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Environmental risk factors contribute to autism spectrum disorders (ASD) etiology. In particular, prenatal exposure to the highly teratogenic anticonvulsant valproic acid (VPA) significantly increases ASD prevalence. Although significant discoveries on the embryopathology of VPA have been reported, its effects on the ability to form enduring social attachment—characteristic of ASD but uncommonly displayed by rats and mice—remains unknown. We aimed to examine the effects of prenatal VPA exposure in the social, monogamous prairie voles (Microtus ochrogaster). Compared to prenatal vehicle-exposed controls, prenatal VPA-exposed prairie voles had lower body weight throughout postnatal development, engaged in fewer social affiliative behaviors in a familial context, exhibited less social interactions with novel conspecifics, and showed enhanced anxiety-like behavior. Along these behavioral deficits, prenatal VPA exposure downregulated prefrontal cortex vasopressin receptor (V1aR) and methyl CpG-binding protein 2 (MeCP2) mRNA expression, but did not alter spine density in adults. Remarkably, adult social bonding behaviors, such as partner preference formation and selective aggression, were not disrupted by prenatal VPA exposure. Collectively, these studies suggest that, in this animal model, VPA alters only certain behavioral domains such as sex-naive anxiety and affiliative behaviors, but does not alter other domains such as social bonding with opposite sex individuals.

Ethnopharmacological relevance Er Shen Wan (ESW), has been empirically used for treating spleen-kidney Yang deficiency (SKYD) syndrome in Traditional Chinese medicine (TCM) for centuries and shows a variety of activities. The medicinal formula is a mixture of two component herbs, Psoraleae Fructus (PF, Bu-Gu-Zhi in Chinese) and Myristicae Semen (MS, Rou-Dou-Kou in Chinese). The current study was designed to evaluate ESWP antidiuretic treatment of polyuria and to explore potential mechanisms of renal water metabolism in the rat model of SKYD-induced diarrhea. Materials and methods An animal model of ‘SKYD–induced diarrhea syndrome’ has been established to evaluate the therapeutic effect and action mechanism according to the clinical syndrome and symptoms. The optimal dose (3.5 g/kg) of ESWP was given to rats by gavage for two weeks. Urinary volumes after 24 h were recorded. After the end of the trial, macroscopic morphological and histological examination of the kidney were conducted. Serum levels of Arginine vasopressin (AVP) and aldosterone (ALD) were also measured. Additionally, quantitative real-time RT-PCR (RT-qPCR) and immunohistochemistry (IHC) analyses were performed to clarify the regulation of aquaporin 2 (AQP 2) and arginine vasopressin type 2 receptor (AVPR 2) in the kidney at the gene and tissue expression levels respectively. Results After the administration of ESWP, urinary output volume after 24 h was found to be significantly decreased in rats. Elevated plasma levels of AVP and ALD were detected. Histological kidney damage appeared to be impeded, and histological disease scores were reduced. In addition, the expression levels of AQP 2 and AVPR 2 were significantly increased. Conclusion This study suggests that ESWP may elicit significant effects on the treatment of polyuria. Potential mechanisms at least partially involve hormone regulation, and alleviating renal pathological damage. Simultaneously, ESWP may alter renal water absorption by increasing AQP 2 and AVPR 2 expression levels. Thus, the in vivo experimental evidence indicates that ESWP has a therapeutic effect on the SKYD syndrome, which is consistent with its traditional usage.

Oxytocin reduces primary sensory afferent excitability and produces analgesia in part through a peripheral mechanism, yet its actions on physiologically characterized, mechanically sensitive afferents in normal and neuropathic conditions are unknown. We recorded intracellularly from L4 dorsal root ganglion neurons characterized as low-threshold mechanoreceptors (LTMRs) or high-threshold mechanoreceptors (HTMRs) in female rats 1 week after L5 partial spinal nerve injury or sham control (n = 24 rats/group) before, during, and after ganglionic perfusion with oxytocin, 1 nM. Nerve injury desensitized and hyperpolarized LTMRs (membrane potential [Em] was -63 ± 1.8 mV in sham vs -76 ± 1.4 mV in nerve injury; P < 0.001), and sensitized HTMRs without affecting Em. In nerve-injured rats, oxytocin depolarized LTMRs towards normal (Em = -69 ± 1.9 mV) and, in 6 of 21 neurons, resulted in spontaneous action potentials. By contrast, oxytocin hyperpolarized HTMRs (Em = -68 ± 2.7 mV before vs -80 ± 3.2 mV during oxytocin exposure; P < 0.01). These effects were reversed after removal of oxytocin, and oxytocin had minimal effects in neurons from sham surgery animals. Sensory afferent neurons immunopositive for the vasopressin 1a receptor were larger (34 ± 6.3 μm, range 16-57 μm) than immunonegative neurons (26 ± 3.4 μm, range 15-43 μm; P < 0.005). These data replicate findings that neuropathic injury desensitizes LTMRs while sensitizing HTMRs and show rapid and divergent oxytocin effects on these afferent subtypes towards normal, potentially rebalancing input to the central nervous system. Vasopressin 1a receptors are present on medium to large diameter afferent neurons and could represent oxytocin's target.

