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Handbook of Experimental Pharmacology 2018Pharmacological chaperones recently opened new possibilities in G protein-coupled receptor drug discovery. Even more interestingly, some unique ligands combine... (Review)
Review
Pharmacological chaperones recently opened new possibilities in G protein-coupled receptor drug discovery. Even more interestingly, some unique ligands combine pharmacological chaperoning and biased agonism properties, boosting their therapeutic interest in many human diseases resulting from G protein-coupled receptor mutation and misfolding. These compounds displaying dual characteristics would constitute a perfect treatment for congenital Nephrogenic Diabetes Insipidus, a typical conformational disease. This X-linked genetic pathology is mostly associated with 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 many V2 receptor mutants. In addition, different classes of specific ligands such as antagonists, agonists as well as biased agonists of the V2 receptor have proven their usefulness in rescuing mutant receptor function. This is particularly relevant for small-molecule biased agonists which only trigger Gs protein activation and cyclic adenosine monophosphate production, the V2-induced signaling pathway responsible for water reabsorption. In parallel, high-throughput screening assays based on receptor trafficking rescue approaches have been developed to discover novel V2 pharmacological chaperone molecules from different chemical libraries. These new hit compounds, which still need to be pharmacologically characterized and functionally tested in vivo, represent promising candidates for the treatment of congenital Nephrogenic Diabetes Insipidus.
Topics: Diabetes Insipidus, Nephrogenic; Drug Discovery; Humans; Ligands; Molecular Chaperones; Mutation; Proteostasis Deficiencies; Receptors, G-Protein-Coupled; Receptors, Vasopressin
PubMed: 28939971
DOI: 10.1007/164_2017_50 -
JCI Insight Jan 2021Subjects with obesity frequently have elevated serum vasopressin levels, noted by measuring the stable analog, copeptin. Vasopressin acts primarily to reabsorb water via...
Subjects with obesity frequently have elevated serum vasopressin levels, noted by measuring the stable analog, copeptin. Vasopressin acts primarily to reabsorb water via urinary concentration. However, fat is also a source of metabolic water, raising the possibility that vasopressin might have a role in fat accumulation. Fructose has also been reported to stimulate vasopressin. Here, we tested the hypothesis that fructose-induced metabolic syndrome is mediated by vasopressin. Orally administered fructose, glucose, or high-fructose corn syrup increased vasopressin (copeptin) concentrations and was mediated by fructokinase, an enzyme specific for fructose metabolism. Suppressing vasopressin with hydration both prevented and ameliorated fructose-induced metabolic syndrome. The vasopressin effects were mediated by the vasopressin 1b receptor (V1bR), as V1bR-KO mice were completely protected, whereas V1a-KO mice paradoxically showed worse metabolic syndrome. The mechanism is likely mediated in part by de novo expression of V1bR in the liver that amplifies fructokinase expression in response to fructose. Thus, our studies document a role for vasopressin in water conservation via the accumulation of fat as a source of metabolic water. Clinically, they also suggest that increased water intake may be a beneficial way to both prevent or treat metabolic syndrome.
Topics: Animals; Disease Models, Animal; Drinking; Fructokinases; Fructose; Hep G2 Cells; Humans; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Vasopressin; Vasopressins
PubMed: 33320834
DOI: 10.1172/jci.insight.140848 -
Hormones and Behavior Sep 2022Early-life social experience can strongly affect adult behavior, yet the behavioral mechanisms underlying developmental trajectories are poorly understood. Here, we use...
