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Advances in Protein Chemistry and... 2019Biased agonists and pharmacological chaperones have demonstrated their potential to harness G protein-coupled receptor signaling and trafficking, and have collectively... (Review)
Review
Biased agonists and pharmacological chaperones have demonstrated their potential to harness G protein-coupled receptor signaling and trafficking, and have collectively opened new possibilities in G protein-coupled receptor drug discovery. Combining pharmacological chaperoning and biased agonism properties into a unique given molecule would be of high therapeutic interest in many human diseases resulting from G protein-coupled receptor mutation and misfolding. This strategy perfectly fits to congenital Nephrogenic Diabetes Insipidus which is a typical conformational disease. In most of the cases, it is associated to inactivating mutations of the renal arginine-vasopressin V2 receptor leading to misfolding and intracellular retention of the receptor, causing the inability of patients to concentrate their urine in response to the antidiuretic hormone. Cell-permeable pharmacological chaperones have been successfully challenged to restore plasma membrane localization of the receptor mutants and to rescue their function. Interestingly, different classes of pharmacological chaperones of the V2 receptor have proven their usefulness and efficacy, such as antagonists, agonists as well as biased agonists. These compounds, particularly small-molecule biased agonists which elicit the V2-induced Gs protein-dependent signaling pathway, but not V2-related arrestin-dependent cell responses, represent a potential therapeutic treatment of this X-linked genetic pathology.
Topics: Diabetes Insipidus, Nephrogenic; Drug Discovery; High-Throughput Screening Assays; Humans; Ligands; Mutation; Protein Folding; Receptors, Vasopressin
PubMed: 31928727
DOI: 10.1016/bs.apcsb.2019.07.002 -
Proceedings. Biological Sciences Jun 2023Although numerous studies have focused on brain functions related to inequity aversion, few have examined its genetic basis. Here, we show the association between...
Although numerous studies have focused on brain functions related to inequity aversion, few have examined its genetic basis. Here, we show the association between estimated inequity aversion and polymorphisms in three genes associated with human sociality. Non-student adult participants took part in five economic game experiments on different days. Disadvantageous inequity aversion (DIA) and advantageous inequity aversion (AIA) were calculated from behavioural responses using Bayesian estimation. We investigated the association between genetic polymorphisms in the oxytocin receptor ( rs53576), arginine vasopressin receptor 1A ( RS3) and opioid receptor mu 1 ( rs1799971) and inequity aversion. Regarding RS3, participants with the SS genotype had higher AIA than those with the SL or LL genotypes, but no association was found for DIA. Moreover, we observed no aversion associations for rs53576 or rs1799971. The results suggest that plays an important role in aversion when one's own gain is greater than that of others. Our findings may provide a solid theoretical basis for future studies on the relationship between genetic polymorphisms and inequity aversion.
Topics: Adult; Humans; Bayes Theorem; Receptors, Vasopressin; Genotype; Affect; Polymorphism, Genetic
PubMed: 37312550
DOI: 10.1098/rspb.2023.0378 -
Frontiers in Neuroendocrinology Apr 2019Vasopressin (AVP) and oxytocin (OXT) regulate social behavior by binding to their canonical receptors, the vasopressin V1a receptor (V1aR) and oxytocin receptor (OTR),... (Review)
Review
Vasopressin (AVP) and oxytocin (OXT) regulate social behavior by binding to their canonical receptors, the vasopressin V1a receptor (V1aR) and oxytocin receptor (OTR), respectively. Recent studies suggest that these neuropeptides may also signal via each other's receptors. The extent to which such cross-system signaling occurs likely depends on anatomical overlap between AVP/OXT fibers and V1aR/OTR expression. By comparing AVP/OXT fiber densities with V1aR/OTR binding densities throughout the rat social behavior neural network (SBNN), we propose the potential for cross-system signaling in four regions: the medial amygdala (MeA), bed nucleus of the stria terminalis (BNSTp), medial preoptic area, and periaqueductal grey. We also discuss possible implications of corresponding sex (higher in males versus females) and age (higher in adults versus juveniles) differences in AVP fiber and OTR binding densities in the MeA and BNSTp. Overall, this review reveals the need to unravel the consequences of potential cross-system signaling between AVP and OXT systems in the SBNN for the regulation of social behavior.
Topics: Animals; Humans; Nerve Net; Oxytocin; Receptors, Oxytocin; Receptors, Vasopressin; Social Behavior; Vasopressins
PubMed: 30753840
DOI: 10.1016/j.yfrne.2019.02.001 -
The role of oxytocin, vasopressin, and their receptors at nociceptors in peripheral pain modulation.Frontiers in Neuroendocrinology Oct 2021Oxytocin and vasopressin are neurohypophyseal hormones with sequence similarity and play a central role in bodily homeostatic regulation. Pain is currently understood to... (Review)
Review
Oxytocin and vasopressin are neurohypophyseal hormones with sequence similarity and play a central role in bodily homeostatic regulation. Pain is currently understood to be an important phenotype that those two neurohormones strongly downregulate. Nociceptors, the first component of the ascending neural circuit for pain signals, have constantly been shown to be modulated by those peptides. The nociceptor modulation appears to be critical in pain attenuation, which has led to a gradual increase in scientific interest about their physiological processes and also drawn attention to their translational potentials. This review focused on what are recently understood and stay under investigation in the functional modulation of nociceptors by oxytocin and vasopressin. Effort to produce a nociceptor-specific view could help to construct a more systematic picture of the peripheral pain modulation by oxytocin and vasopressin.