Background: Vasopressin V2 receptor inhibition is a clinically validated mechanism of action in the treatment of autosomal dominant polycystic kidney disease (ADPKD). In this study, the effect of lixivaptan, a potent, selective vasopressin V2 antagonist, was evaluated in PCK rats, a validated animal model of PKD. Methods: Four-week old PCK rats were fed rodent chow with 0.5% lixivaptan (low dose) or 1% lixivaptan (high dose), or chow only (control) for 8 weeks. Urine output was measured at weeks 7 and 10 of age. Animals were killed at 12 weeks of age; kidneys and livers were collected, weighted, and analyzed for cyclic adenosine 3′,5′-monophosphate (cAMP) levels and cystic burden and fibrosis; serum creatinine and sodium were measured. Results: Consistent with the development of a polycystic kidney phenotype, control PCK rats showed enlarged kidneys, extensive cyst formation, and early signs of serum creatinine elevation at 12 weeks of age. Compared to controls, PCK rats treated with low-dose lixivaptan showed a 26% reduction in % kidney weight/body weight (p < 0.01); a 54% reduction in kidney cystic score (p < 0.001), a histomorphometric measure of cystic burden; a 23% reduction in kidney cAMP levels (p < 0.05), a biochemical marker of disease; and a 13% reduction in plasma creatinine (p < 0.001), indicating preserved renal function. These reductions were associated with 3-fold increases in 24-h urine output, demonstrating the potent aquaretic effect of lixivaptan. The fact that the high dose was less efficacious than the low dose is discussed. Conclusions: These results provide the first evidence of the potential utility of lixivaptan for the treatment of ADPKD.

Activation of G protein-coupled receptors by agonists may result in the activation of one or more G proteins and recruitment of arrestins. The extent of the activation of each of these pathways depends on the intrinsic efficacy of the ligand. Quantification of intrinsic efficacy relative to a reference compound is essential for the development of novel compounds. In the operational model, changes in efficacy can be compensated by changes in the "functional" affinity, resulting in poorly defined values. To separate the effects of ligand affinity from the intrinsic activity of the receptor, we developed a Michaelis-Menten based quantification of G protein activation bias that uses experimentally measured ligand affinities and provides a single measure of ligand efficacy. We used it to evaluate the signaling of a promiscuous model receptor, the Vasopressin V2 receptor (V2R). Using BRET-based biosensors, we show that the V2R engages many different G proteins across all G protein subfamilies in response to its primary endogenous agonist, arginine vasopressin, including Gs and members of the Gi/o and G12/13 families. These signaling pathways are also activated by the synthetic peptide desmopressin, oxytocin, and the nonmammalian hormone vasotocin. We compared bias quantification using the operational model with Michaelis-Menten based quantification; the latter accurately quantified ligand efficacies despite large difference in ligand affinities. Together, these results showed that the V2R is promiscuous in its ability to engage several G proteins and that its' signaling profile is biased by small structural changes in the ligand. SIGNIFICANCE STATEMENT: By modelling the G protein activation as Michaelis-Menten reaction, we developed a novel way of quantifying signalling bias. V2R activates, or at least engages, G proteins from all G protein subfamilies, including Gi2, Gz, Gq, G12, and G13. Their relative activation may explain its Gs-independent signalling.

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

Hyponatremia is the most frequent electrolyte disorder in hospitalised patients. Acute and severe hyponatremia may be a life-threatening situation. However, also mild and chronic hyponatremia may negatively affect the health status (i.e. gait disturbances, attention deficits, falls and fractures, and bone loss) and may increase the risk of death. Therefore, it is of paramount importance for clinicians to have an in-depth knowledge on this topic, in order to appropriately manage patients affected by hyponatremia.This review will cover different areas related to this electrolyte disorder. Because many pathologic conditions may be associated with hyponatremia, thorough investigations have to be performed in order to establish the underlying etiology. To establish the cause of hyponatremia is of great importance, because an appropriate therapeutic strategy is strictly dependent on a correct diagnosis. A description of the different available therapeutic approaches for the correction of hyponatremia, including vaptans, will follow.Undoubtedly, the studies that have been published in recent years and the introduction of vaptans in clinical practice have contributed to increase the awareness on hyponatremia among clinicians. Nevertheless, additional studies are needed in order to clarify some partially uncovered areas.