Early-life social experience can strongly affect adult behavior, yet the behavioral mechanisms underlying developmental trajectories are poorly understood. Here, we use the highly social cichlid, Burton's Mouthbrooder (Astatotilapia burtoni) to investigate juvenile social status and behavior, as well as the underlying neuroendocrine mechanisms. We placed juveniles in pairs or triads and found that they readily establish social status hierarchies, with some group structural variation depending on group size, as well as the relative body size of the group members. Next, we used intracerebroventricular injections to test the hypothesis that arginine vasopressin (AVP) regulates juvenile social behavior and status, similar to adult A. burtoni. While we found no direct behavioral effects of experimentally increasing (via vasotocin) or decreasing (via antagonist Manning Compound) AVP signaling, social interactions directed at the treated individual were significantly altered. This group-level effect of central AVP manipulation was also reflected in a significant shift in whole brain expression of genes involved in nonapeptide signaling (AVP, oxytocin, and oxytocin receptor) and the neuroendocrine stress axis (corticotropin-releasing factor (CRF), glucocorticoid receptors (GR) 1a and 1b). Further, social status was associated with the expression of genes involved in glucocorticoid signaling (GR1a, GR1b, GR2, mineralocorticoid receptor), social interactions with the dominant fish, and nonapeptide signaling activity (AVP, AVP receptor V1aR2, OTR). Together, our results considerably expand our understanding of the context-specific emergence of social dominance hierarchies in juveniles and demonstrate a role for nonapeptide and stress axis signaling in the regulation of social status and social group dynamics.
Topics: Animals; Arginine Vasopressin; Cichlids; Corticotropin-Releasing Hormone; Glucocorticoids; Oxytocin; Receptors, Glucocorticoid; Receptors, Mineralocorticoid; Receptors, Oxytocin; Receptors, Vasopressin; Social Dominance; Vasopressins; Vasotocin
PubMed: 35932752
DOI: 10.1016/j.yhbeh.2022.105238 -
Peptides Jun 2022The Avpr1a (V1a) and Avpr1b (V1b) receptor selective, vasopressin (AVP) analogue, Ac3IV has been shown to improve metabolism and pancreatic islet structure in diabetes...
The Avpr1a (V1a) and Avpr1b (V1b) receptor selective, vasopressin (AVP) analogue, Ac3IV has been shown to improve metabolism and pancreatic islet structure in diabetes and insulin resistance. The present study further investigates these actions by assessing the ability of Ac3IV to protect against pancreatic islet architectural disturbances induced by hydrocortisone (HC) treatment in transgenic Ins1;Rosa26-eYFP mice, that possess beta-cell lineage tracing capabilities. HC intervention increased (p < 0.001) energy intake but reduced (p < 0.01) body weight gain, with no impact of Ac3IV. All HC mice had reduced (p < 0.05) circulating glucose, but plasma insulin and glucagon concentrations remained unchanged. However, HC mice presented with increased (p < 0.001) pancreatic insulin content, which was further augmented by Ac3IV. In addition, Ac3IV treatment countered HC-induced increases in islet-, beta- and alpha-cell areas (p < 0.01), as well as promoting islet number towards control levels. This was accompanied by reduced (p < 0.05) beta-cell growth, but enhanced (p < 0.001) alpha-cell proliferation. There were no changes in islet cell apoptotic rates in any of the groups of HC mice, but co-expression of CK19 with insulin in pancreatic ductal cells was reduced by Ac3IV. Assessment of beta-cell lineage revealed that Ac3IV partially protected against HC-mediated de-differentiation of mature beta-cells, whilst also decreasing (p < 0.01) beta- to alpha-cell transdifferentiation. Our data indicate that sustained activation of V1a and V1b receptors exerts positive islet cell transition effects to help retain beta-cell identity in HC mice.
Topics: Animals; Cell Lineage; Diabetes Mellitus, Experimental; Hydrocortisone; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Mice; Receptors, Vasopressin; Vasopressins
PubMed: 35202749
DOI: 10.1016/j.peptides.2022.170772 -
The American Journal of the Medical... Feb 2019Myocardial fibrosis is a major pathophysiologic substrate of heart failure with preserved ejection fraction. Vasopressin is an important therapeutic target in heart...
