence, expression, and chromosomal localization of the human V1a vasopressin receptor gene. Genomics, 31 (3): 327-34. [PMID:8838314]

67. Wersinger SR, Caldwell HK, Christiansen M, Young 3rd WS. (2007) Disruption of the vasopressin 1b receptor gene impairs the attack component of aggressive behavior in mice. Genes Brain Behav., 6 (7): 653-60. [PMID:17284170]

68. Wersinger SR, Caldwell HK, Martinez L, Gold P, Hu SB, Young 3rd WS. (2007) Vasopressin 1a receptor knockout mice have a subtle olfactory deficit but normal aggression. Genes Brain Behav., 6 (6): 540-51. [PMID:17083331]

69. Wersinger SR, Ginns EI, O'Carroll AM, Lolait SJ, Young 3rd WS. (2002) Vasopressin V1b receptor knockout reduces aggressive behavior in male mice. Mol. Psychiatry, 7 (9): 975-84. [PMID:12399951]

70. Wersinger SR, Temple JL, Caldwell HK, Young 3rd WS. (2008) Inactivation of the oxytocin and the vasopressin (Avp) 1b receptor genes, but not the Avp 1a receptor gene, differentially impairs the Bruce effect in laboratory mice (Mus musculus). Endocrinology, 149 (1): 116-21. [PMID:17947352]

71. Wheatley M, Simms J, Hawtin SR, Wesley VJ, Wootten D, Conner M, Lawson Z, Conner AC, Baker A, Cashmore Y et al.. (2007) Extracellular loops and ligand binding to a subfamily of Family A G-protein-coupled receptors. Biochem. Soc. Trans., 35 (Pt 4): 717-20. [PMID:17635132]

72. Winslow JT, Hastings N, Carter CS, Harbaugh CR, Insel TR. (1993) A role for central vasopressin in pair bonding in monogamous prairie voles. Nature, 365 (6446): 545-8. [PMID:8413608]

73. Yates FE, Russell SM, Dallman MF, Hodge GA, McCann SM, Dhariwal AP. (1971) Potentiation by vasopressin of corticotropin release induced by corticotropin-releasing factor. Endocrinology, 88 (1): 3-15. [PMID:4320769]

74. Young LJ, Flanagan-Cato LM. (2012) Editorial comment: oxytocin, vasopressin and social behavior. Horm Behav, 61 (3): 227-9. [PMID:22443808]

How to cite this page

To cite this family introduction, please use the following:

Database page citation (select format):