Cardioplegic arrest (CP) and cardiopulmonary bypass (CPB) are associated with vasomotor dysfunction of coronary arterioles in patients with diabetes (DM) undergoing cardiac surgery. We hypothesized that DM may up-regulate vasopressin receptor expression and alter the contractile response of coronary arterioles to vasopressin in the setting of CP/CPB.Right atrial tissue samples of patients with DM and without (ND) (n = 8 in each group) undergoing cardiac surgery were harvested before and after CP/CPB. The isolated coronary arterioles (80-150 μm) dissected from the harvested right atrial tissue samples were cannulated and pressurized (40 mm Hg) in a no-flow state. The changes in diameter were measured with video microscopy. The protein expression/localization of vasopressin 1A receptors (V1A) and vasopressin 1B receptors (V1B) in the atrial tissue were measured by immune-blotting and immunohistochemistry.The pre-CP/CPB contractile responses of the coronary arterioles to vasopressin were significantly increased post-CP/CPB in both the ND and DM groups. This effect was more pronounced in the vessels from patients in the DM group than that of vessels from patients in the ND group (P .05). Vasopressin-induced contractile response of the coronary arterioles was inhibited in the presence of the specific V1A antagonist SR 49059 (10CP/CPB and DM are both associated with up-regulation in V1 receptor expression/localization in human myocardium. Vasopressin may induce coronary arteriolar constriction via V1A. This alteration may lead to increased coronary arteriolar spasm in patients with DM undergoing CP/CPB and cardiac surgery.

Targeting the collecting duct water channel aquaporin 2 (AQP2) to the plasma membrane is essential for the maintenance of mammalian water homeostasis. The vasopressin V2 receptor (V2R), which is a G

Oxytocin (OT) and vasopressin (AVP) are endogenous ligands for OT and AVP receptors in the brain and in the peripheral system. Several studies demonstrate that OT and AVP have opposite roles in modulating stress, anxiety and social behaviours. Interestingly, both peptides and their receptors exhibit high sequence homology which could account for the biased signalling interaction of the peptides with OT and AVP receptors. However, how and under which conditions this crosstalk occurs in vivo remains unclear. In this review we shed light on the complexity of the roles of OT and AVP, by focusing on their signalling and behavioural differences and exploring the crosstalk between the receptor systems. Moreover, we discuss the potential of OT and AVP receptors as therapeutic targets to treat human disorders, such as autism, schizophrenia and drug abuse. LINKED ARTICLES: This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.8/issuetoc.

Previous studies found associations between autism-related phenotypes and both rearing and V1A arginine vasopressin receptor (AVPR1A) genotypes. We tested whether these exposures as well as their interaction were associated with autism-related phenotypes in 121 laboratory-housed chimpanzees. We used expert-derived weights to obtain autism scores from ratings on the 43-item Chimpanzee Personality Questionnaire; higher scores indicated more autistic-like traits. The first model included fixed effects for sex, age, and rearing, and a random effect that addressed the relatedness of subjects. The second model was the same except that it also included the rearing × AVPR1A genotype interaction as a fixed effect. Both models indicated that the phenotype was moderately heritable and that chimpanzees reared by their mothers had lower scores on the scale. The effect of genotype in both models indicated that chimpanzees with an indel deletion had higher scores on the scale, although the credible interval included zero. Moreover, the rearing × genotype interaction in the second model indicated that chimpanzees who possessed the non-deletion genotype and who were reared by their mother were at even greater risk. The credible interval for this effect did not include zero, but fit statistics indicated that the model without the interaction was marginally better, and the interaction was in the opposite direction than we expected based on previous work. These findings highlight the importance of rearing effects in the typical social development of our closet-living nonhuman relative. LAY SUMMARY: We tested whether, in chimpanzees, scores on a scale comprising traits that resembled aspects of autism were related to a gene associated with autism in prior research and/or early rearing. Human-reared chimpanzees had higher scores (indicating more autistic-like traits). Chimpanzees that possessed the gene also had higher scores, but we could not exclude the possibility that there was no effect of genotype. These findings suggest that we can measure autism-like characteristics in chimpanzees, and so study it in this species.