Topics: Humans; Nociceptors; Oxytocin; Pain; Receptors, Oxytocin; Receptors, Vasopressin; Vasopressins
PubMed: 34437871
DOI: 10.1016/j.yfrne.2021.100942 -
Journal of Internal Medicine Oct 2017Vasopressin has many physiological actions in addition to its well-defined role in the control of fluid homeostasis and urine concentration. An increasing body of... (Review)
Review
Vasopressin has many physiological actions in addition to its well-defined role in the control of fluid homeostasis and urine concentration. An increasing body of evidence suggests that the vasopressin-hydration axis plays a role in glucose homeostasis. This review summarizes the knowledge accumulated over the last decades about the influence of vasopressin in the short-term regulation of glycaemia. It describes the possible role of this hormone through activation of V1a and V1b receptors on liver and pancreas functions and on the hypothalamic-pituitary-adrenal axis. Moreover, we report recent in vivo studies demonstrating the role of vasopressin in the long-term regulation of glycaemia. Indeed, V1a- or double-V1aV1b-receptor knockout mice display significant changes in the glucose and lipid metabolism. In rats, sustained high V1aR activation increases basal glycaemia and aggravates glucose intolerance in obese rats. Finally, the translation from animal findings to human was evidenced by epidemiological and genetic studies that showed that high vasopressin level is a risk factor for hyperglycaemia, metabolic disorders and diabetes.
Topics: Animals; Blood Glucose; Glucose; Glycopeptides; Homeostasis; Humans; Metabolic Diseases; Obesity; Rats; Receptors, Vasopressin; Vasopressins
PubMed: 28688111
DOI: 10.1111/joim.12649 -
Stress (Amsterdam, Netherlands) Nov 2020Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition with a wide range of behavioral disturbances and serious consequences for both patient and...
Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition with a wide range of behavioral disturbances and serious consequences for both patient and society. One of the main reasons for unsuccessful therapies is insufficient knowledge about its underlying pathomechanism. In the search for centrally signaling molecules that might be relevant to the development of PTSD we focus here on arginine vasopressin (AVP). So far AVP has not been strongly implicated in PTSD, but different lines of evidence suggest a possible impact of its signaling in all clusters of PTSD symptomatology. More specifically, in laboratory rodents, AVP agonists affect behavior in a PTSD-like manner, while significant reduction of AVP signaling in the brain e.g. in AVP-deficient Brattleboro rats, ameliorated defined behavioral parameters that can be linked to PTSD symptoms. Different animal models of PTSD also show alterations in the AVP signaling in distinct brain areas. However, pharmacological treatment targeting central AVP receptors via systemic routes is hampered by possible side effects that are linked to the peripheral action of AVP as a hormone. Indeed, the V1a receptor, the most common receptor subtype in the brain, is implicated in vasoconstriction. Thus, systemic treatment with V1a receptor antagonists would be implicated in hypotonia. This implies that novel treatment concepts are needed to target AVP receptors not only at brain level but also in distinct brain areas, to offer alternative treatments for PTSD.
Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Humans; Rats; Rats, Brattleboro; Receptors, Vasopressin; Stress Disorders, Post-Traumatic; Stress, Psychological; Vasopressins
PubMed: 33043781
DOI: 10.1080/10253890.2020.1826430 -
American Journal of Physiology. Renal... Dec 2016Fundamental kidney physiology research can provide important insight into how the kidney works and suggest novel therapeutic opportunities to treat human diseases. This... (Review)
Review
Fundamental kidney physiology research can provide important insight into how the kidney works and suggest novel therapeutic opportunities to treat human diseases. This is especially true for nephrogenic diabetes insipidus (NDI). Over the past decade, studies elucidating the molecular physiology and signaling pathways regulating water transport have suggested novel therapeutic possibilities. In patients with congenital NDI due to mutations in the type 2 vasopressin receptor (V2R) or acquired NDI due to lithium (or other medications), there are no functional abnormalities in the aquaporin-2 (AQP2) water channel, or in another key inner medullary transport protein, the UT-A1 urea transporter. If it is possible to phosphorylate and/or increase the apical membrane accumulation of these proteins, independent of vasopressin or cAMP, one may be able to treat NDI. Sildenifil (through cGMP), erlotinib, and simvastatin each stimulate AQP2 insertion into the apical plasma membrane. Some recent human data suggest that sildenafil and simvastatin may improve urine concentrating ability. ONO-AE1-329 (ONO) stimulates the EP4 prostanoid receptor (EP4), which stimulates kinases that in turn phosphorylate AQP2 and UT-A1. Clopidogrel is a P2Y12-R antagonist that potentiates the effect of vasopressin and increases AQP2 abundance. Metformin stimulates AMPK to phosphorylate and activate AQP2 and UT-A1, and it increases urine concentrating ability in two rodent models of NDI. Since metformin, sildenafil, and simvastatin are commercially available and have excellent safety records, the potential for rapidly advancing them into clinical trials is high.