BACKGROUND
Myocardial fibrosis is a major pathophysiologic substrate of heart failure with preserved ejection fraction. Vasopressin is an important therapeutic target in heart failure with preserved ejection fraction since it can modulate fluid balance, and based on a few studies, myocardial matrix deposition. Hence we examined the role of vasopressin antagonism in modulating myocardial matrix metabolism in vivo and in vitro.
MATERIALS AND METHODS
In vivo studies utilized an established model of hyperhomocysteinemia-induced myocardial fibrosis in Sprague-Dawley rats combined with high salt diet; in vivo studies also utilized the same profibrotic stimuli of homocysteine and NaCl in cultured rat cardiac fibroblasts.
RESULTS
Hyperhomocysteinemia combined with high-salt diet promoted myocardial fibrosis, profibrotic and matrix gene expression and tolvaptan attenuated all these in vivo effects. In cultured cardiac fibroblasts, combined treatment with homocysteine and NaCl increased profibrotic and matrix gene expression and activation of PI3/Akt pathway; all these effects were attenuated by tolvaptan Vasopressin levels, gene expression and V2 receptor expression were increased in vivo and in vitro on exposure to profibrotic stimuli, and tolvaptan attenuated these in vivo and in vitro effects.
CONCLUSIONS
Antagonism of vasopressin V2 receptor, via direct actions on cardiac fibroblast, attenuates myocardial matrix deposition.
Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Cardiomyopathies; Diet; Fibrosis; Heart Failure; Male; Rats; Rats, Sprague-Dawley; Receptors, Vasopressin; Sodium Chloride; Tolvaptan
PubMed: 30665496
DOI: 10.1016/j.amjms.2018.11.010 -
Vitamins and Hormones 2020Since its discovery, arginine vasopressin (AVP) was subjected to several modifications with the aim of obtaining novel derivatives with increased potency and selectivity... (Review)
Review
Since its discovery, arginine vasopressin (AVP) was subjected to several modifications with the aim of obtaining novel derivatives with increased potency and selectivity for biomedical use. Desmopressin (dDAVP) is a first generation synthetic analog of AVP with hemostatic and antimetastatic activity. dDAVP acts as a selective agonist of the arginine vasopressin type 2 receptor (AVPR2) present in microvascular endothelium and cancer cells. Considering its selective effects on AVPR2-expressing malignant and vascular tissue, and interesting antitumor profile, dDAVP was used as a lead compound for the development of novel peptide analogs with enhanced anticancer efficacy. After conducting different structure-activity relationship studies to determine key aminoacidic positions for its antitumor activity against AVPR2-expressing malignant cells, dDAVP was rationally modified and a wide panel of synthetic analogs with different sequence and structural modifications was assessed. As a result of this structure-based drug derivatization novel AVP analog [VQ]dDAVP (1-deamino-4-valine-5-glutamine-8-d-arginine vasopressin) was selected as the most active candidate and further developed. [VQ]dDAVP was evaluated in highly aggressive and metastatic cancer preclinical models deploying enhanced cytostatic, antimetastatic and angiostatic effects in comparison to parental peptide dDAVP. In addition, novel compound demonstrated good tolerability as evaluated in several toxicological studies, and cooperative therapeutic effects after combination with standard-of-care chemotherapy. In summary, due to its ability to inhibit growth and tumor-associated angiogenesis, as well as impairing progression of metastatic disease, AVP analogs such as novel [VQ]dDAVP are promising compounds for further development as coadjuvant agents for the management of advance or recurrent cancers.
Topics: Animals; Antineoplastic Agents; Deamino Arginine Vasopressin; Disease Models, Animal; Mice; Neoplasms; Receptors, Vasopressin
PubMed: 32138951
DOI: 10.1016/bs.vh.2019.08.010 -
Physiology & Behavior Oct 2022Empathy, consisting of cognitive empathy and affective empathy, is essential for creating relationships with others. Since the genetic polymorphism of oxytocin receptor...