X-linked nephrogenic diabetes insipidus (X-linked NDI) is a rare inherited disease mainly caused by lost-of-function mutations in human AVPR2 gene encoding arginine vasopressin receptor 2 (V2R). Our focus of the current study is on exploration of the functional and biochemical properties of Ile324Met (I324M) mutation identified in a pedigree showing as typical recessive X-linked NDI. We demonstrated that I324M mutation interfered with the conformation of complex glycosylation of V2R. Moreover, almost all of the I324M-V2R failed to express on the cell surface due to being captured by the endoplasmic reticulum control system. We further examined the signaling activity of DDAVP-medicated cAMP and ERK1/2 pathways and the results revealed that the mutant receptor lost the ability in response to DDAVP stimulation contributed to the failure of accumulation of cAMP and phosphorylated ERK1/2. Based on the characteristics of molecular defects of I324M mutant, we selected two reagents (SR49059 and alvespimycin) to determine whether the functions of I324M-V2R can be restored and we found that both compounds can significantly “rescue” I324M mutation. Our findings may provide further insights for understanding the pathogenic mechanism of AVPR2 gene mutations and may offer some implications on development of promising treatments for patients with X-linked NDI.

Arginine vasopressin (AVP) and oxytocin (OXY) are released by magnocellular neurosecretory cells that project to the posterior pituitary. While AVP and OXY currently receive more attention for their contributions to affiliative behavior, this mini-review discusses their roles in cardiovascular function broadly defined to include indirect effects that influence cardiovascular function. The traditional view is that neither AVP nor OXY contributes to basal cardiovascular function, although some recent studies suggest that this position might be re-evaluated. More evidence indicates that adaptations and neuroplasticity of AVP and OXY neurons contribute to cardiovascular pathophysiology.

Oxytocin (OT) is a crucial regulator of reproductive behaviors, including parturition in mammals. Arg-vasopressin (AVP) is a nonapeptide homologous to Arg-vasotocin (AVT) in teleosts that has comparable affinity for the OT receptor. In the present study, ovoviviparous guppies (Poecilia reticulata) were used to study the effect of AVT on delivery mediated by the activation of prostaglandin (PG) biosynthesis via isotocin (IT) receptors (ITRs). One copy each of it and avt and two copies of itrs were identified in guppies. The results of the affinity assay showed that various concentrations of AVT and IT (10−6, 10−7, and 10−8 mol/L) significantly activated itr1 (P < 0.05). In vitro experiments revealed significant upregulation (P < 0.05) of cyclooxygenase 2 (cox2), which is the rate-limiting enzyme involved in PG biosynthesis, and itr1 by AVT and IT. Furthermore, dual in situ hybridization detected positive signals for itr1 and cox2 at the same site, implying that ITR1 may regulate cox2 gene expression. Measurement of prostaglandin F2a (PGF2a) concentrations showed that AVT induced PGF2a synthesis (P < 0.05) and that the effect of IT was not significant. Finally, intraperitoneal administration of PGF2a significantly induced premature parturition of guppies. This study is the first to identify and characterize AVT and ITRs in guppies. The findings suggest that AVT promotes PG biosynthesis via ITR and that PGF2a induces delivery behavior in ovoviviparous guppies.

Nephrogenic diabetes insipidus (NDI) patients produce large amounts of dilute urine. NDI can be congenital, resulting from mutations in the type-2 vasopressin receptor (V2R), or acquired, resulting from medications such as lithium. There are no effective treatment options for NDI. Activation of PKA is disrupted in both congenital and acquired NDI, resulting in decreased aquaporin-2 phosphorylation and water reabsorption. We show that adenosine monophosphate-activated protein kinase (AMPK) also phosphorylates aquaporin-2. We identified an activator of AMPK, NDI-5033, and we tested its ability to increase urine concentration in animal models of NDI. NDI-5033 increased AMPK phosphorylation by 2.5-fold, confirming activation. It increased urine osmolality in tolvaptan-treated NDI rats by 30%-50% and in V2R-KO mice by 50%. Metformin, another AMPK activator, can cause hypoglycemia, which makes it a risky option for treating NDI patients, especially children. Rats with NDI receiving NDI-5033 showed no hypoglycemia in a calorie-restricted, exercise protocol. Congenital NDI therapy needs to be effective long-term. We administered NDI-5033 for 3 weeks and saw no reduction in efficacy. We conclude that NDI-5033 can improve urine concentration in animals with NDI and holds promise as a potential therapy for patients with congenital NDI due to V2R mutations.

