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The International Journal of... Jul 2021Accumulating evidence shows that certain populations of depressed patients have impaired hypothalamus-pituitary-adrenal (HPA) axis function. Arginine-vasopressin (AVP)... (Review)
Review
Accumulating evidence shows that certain populations of depressed patients have impaired hypothalamus-pituitary-adrenal (HPA) axis function. Arginine-vasopressin (AVP) is one of the primary factors in HPA axis regulation under stress situations, and AVP and its receptor subtype (V1B receptor) play a pivotal role in HPA axis abnormalities observed in depression. Based on this hypothesis, several non-peptide V1B receptor antagonists have been synthesized, and the efficacies of some V1B receptor antagonists have been investigated in both animals and humans. V1B receptor antagonists exert antidepressant-like effects in several animal models at doses that attenuate the hyperactivity of the HPA axis, and some of their detailed mechanisms have been delineated. These results obtained in animal models were, at least partly, reproduced in clinical trials. At least 2 V1B receptor antagonists (TS-121 and ABT-436) showed tendencies to reduce the depression scores of patients with major depressive disorder at doses that attenuate HPA axis hyperactivity or block the pituitary V1B receptor. Importantly, TS-121 showed a clearer efficacy for patients with higher basal cortisol levels than for those with lower basal cortisol levels, which was consistent with the hypothesis that V1B receptor antagonists may be more effective for patients with HPA axis hyperactivity. Therefore, V1B receptor antagonists are promising approaches for the treatment of depression involving HPA axis impairment such as depression.
Topics: Animals; Antidepressive Agents; Antidiuretic Hormone Receptor Antagonists; Depressive Disorder, Major; Humans; Hypothalamo-Hypophyseal System; Receptors, Vasopressin
PubMed: 33733667
DOI: 10.1093/ijnp/pyab013 -
Cancer Chemotherapy and Pharmacology Oct 2017Small-molecule inhibitors of heat-shock protein 90 (HSP90) have been under development as chemotherapeutic agents. The adverse events reported from early clinical trials...
PURPOSE
Small-molecule inhibitors of heat-shock protein 90 (HSP90) have been under development as chemotherapeutic agents. The adverse events reported from early clinical trials included hyponatremia. Given the limited number of patients enrolled, the number of hyponatremia incidents was remarkable and repeatedly, the event was judged as severe. Inappropriate V2 vasopressin receptor stimulation is an established cause of hyponatremia. We explored the hypothesis that HSP90 inhibition produces hypersensitivity to vasopressin by upregulating V2-receptors.
METHODS
Experiments were carried out in cell culture using HEK293 cells with heterologous expression of the human V2-receptor and HELA cells with an endogenous V2-receptor complement. We tested the effect of HSP90 inhibition by three structurally unrelated compounds (alvespimycin, luminespib, radicicol) and asserted its specificity in cells depleted of cytosolic HSP90 (by RNA interference). Assays encompassed surface V2-receptor density and vasopressin-stimulated formation of cyclic AMP (cAMP).
RESULTS
The results demonstrate a twofold increase in cell-surface receptor density following pre-incubation with each of the HSP90 inhibitors. The effect had a concentration-dependence consistent with the individual potencies to inhibit HSP90. Similarly, depletion of cytosolic HSP90 increased surface-receptor density and at the same time, reduced the inhibitor effect. Upregulated V2-receptors were fully functional; hence, in culture treated with an HSP90 inhibitor, addition of vasopressin resulted in higher levels of cAMP than in controls.
CONCLUSION
Since formation of cAMP is the first signalling step in raising water permeability of the collecting duct epithelia, we suggest that V2-receptor upregulation generates hypersensitivity to vasopressin linking HSP90 inhibition to the development of hyponatremia.
Topics: Benzoquinones; Cyclic AMP; Cytosol; HEK293 Cells; HSP90 Heat-Shock Proteins; HeLa Cells; Humans; Hyponatremia; Isoxazoles; Lactams, Macrocyclic; Macrolides; RNA Interference; Receptors, Vasopressin; Resorcinols; Up-Regulation; Vasopressins
PubMed: 28779264
DOI: 10.1007/s00280-017-3390-x -
Hormones and Behavior Feb 2023Genetic knockouts of the vasopressin receptor 1a (Avpr1a), oxytocin receptor (Oxtr), or oxytocin (Oxt) gene in mice have helped cement the causal relationship between...