BACKGROUND
Empathy, consisting of cognitive empathy and affective empathy, is essential for creating relationships with others. Since the genetic polymorphism of oxytocin receptor (OXTR) and arginine-vasopressin V1B receptor (AVPR1B) relate to prosocial behavior and empathy, it would need to innovate strategies for treating human empathy by considering individual genetic variations. Physical activity is expected as a possible strategy; here, we investigated the influences of genetic polymorphisms in OXTR SNP rs53576 and AVPR1B SNP rs28373064, on the relationships of self-reported empathy with physical activity.
METHODS
The saliva is collected from a hundred Japanese college students for determining the individual polymorphism of OXTR SNP rs53576 (AA, AG, or GG genotype) and AVPR1B SNP rs28373064 (TT, TC, or CC genotype). In addition, the participants' self-reported cognitive and affective empathy, amounts of physical activity, and sitting time were evaluated with questionaries.
RESULTS
The participants with OXTR SNP rs53576 GG genotype showed a significant negative correlation between sitting time and cognitive empathy adjusted by age, gender, and sports experience. Further, there was a trend to correlate between physical activity amounts and cognitive empathy in the participants carrying the G variant in OXTR SNP rs53576 (AG or GG). As for AVPR1B SNP rs28373064, the persons with TT genotype exhibited a negative correlation trend between sitting time and cognitive empathy.
CONCLUSIONS
There are possible correlations between the self-reported cognitive empathy and physical activity amounts in the persons carrying the G variant of OXTR rs53576 or with the TT genotype for AVPR1B SNP rs28373064.
Topics: Empathy; Exercise; Genotype; Humans; Japan; Oxytocin; Receptors, Oxytocin; Receptors, Vasopressin; Young Adult
PubMed: 35905808
DOI: 10.1016/j.physbeh.2022.113930 -
Vitamins and Hormones 2020The regulation of stress in birds includes a complex interaction of neural systems affecting the hypothalamic-pituitary-adrenal (HPA) axis. In addition to the... (Review)
Review
The regulation of stress in birds includes a complex interaction of neural systems affecting the hypothalamic-pituitary-adrenal (HPA) axis. In addition to the hypothalamic paraventricular nucleus, a structure called the nucleus of the hippocampal commissure likewise affects the output of pituitary stress hormones and appears to be unique to avian species. Within the anterior pituitary, the avian V1a and V1b receptors were found in corticotropes. Based on our studies with central administration of hormones in the chicken, corticotropic releasing hormone (CRH) is a more potent ACTH secretagogue than arginine vasotocin (AVT). In contrast, when applied peripherally, AVT is more efficacious. Co-administration of AVT and CRH peripherally, resulted in a synergistic stimulation of corticosterone release. Data suggest receptor oligomerization as one possible mechanism. In birds, vasotocin receptors associated with stress responses include the V1a and V1b receptors. Three-dimensional, homology-based structural models of the avian V1aR were built to test agonists and antagonists for each receptor that were screened by molecular docking to map their binding sites on each receptor. Additionally, binding affinity values for each available peptide antagonist to the V1aR and V1bR were determined. An anterior pituitary primary culture system was developed to determine how effective each antagonist blocked the function of each receptor in culture when stimulated by a combination of AVT/CRH administration. Use of an antagonist in subsequent in vivo studies identified the V1aR in regulating food intake in birds. The V1aR was likewise found in circumventricular organs of the brain, suggesting a possible function in stress.
Topics: Animals; Birds; Chickens; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Receptors, Vasopressin; Stress, Physiological; Vasotocin
PubMed: 32138948
DOI: 10.1016/bs.vh.2019.10.004 -
Open Biology Jan 2018Recent observations suggest that atypical chemokine receptor (ACKR)3 and chemokine (C-X-C motif) receptor (CXCR)4 regulate human vascular smooth muscle function through...