Arrestins recognize different receptor phosphorylation patterns and convert this information to selective arrestin functions to expand the functional diversity of the G protein-coupled receptor (GPCR) superfamilies. However, the principles governing arrestin-phospho-receptor interactions, as well as the contribution of each single phospho-interaction to selective arrestin structural and functional states, are undefined. Here, we determined the crystal structures of arrestin2 in complex with four different phosphopeptides derived from the vasopressin receptor-2 (V2R) C-tail. A comparison of these four crystal structures with previously solved Arrestin2 structures demonstrated that a single phospho-interaction change results in measurable conformational changes at remote sites in the complex. This conformational bias introduced by specific phosphorylation patterns was further inspected by FRET and 1H NMR spectrum analysis facilitated via genetic code expansion. Moreover, an interdependent phospho-binding mechanism of phospho-receptor-arrestin interactions between different phospho-interaction sites was unexpectedly revealed. Taken together, our results provide evidence showing that phospho-interaction changes at different arrestin sites can elicit changes in affinity and structural states at remote sites, which correlate with selective arrestin functions., The interaction between a GPCR, such as the vasopressin receptor-2 (V2R), and arrestin depends on the receptors’ phosphorylation pattern. Here authors use FRET and NMR to analyze the phosphorylation patterns of the V2R-arrestin complex and show that phospho-interactions are the key determinants of selective arrestin conformational states and correlated functions.

Arginine vasopressin is a hormone that is synthesized mainly in the hypothalamus and stored in the posterior pituitary. Receptors for vasopressin are categorized into at least 3 subtypes (V

During the emission phase of ejaculation, the sperm is driven from the cauda epididymidis, where it is stored, through the vas deferens by strong contractions. These contractions are thought of as being mainly induced by the sympathetic nervous system and the neurotransmitter noradrenaline. In the present study, we investigated the effect of oxytocin (suggested to exert effects during ejaculation as well) on defined segments of the rat and human epididymis using live imaging. Our results indicate that it is the very last part of the epididymis, segment 19 (S19) in rat and likewise segment 9 in human, which responds in a uniquely strong and rapid manner to oxytocin (similar to noradrenaline). Because of the complex nature of this contractile response, we developed an imaging analysis method, which allowed us to quantify multidirectional contractions and to display them using heat maps. The reaction of S19 to oxytocin was concentration-dependent and could be inhibited by pretreatment with oxytocin antagonists (atosiban and cligosiban), but not with an arginine vasopressin 1A antagonist (SR49059). In both rat and human tissue, pretreatment with the alpha-1 adrenoreceptor antagonist tamsulosin inhibited the response to noradrenaline, whereas the effect of oxytocin was unimpaired. Our data (from men and rodents) strongly suggest that the hormone oxytocin is involved in the ejaculatory process. Thus, oxytocin-based medications might be a promising non-adrenergic treatment option for ejaculatory disorders. Additionally, we propose that S19 could be an advantageous model (detecting very low concentrations of oxytocin) to test the bioactivity of new oxytocin agonists and oxytocin antagonists.

The authors recently reported the presence and distribution of oxytocin/vasopressin-like peptide in Portunus pelagicus as well as demonstrated its function to inhibit ovarian steroid release (Saetan et al., 2018). Here, the full-length receptor of this peptide, namely oxytocin/vasopressin-like peptide receptor (PpelOT/VP-like peptide receptor) is reported. The coding region of the PpelOT/VP-like peptide receptor contained 1497 bp which translationally corresponded to 499 amino acids. Sequence analysis revealed its seven transmembrane characteristics, with -two N-linked glycosylation residues located before the first transmembrane domain (TM I). The phylogenetic tree revealed that the PpelOT/VP-like peptide receptor was placed in the group of invertebrate OT/VP-like receptors, and was clearly distinguishable from the V1R, V2R and OTR of vertebrates. Also, this receptor gene transcript was detected in several organs of the blue swimming crab with highest abundance found in brain tissue. In situ hybridization exhibited its distribution in all neuronal clusters of the eyestalk, brain, ventral nerve cord (VNC), as well as in the ovary. Comparative gene expressions between this receptor and its corresponding peptide in immature and mature female crabs revealed no significant difference of the PpelOT/VP-like peptide receptor gene expression in the central nervous system (CNS) and ovary. In contrast, the PpelOT/VP-like peptide gene was shown to significantly express higher in the VNC of immature crabs and in the ovary of mature crabs. Changes in expression of this peptide gene, but not its receptor, might result in ovarian steroid release inhibition. However, the detailed mechanism of this peptide in reproduction regulation will be included in our further studies.

Background Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare inherited disorder characterised by hyponatraemia. To date, most reported cases are Caucasians with gain-of-function variants in AVPR2, an X-linked gene which encodes the vasopressin V2 receptor (V2R). Recently, germline gain-of-function variants in the stimulatory G protein α-subunit (Gsα) were reported to cause dominantly inherited NSIAD. Case report We report the first Chinese adult diagnosed with NSIAD. He was found to be hemizygous for R137C-V2R, the most prevalent pathogenic variant among Caucasians. After the genetic diagnosis and counselling on the importance of fluid restriction, he had no recurrence of hyponatraemia to date. Literature review Case reports of NSIAD published in the English literature in PubMed were reviewed to summarise the genetic and phenotypic heterogeneity of this disorder. Conclusion NSIAD is ethnically, genetically and phenotypically diverse. The diagnosis should especially be considered in young patients with otherwise unexplained hyponatraemia. Target analysis of R137C-V2R should make the diagnosis in most cases. Genetic testing could confirm the diagnosis, motivate adherence to treatment, offer the possibility of genotype-guided therapy, and allow cascade screening to prevent hyponatraemia.

