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 V_1A, V_1B 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 V_1A (the hepatic receptor) and V_1B (the adenohypophysial receptor) subtypes by Jard and colleagues. The OT receptor displays unique pharmacological and tissue localization properties.

V_1A 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 V_1A receptor was published, after cloning of the corresponding cDNA from a liver cDNA library [65]. The V_1A receptor is named the hepatic/vascular subtype. Human and rat receptors share 72% sequence identity. The V_1A 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 V_1A 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 V_1A 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 V_1A agonists and antagonists have been described [12]. Interestingly, OT is able to bind and activate V_1A 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 V_1A.

V_1B receptor

The V_1B 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 V_1B was demonstrated one year after cloning of the corresponding rat V_1B receptor [59]. The V_1B receptor is named the corticotrope AVP receptor. It displays a high percentage identity with all other AVP/OT receptors V_1A, V₂ and the OT receptor. Like the V_1A subtype, the V_1B 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 V_1B is also coupled to Gs and activation of adenylyl cyclase, although with a much lower potency [52]. The V_1B 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 V_1A and renal V₂ AVP receptors by its differential binding affinities for structural analogues of AVP. Selective V_1B agonists and antagonists have been described [12]. Once again, like for the V_1A, there are important differences between species in the pharmacology of the V_1B.

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, V_1A, V1_B 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 V_1A-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. V_1A, V_1B, 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, V_1A, V1_B, 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 V_1A, V_1B, 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 V_1A 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 V_1B 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 V_1B subtype [53]. The activation of the V1_B 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 V_1A 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 V_1B subtype but was preserved in mice lacking the V_1A 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, V_1A and V_1B 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".

V_1A 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].

V_1B 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].

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