Topics: Adenylate Kinase; Animals; Aquaporin 2; Diabetes Insipidus, Nephrogenic; Erlotinib Hydrochloride; Humans; Metformin; Mutation; Phosphorylation; Receptors, Vasopressin; Sildenafil Citrate; Simvastatin
PubMed: 27534996
DOI: 10.1152/ajprenal.00418.2016 -
Experimental and Clinical Endocrinology... Apr 2020We investigated the expression of vasopressin receptor 2 and 3 on corticotrophin tumor cells, their role in regulating ACTH secretion, and their potential therapeutic...
PURPOSE
We investigated the expression of vasopressin receptor 2 and 3 on corticotrophin tumor cells, their role in regulating ACTH secretion, and their potential therapeutic implications.
METHODS
We retrospectively assessed 52 hospitalized patients with pathologically confirmed ACTH-secreting tumors. The expression of vasopressin receptor 2 and 3 was explored via qualitative and quantitative immunohistochemistry analyses. The role of vasopressin receptors in regulating ACTH secretion was further studied in the AtT-20 cell line.
RESULTS
Among 50 cases of pituitary corticotrophin adenoma, 31 were vasopressin receptor 2 positive, 38 were vasopressin receptor 3 positive, and 24 were both vasopressin receptor 2 and 3 positive. Two patients with ectopic ACTH syndrome were vasopressin receptor 3 positive, and one was also vasopressin receptor 2 positive. In 12 patients who underwent bilateral inferior petrosal sinus sampling before surgery, the central ACTH increment ratio after desmopressin stimulation was correlated with vasopressin receptor 2 but not with vasopressin receptor 3 staining intensity. In an study, the expression of both vasopressin receptor 2 and 3 on AtT-20 cells was confirmed. The vasopressin receptor 2 antagonist Tolvaptan inhibited desmopressin-induced ACTH secretion in a dose-dependent manner.
CONCLUSIONS
Both vasopressin receptor 2 and 3 are expressed in ACTH-secreting tumors. Vasopressin receptor 2 rather than vasopressin receptor 3 is the primary receptor that seems to mediate the ACTH response in corticotrophin tumors. A vasopressin receptor 2 antagonist can inhibit ACTH secretion induced by desmopressin in AtT-20 cells.
Topics: ACTH Syndrome, Ectopic; Adolescent; Adrenocorticotropic Hormone; Adult; Antidiuretic Hormone Receptor Antagonists; Cell Line, Tumor; Deamino Arginine Vasopressin; Female; Humans; Male; Middle Aged; Pituitary ACTH Hypersecretion; Receptors, Vasopressin; Retrospective Studies; Tumor Cells, Cultured; Young Adult
PubMed: 30669168
DOI: 10.1055/a-0808-4227 -
European Journal of Pharmacology Aug 2020The vasopressin V receptor belongs to the superfamily of G protein-coupled receptors (GPCRs) and is a potential drug target for water balance disorders such as...
The vasopressin V receptor belongs to the superfamily of G protein-coupled receptors (GPCRs) and is a potential drug target for water balance disorders such as polycystic kidney disease. Traditionally, the discovery of novel agents for the vasopressin V receptor has been guided by evaluating their receptor affinity, largely ignoring the binding kinetics. However, the latter is receiving increasing attention in the drug research community and has been proved to be a more complete descriptor of the dynamic process of ligand-receptor interaction. Herein we aim to revisit the molecular basis of ligand-vasopressin V receptor interaction from the less-investigated kinetic perspective. A homogenous time-resolved fluorescence resonance energy transfer (TR-FRET) assay was set up and optimized, which enabled accurate kinetic profiling of unlabeled vasopressin V receptor ligands. Receptor occupancy profiles of two representative antagonists with distinct target residence time were simulated. Their functional effects were further explored in cAMP assays. Our results showed that the antagonist with longer receptor residence time (lixivaptan) displayed sustained target occupancy than the antagonist with shorter receptor residence time (mozavaptan). In accordance, lixivaptan displayed insurmountable antagonism and wash-resistant inhibitory effect on the cellular cAMP level, while not so for mozavaptan. Together, our data provide evidence that binding kinetics, next to their affinity, offers additional information for the dynamic process of ligand-receptor interaction. Hopefully, this study may lead to more kinetics-directed medicinal chemistry efforts and aid the design and discovery of different-in-class of vasopressin V receptor ligands for clinical applications.
Topics: Animals; Antidiuretic Hormone Receptor Antagonists; CHO Cells; Cricetulus; Cyclic AMP; HEK293 Cells; Humans; Kinetics; Ligands; Protein Binding; Receptors, Vasopressin
PubMed: 32360346
DOI: 10.1016/j.ejphar.2020.173157 -
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