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD. Supplementary Information The online version contains supplementary material available at 10.1186/s13041-021-00769-8.

Contemporary theory that emphasizes the roles of oxytocin and vasopressin in mammalian sociality has been shaped by seminal vole research that revealed interspecific variation in neuroendocrine circuitry by mating system. However, substantial challenges exist in interpreting and translating these rodent findings to other mammalian groups, including humans, making research on nonhuman primates crucial. Both monogamous and non-monogamous species exist within Eulemur, a genus of strepsirrhine primate, offering a rare opportunity to broaden a comparative perspective on oxytocin and vasopressin neurocircuitry with increased evolutionary relevance to humans. We performed oxytocin and arginine vasopressin 1a receptor autoradiography on 12 Eulemur brains from seven closely related species to (1) characterize receptor distributions across the genus, and (2) examine differences between monogamous and non-monogamous species in regions part of putative “pair-bonding circuits”. We find some binding patterns across Eulemur reminiscent of olfactory-guided rodents, but others congruent with more visually oriented anthropoids, consistent with lemurs occupying an ‘intermediary’ evolutionary niche between haplorhine primates and other mammalian groups. We find little evidence of a “pair-bonding circuit” in Eulemur akin to those proposed in previous rodent or primate research. Mapping neuropeptide receptors in these nontraditional species questions existing assumptions and informs proposed evolutionary explanations about the biological bases of monogamy.

Vertebrate genome evolution remains a hotly debated topic, specifically as regards the number and the timing of putative rounds of whole genome duplication events. In this study, I sought to shed light to this conundrum through assessing the evolutionary history of the oxytocin/vasotocin receptor family. I performed ancestral analyses of the genomic segments containing oxytocin and vasotocin receptors (OTR-VTRs) by mapping them back to the reconstructed ancestral vertebrate/chordate karyotypes reported in five independent studies (Nakatani et al., 2007; Putnam et al., 2008; Smith and Keinath, 2015; Smith et al., 2018; Simakov et al., 2020) and found that two alternative scenarios can account for their evolution: one consistent with one round of whole genome duplication in the common ancestor of lampreys and gnathostomes, followed by segmental duplications in both lineages, and another consistent with two rounds of whole genome duplication, with the first occurring in the gnathostome-lamprey ancestor and the second in the jawed vertebrate ancestor. Combining the data reported here with synteny and phylogeny data reported in our previous study (Theofanopoulou et al., 2021), I put forward that a single round of whole genome duplication scenario is more consistent with the synteny and evolution of chromosomes where OTR-VTRs are encountered, without excluding the possibility of a scenario including two rounds of whole genome duplication. Although the analysis of one gene family is not able to capture the full complexity of vertebrate genome evolution, this study can provide solid insight, since the gene family used here has been meticulously analyzed for its genes’ orthologous and paralogous relationships across species using high quality genomes.

Vasopressin type 2 receptor (V2R) belongs to the vasopressin (VP)/oxytocin (OT) receptor subfamily of G protein-coupled receptors (GPCRs), which comprises at least four closely related receptor subtypes: V1aR, V1bR, V2R, and OTR. These receptors are activated by arginine vasopressin (AVP) and OT, two endogenous nine-amino acid neurohypophysial hormones, which are thought to mediate a biologically conserved role in social behavior and sexual reproduction. V2R is mainly expressed in the renal collecting duct principal cells and mediates the antidiuretic action of AVP by accelerating water reabsorption, thereby playing a vital role in controlling water homeostasis. Moreover, numerous gain-of-function and loss-of-function mutations of V2R have been identified and are closely associated with human diseases, including nephrogenic syndrome of inappropriate diuresis (NSIAD) and X-linked congenital nephrogenic diabetes insipidus (NDI). Thus, V2R has attracted intense interest as a drug target. However, due to a lack of structural information, how AVP recognizes and activates V2R remains elusive, which hampers the V2R-targeted drug design. Here, we determined a 2.6 Å resolution cryo-EM structure of the full-length, G s -coupled human V2R bound to AVP (Fig. 1a; Supplementary information, Table S1). The G s protein was engineered based on mini-G s that was used in the crystal structure determination of the G s -coupled adenosine A 2A receptor (A 2A R) to stabilize the V2R–G s protein complex (Supplementary information, Data S1). The final structure of the AVP–V2R–G s complex contains all residues of AVP (residues 1–9), the Gα s Ras-like domain, Gβγ subunits, Nb35, scFv16, and the V2R residues from T31 to L339 8.57 (superscripts refer to Ballesteros–Weinstein numbering). The majority of amino acid side chains, including AVP, transmembrane domain (TMD), all flexible intracellular loops (ICLs) and extracellular loops (ECLs) except for ICL3 and G185–G188 in ECL2, were well resolved in the model, refined against the EM density map (Fig. 1a; Supplementary information, Figs. S1–3). The complex structure can provide detailed information on the binding interface between AVP and helix bundle of the receptor, as well as the receptor–G s interface.