Genetic knockouts of the vasopressin receptor 1a (Avpr1a), oxytocin receptor (Oxtr), or oxytocin (Oxt) gene in mice have helped cement the causal relationship between these neuropeptide systems and various social behaviors (e.g., social investigation, recognition, and communication, as well as territoriality and aggression). In mice, these social behaviors depend upon the olfactory system. Thus, it is critical to assess the olfactory capabilities of these knockout models to accurately interpret the observed differences in social behavior. Prior studies utilizing these transgenic mice have sought to test for baseline deficits in olfactory processing; predominantly through use of odor habituation/dishabituation tasks, buried food tests, or investigation assays using non-social odorants. While informative, these assays rely on the animal's intrinsic motivation and locomotor behavior to measure olfactory capabilities and thus, often yield mixed results. Instead, psychophysical analyses using operant conditioning procedures and flow-dilution olfactometry are ideally suited to precisely quantify olfactory perception. In the present study, we used these methods to assess the main olfactory capabilities of adult male and female Avpr1a, Oxtr, and Oxt transgenic mice to volatile non-social odorants. Our results indicate that homozygous and heterozygous knockout mice of all three strains have the same sensitivity and discrimination ability as their wild-type littermates. These data strongly support the hypothesis that the observed social deficits of these global knockout mice are not due to baseline deficits of their main olfactory system.
Topics: Mice; Male; Female; Animals; Receptors, Oxytocin; Oxytocin; Odorants; Receptors, Vasopressin; Social Behavior; Mice, Transgenic; Mice, Knockout
PubMed: 36628861
DOI: 10.1016/j.yhbeh.2022.105302 -
Stress (Amsterdam, Netherlands) Jan 2011The distribution, pharmacology and function of the arginine vasopressin (Avp) 1b receptor subtype (Avpr1b) has proved more challenging to investigate compared to other... (Review)
Review
The distribution, pharmacology and function of the arginine vasopressin (Avp) 1b receptor subtype (Avpr1b) has proved more challenging to investigate compared to other members of the Avp receptor family. Avp is increasingly recognised as an important modulator of the hypothalamic-pituitary-adrenal (HPA) axis, an action mediated by the Avpr1b present on anterior pituitary corticotrophs. The Avpr1b is also expressed in some peripheral tissues including pancreas and adrenal, and in the hippocampus (HIP), paraventricular nucleus and olfactory bulb of the rodent brain where its function is unknown. The central distribution of Avpr1bs is far more restricted than that of the Avpr1a, the main Avp receptor subtype found in the brain. Whether Avpr1b expression in rodent tissues is dependent on differences in the length of microsatellite dinucleotide repeats present in the 5' promoter region of the Avpr1b gene remains to be determined. One difficulty of functional studies on the Avpr1b, especially its involvement in the HPA axis response to stress, which prompted the generation of Avpr1b knockout (KO) mouse models, was the shortage of commercially available Avpr1b ligands, particularly antagonists. Research on mice lacking functional Avpr1bs has highlighted behavioural deficits in social memory and aggression. The Avpr1b KO also appears to be an excellent model to study the contribution of the Avpr1b in the HPA axis response to acute and perhaps some chronic (repeated) stressors where corticotrophin-releasing hormone and other genes involved in the HPA axis response to stress do not appear to compensate for the loss of the Avpr1b.
Topics: Aggression; Animals; Brain; Hypothalamo-Hypophyseal System; Mice; Mice, Knockout; Pituitary-Adrenal System; Receptors, Vasopressin; Stress, Physiological; Tissue Distribution
PubMed: 20828336
DOI: 10.3109/10253890.2010.512376 -
Traffic (Copenhagen, Denmark) Jan 2018The signaling pathway of G protein-coupled receptors is strongly linked to their trafficking profile. Little is known about the molecular mechanisms involved in the...
The signaling pathway of G protein-coupled receptors is strongly linked to their trafficking profile. Little is known about the molecular mechanisms involved in the vasopressin receptor V subtype (V R) trafficking and its impact on receptor signaling and regulation. For this purpose, we investigated the role of β-arrestins in receptor desensitization, internalization and recycling and attempted to dissect the V R-mediated MAP kinase pathway. Using MEF cells Knocked-out for β-arrestins 1 and 2, we demonstrated that both β-arrestins 1 and 2 play a fundamental role in internalization and recycling of V R with a rapid and transient V R-β-arrestin interaction in contrast to a slow and long-lasting β-arrestin recruitment of the V vasopressin receptor subtype (V R). Using V R-V R chimeras and V R C-terminus truncations, we demonstrated the critical role of the V R C-terminus in its interaction with β-arrestins thereby regulating the receptor internalization and recycling kinetics in a phosphorylation-independent manner. In parallel, V R MAP kinase activation was dependent on arrestins and Src-kinase but independent on G proteins. Interestingly, Src interacted with hV R at basal state and dissociated when receptor internalization occurred. Altogether, our data describe for the first time the trafficking profile and MAP kinase pathway of V R involving both arrestins and Src kinase family.