Recent observations suggest that atypical chemokine receptor (ACKR)3 and chemokine (C-X-C motif) receptor (CXCR)4 regulate human vascular smooth muscle function through hetero-oligomerization with α-adrenoceptors. Here, we show that ACKR3 also regulates arginine vasopressin receptor (AVPR)1A. We observed that ACKR3 agonists inhibit arginine vasopressin (aVP)-induced inositol trisphosphate (IP) production in human vascular smooth muscle cells (hVSMCs) and antagonize aVP-mediated constriction of isolated arteries. Proximity ligation assays, co-immunoprecipitation and bioluminescence resonance energy transfer experiments suggested that recombinant and endogenous ACKR3 and AVPR1A interact on the cell surface. Interference with ACKR3 : AVPR1A heteromerization using siRNA and peptide analogues of transmembrane domains of ACKR3 abolished aVP-induced IP production. aVP stimulation resulted in β-arrestin 2 recruitment to AVPR1A and ACKR3. While ACKR3 activation failed to cross-recruit β-arrestin 2 to AVPR1A, the presence of ACKR3 reduced the efficacy of aVP-induced β-arrestin 2 recruitment to AVPR1A. AVPR1A and ACKR3 co-internalized upon agonist stimulation in hVSMC. These data suggest that AVPR1A : ACKR3 heteromers are constitutively expressed in hVSMC, provide insights into molecular events at the heteromeric receptor complex, and offer a mechanistic basis for interactions between the innate immune and vasoactive neurohormonal systems. Our findings suggest that ACKR3 is a regulator of vascular smooth muscle function and a possible drug target in diseases associated with impaired vascular reactivity.
Topics: Animals; Arginine Vasopressin; Cells, Cultured; HEK293 Cells; Humans; Inositol Phosphates; Male; Muscle, Smooth, Vascular; Protein Multimerization; Rats; Rats, Sprague-Dawley; Receptors, CXCR; Receptors, Vasopressin; beta-Arrestins
PubMed: 29386406
DOI: 10.1098/rsob.170207 -
Biomedicine & Pharmacotherapy =... Apr 2023Ketamine is a widely used anesthetic with N-methyl-D-aspartate (NMDA) receptor antagonism. Exposure to ketamine and NMDA receptor antagonists may induce psychosis....
Ketamine is a widely used anesthetic with N-methyl-D-aspartate (NMDA) receptor antagonism. Exposure to ketamine and NMDA receptor antagonists may induce psychosis. However, the mechanism underlying the effects of ketamine on the immature brain remains unclear. In this study, NMDA receptor antagonists, ketamine and methoxetamine, were administered to pregnant F344 rats (E17). These regimens induce psychosis-like behaviors in the offspring, such as hyperlocomotion induced by MK-801, a non-competitive NMDA receptor antagonist. We also observed that prepulse inhibition (PPI) was significantly reduced. Interestingly, ketamine administration increased the arginine vasopressin receptor 1A (Avpr1a) expression levels in the striatum of offspring with abnormal behaviors. Methoxetamine, another NMDA receptor antagonist, also showed similar results. In addition, we demonstrated a viral vector-induced Avpr1a overexpression in the striatum-inhibited PPI. In the striatum of offspring, ketamine or methoxetamine treatment increased glutamate decarboxylase 67 (GAD67) and δ-aminobutyric acid (GABA) levels. These results show that prenatal NMDA receptor antagonist treatment induces GABAergic neuronal dysfunction and abnormalities in sensorimotor gating via regulating Avpr1a expression in the striatum.
Topics: Rats; Animals; Pregnancy; Female; Ketamine; Prepulse Inhibition; Receptors, Vasopressin; Receptors, N-Methyl-D-Aspartate; Rats, Inbred F344; Dizocilpine Maleate
PubMed: 36738499
DOI: 10.1016/j.biopha.2023.114318