Liver diseases, including cirrhosis, viral hepatitis, and hepatocellular carcinoma, account for approximately two million annual deaths worldwide. They place a huge burden on the global healthcare systems, compelling researchers to find effective treatment for liver fibrosis-cirrhosis. Portacaval anastomosis (PCA) is a model of liver damage and fibrosis. Arginine vasopressin (AVP) has been implicated as a proinflammatory-profibrotic hormone. In rats, neurointermediate pituitary lobectomy (NIL) induces a permanent drop (80%) in AVP serum levels. We hypothesized that AVP deficiency (NIL-induced) may decrease liver damage and fibrosis in a rat PCA model. Male Wistar rats were divided into intact control (IC), NIL, PCA, and PCA+NIL groups. Liver function tests, liver gene relative expressions (IL-1, IL-10, TGF-β, COLL-I, MMP-9, and MMP-13), and histopathological assessments were performed. In comparison with those in the IC and PCA groups, bilirubin, protein serum, and liver glycogen levels were restored in the PCA+NIL group. NIL in the PCA animals also decreased the gene expression levels of IL-1 and COLL-I, while increasing those of IL-10, TGF-β, and MMP-13. Histopathology of this group also showed significantly decreased signs of liver damage with lower extent of collagen deposition and fibrosis. Low AVP serum levels were not enough to fully activate the AVP receptors resulting in the decreased activation of cell signaling pathways associated with proinflammatory-profibrotic responses, while activating cell molecular signaling pathways associated with an anti-inflammatory-fibrotic state. Thus, partial reversion of liver damage and fibrosis was observed. The study supports the crucial role of AVP in the inflammatory-fibrotic processes and maintenance of immune competence. The success of the AVP deficiency strategy suggests that blocking AVP receptors may be therapeutically useful to treat inflammatory-fibrotic liver diseases.

Non-visual arrestins (β-arrestins) are endocytic proteins that mediate agonist-activated GPCRs internalization and signaling pathways in an independent manner. The involvement of β-arrestins in cancer invasion and metastasis is increasingly reported. So, it is hypothesized that inhibition of β-arrestins may diminish the survival chances of cancer cells. This study aimed to evaluate the in vitro impact of inhibiting β-arrestins on the autophagic and/or apoptotic responsiveness of breast cancer cells. We used Barbadin to selectively inhibit β-Arr/AP2 interaction in AVP-stimulated V2R receptor of triple-negative breast cancer cells (MDA MB-231). Autophagy was assessed by the microtubule-associated protein 1 light chain 3-II (LC3II), apoptosis was measured by Annexin-V/PI staining and cell cycle distribution was investigated based upon the DNA content using flow cytometry. Barbadin reduced cell viability to 69.1% and increased the autophagy marker LC3II and its autophagic effect disappeared in cells transiently starved in Earle's balanced salt solution (EBSS). Also, Barbadin mildly enhanced the expression of P62 mRNA and arrested 63.7% of cells in G0/G1 phase. In parallel, the drug-induced apoptosis in 29.9% of cells (by AV/PI) and 27.8% of cells were trapped in sub-G1 phase. The apoptotic effect of Barbadin was enhanced when autophagy was inhibited by the PI3K inhibitor (Wortmannin). Conclusively, the data demonstrate the dual autophagic and apoptotic effects of β-βArr/AP2 inhibition in triple-negative breast cancer cells. These observations nominate β-Arrs as selective targets in breast cancer treatment.

Arginine vasopressin (AVP) is a nonapeptide that serves as a neuromodulator in the brain and a hormone in the periphery that regulates water homeostasis and vasoconstriction. The subiculum is the major output region of the hippocampus and an integral component in the networks that processes sensory and motor cues to form a cognitive map encoding spatial, contextual, and emotional information. Whereas the subiculum expresses high densities of AVP-binding sites and AVP has been shown to increase the synaptic excitability of subicular pyramidal neurons, the underlying cellular and molecular mechanisms have not been determined. We found that activation of V(1a) receptors increased the excitability subicular pyramidal neurons via activation of TRPV1 channels and depression of the GIRK channels. V(1a) receptor-induced excitation of subicular pyramidal neurons required the function of phospholipase Cβ, but was independent of intracellular Ca(2+) release. Protein kinase C was responsible for AVP-mediated depression of GIRK channels, whereas degradation of phosphatidylinositol 4,5-bisphosphate was involved in V(1a) receptor-elicited activation of TRPV1 channels. Our results may provide one of the cellular and molecular mechanisms to explain the physiological functions of AVP in the brain.