Topics: Animals; Binding Sites; GTP-Binding Proteins; HEK293 Cells; Humans; MAP Kinase Signaling System; Mice; Protein Binding; Protein Transport; Receptors, Vasopressin; beta-Arrestins; src-Family Kinases
PubMed: 29044966
DOI: 10.1111/tra.12535 -
American Journal of Physiology. Renal... Mar 2021Renal arginine vasopressin receptor 2 (AVPR2) plays a crucial role in osmoregulation. Engagement of ligand with AVPR2 results in aquaporin 2 movement to the apical...
Renal arginine vasopressin receptor 2 (AVPR2) plays a crucial role in osmoregulation. Engagement of ligand with AVPR2 results in aquaporin 2 movement to the apical membrane and water reabsorption from the urinary filtrate. Despite this essential role, little is known about transcriptional regulation of . Here, we identify novel roles for PAX2, a transcription factor crucial for kidney development, and its adaptor protein, Pax transcription interacting protein (PTIP), for epigenetic regulation of and thus body water balance. Chromatin immunoprecipitation (ChIP) from murine inner medulla cells (IMCD-3) identified the minimal DNA-binding region of PAX2 on the promoter. Regulation of by PAX2 was confirmed using a heterologous DNA expression system. PAX2 recruits the adaptor protein PTIP and its associated histone methyltransferase (HMT) complex to promoter, imposing epigenetic marks on this region and throughout the coding sequence that modulate gene transcription. Reduction of PAX2 or PTIP protein levels by siRNA prevented histone lysine methylation and expression of . ChIP using mouse or human kidneys determined that PAX2 is highly enriched in the promoter alongside PTIP and HMT proteins, leading to high levels of histone H3 lysine trimethylation within the promoter and throughout the gene. In conclusion, PAX2 provides locus specificity for PTIP, allowing the HMT complex to impart epigenetic changes at the locus and regulate transcription. These finding have major implications for understanding regulation of body water balance. The transcription factor PAX2 plays an indispensable role in kidney development. In the adult kidney, we identified the first described protein this protein regulates. PAX2 and its interacting partner Pax transcription interacting protein recruit a histone methyltransferase complex to the promoter and epigentically regulate the expression of arginine vasopressin receptor 2, a protein that plays a crucial role in osmoregulation in the distal tubule.
Topics: Animals; Carrier Proteins; Cell Nucleus; Epigenesis, Genetic; Gene Expression Regulation; Nuclear Proteins; PAX2 Transcription Factor; Receptors, Vasopressin
PubMed: 33522413
DOI: 10.1152/ajprenal.00371.2020 -
Hormones and Behavior Mar 2012To date, much of the work in rodents implicating vasopressin (Avp) in the regulation of social behavior has focused on its action via the Avp 1a receptor (Avpr1a).... (Review)
Review
To date, much of the work in rodents implicating vasopressin (Avp) in the regulation of social behavior has focused on its action via the Avp 1a receptor (Avpr1a). However, there is mounting evidence that the Avp 1b receptor (Avpr1b) also plays a significant role in Avp's modulation of social behavior. The Avpr1b is heavily expressed on the anterior pituitary cortiocotrophs where it acts as an important modulator of the endocrine stress response. In the brain, the Avpr1b is prominent in the CA2 region of the hippocampus, but can also be found in areas such as the paraventricular nucleus of the hypothalamus and the olfactory bulb. Studies that have employed genetic knockouts or pharmacological manipulation of the Avpr1b point to the importance of central Avpr1b in the modulation of social behavior. However, there continues to be a knowledge gap in our understanding of where in the brain this is occurring, as well as how and if the central actions of Avp acting via the Avpr1b interact with the stress axis. In this review we focus on the genetic and pharmacological studies that have implicated the Avpr1b in the neural regulation of social behaviors, including social forms of aggressive behavior, social memory, and social motivation. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.
Topics: Affect; Aggression; Animals; Brain Chemistry; Humans; Memory; Mice; Mice, Knockout; Motivation; Receptors, Vasopressin; Recognition, Psychology; Social Behavior; Stress, Psychological
PubMed: 22178035
DOI: 10.1016/j.yhbeh.2011.11.009 -
Behavior Genetics Mar 2017Polymorphisms of the arginine vasopressin receptor 1a (AVPR1a) gene have been linked to various measures related to human social behavior, including sibling conflict and...
Polymorphisms of the arginine vasopressin receptor 1a (AVPR1a) gene have been linked to various measures related to human social behavior, including sibling conflict and agreeableness. In chimpanzees, AVPR1a polymorphisms have been associated with traits important for social interactions, including sociability, joint attention, dominance, conscientiousness, and hierarchical personality dimensions named low alpha/stability, disinhibition, and negative emotionality/low dominance. We examined associations between AVPR1a and six personality domains and hierarchical personality dimensions in 129 chimpanzees (Pan troglodytes) living in Japan or in a sanctuary in Guinea. We fit three linear and three animal models. The first model included genotype, the second included sex and genotype, and the third included genotype, sex, and sex × genotype. All personality phenotypes were heritable. Chimpanzees possessing the long form of the allele were higher in conscientiousness, but only in models that did not include the other predictors; however, additional analyses suggested that this may have been a consequence of study design. In animal models that included sex and sex × genotype, chimpanzees homozygous for the short form of the allele were higher in extraversion. Taken with the findings of previous studies of chimpanzees and humans, the findings related to conscientiousness suggest that AVPR1a may be related to lower levels of impulsive aggression. The direction of the association between AVPR1a genotype and extraversion ran counter to what one would expect if AVPR1a was related to social behaviors. These results help us further understand the genetic basis of personality in chimpanzees.
Topics: Aggression; Alleles; Animals; Arginine; Behavior, Animal; Genotype; Models, Animal; Pan troglodytes; Personality; Phenotype; Polymorphism, Genetic; Receptors, Vasopressin; Social Behavior
PubMed: 27804047
DOI: 10.1007/s10519-016-9822-2 -
Critical Care (London, England) Dec 2003Vasopressin is emerging as a rational therapy for vasodilatory shock states. Unlike other vasoconstrictor agents, vasopressin also has vasodilatory properties. The goal... (Review)
Review
Vasopressin is emerging as a rational therapy for vasodilatory shock states. Unlike other vasoconstrictor agents, vasopressin also has vasodilatory properties. The goal of the present review is to explore the vascular actions of vasopressin. In part 1 of the review we discuss structure, signaling pathways, and tissue distributions of the classic vasopressin receptors, namely V1 vascular, V2 renal, V3 pituitary and oxytocin receptors, and the P2 class of purinoreceptors. Knowledge of the function and distribution of vasopressin receptors is key to understanding the seemingly contradictory actions of vasopressin on the vascular system. In part 2 of the review we discuss the effects of vasopressin on vascular smooth muscle and the heart, and we summarize clinical studies of vasopressin in shock states.
Topics: Humans; Muscle, Smooth, Vascular; Receptors, Vasopressin; Signal Transduction; Vasopressins
PubMed: 14624682
DOI: 10.1186/cc2337 -
The Pan African Medical Journal 2019Disorders of water balance are a disease commonly encountered in our clinical practice. Analysis of vasopressin receptor type II (V2R) is essential to understand the... (Review)
Review
Disorders of water balance are a disease commonly encountered in our clinical practice. Analysis of vasopressin receptor type II (V2R) is essential to understand the physiology of water balance and it is used as a biological prototype of G protein-coupled receptors (GPCRs). Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a syndrome of inappropriate antidiuretic hormone secretion (SIADH) with low plasmatic vasopressin. The evidence on the role of V2 receptor and of aquaporin (AQP) in the mechanism of action for antidiuretic hormone (ADH) was based on the identification of protein gene mutations in patients with nephrogenic diabetes insipidus and NSIAD syndrome. V2R activating mutations were found in patients with NSIAD, contrasting with the numerous V2R inactivating mutations related to X-linked mutations described in patients with nephrogenic diabetes insipidus.
Topics: Aquaporins; Diabetes Insipidus, Nephrogenic; Genetic Diseases, X-Linked; Humans; Inappropriate ADH Syndrome; Mutation; Neurophysins; Protein Precursors; Receptors, Vasopressin; Vasopressins
PubMed: 31312322
DOI: 10.11604/pamj.2019.32.210.6006