During the development of analgesic tolerance to morphine, the V1b vasopressin receptor has been proposed to bind to β-arrestin 2 and the µ-opioid receptor to enable their interaction. However, direct evidence of such a high-order complex is lacking. Using bioluminescent resonance energy transfer between a split Nanoluciferase and the Venus fluorescent protein, the NanoBit-NanoBRET system, we found that β-arrestin 2 closely located near the heteromer µ-V1b receptor in the absence of an agonist and moved closer to the receptor carboxyl-termini upon agonist stimulation. An additive effect of the two agonists for opioid and vasopressin receptors was detected on the NanoBRET between the µ-V1b heteromer and β-arrestin 2. To increase the agonist response of NanoBRET, the ratio of the donor luminophore to the acceptor fluorophore was decreased to the detection limit of luminescence. In the first phase of access, β-arrestin 2 was likely to bind to the unstimulated V1b receptor in both its phosphorylated and unphosphorylated forms. In contrast, the second-phase access of β-arrestin 2 was agonist dependent, indicating a possible pharmacological intervention strategy. Therefore, our efficient method should be useful for evaluating chemicals that directly target the vasopressin binding site in the µ-V1b heteromer to reduce the second-phase access of β-arrestin 2 and thereby to alleviate tolerance to morphine analgesia.

For decades, plasma arginine vasopressin (AVP) levels have been known to be elevated in patients with congestive heart failure (HF). Excessive AVP signaling at either or both the V1a and V2 receptors could contribute to the pathophysiology of HF by several mechanisms. V1a activation could cause vasoconstriction and/or direct myocardial hypertrophy as intracellular signaling pathways are closely related to those for angiotensin II. V2 activation could cause fluid retention and hyponatremia. A hemodynamic study with the pure V2 antagonist tolvaptan (TV) showed minimal hemodynamic effects. Compared with furosemide in another study, the renal and neurohormonal effects of TV were favorable. Several clinical trials with TV as adjunctive therapy in acute HF have shown beneficial effects on fluid balance and dyspnea, with no worsening of renal function or neurohormonal stimulation. Two smaller studies, one in acute and one in chronic HF, have shown comparable clinical and more favorable renal and neurohormonal effects of TV compared with loop diuretics. However, long-term treatment with TV did not alter outcomes in acute HF. No data are available other than single-dose studies of an intravenous pure V1a antagonist, which showed a vasodilating effect if plasma AVP levels were elevated. One hemodynamic study and one short-duration clinical trial with the balanced intravenous V1a/V2 antagonist conivaptan (CV) showed hemodynamic and clinical effects largely similar to those with TV in similar studies. A new orally effective balanced V1/V2 antagonist (pecavaptan) is currently undergoing phase II study as both adjunctive and alternative therapy during and after hospitalization for acute HF. The purpose of this review is to summarize what we have learned from the clinical experience with TV and CV, and to suggest implications of these findings for future work with newer agents.

Restraint stress (RS) is an unavoidable stress model that triggers activation of the autonomic nervous system, endocrine activity, and behavioral changes in rodents. Furthermore, RS induces secretion of oxytocin into the bloodstream, indicating a possible physiological role in the stress response in this model. The presence of oxytocin receptors in vessels and heart favors this possible idea. However, the role of oxytocin secreted in RS and effects on the cardiovascular system are still unclear. The aim of this study was to analyze the influence of oxytocin on cardiovascular effects during RS sessions. Rats were subjected to pharmacological (blockade of either oxytocin, vasopressin, or muscarinic receptors) or surgical (hypophysectomy or sinoaortic denervation) approaches to study the functional role of oxytocin and its receptor during RS. Plasma levels of oxytocin and vasopressin were measured after RS. RS increased arterial pressure, heart rate, and plasma oxytocin content, but not vasopressin. Treatment with atosiban (a Gi biased agonist) inhibited restraint-evoked tachycardia without affecting blood pressure. However, this effect was no longer observed after sinoaortic denervation, homatropine (M2 muscarinic antagonist) treatment or hypophysectomy, indicating that parasympathetic activation mediated by oxytocin secreted to the periphery is responsible for blocking the increase in tachycardic responses observed in the atosiban-treated group. Corroborating this, L-368,899 (oxytocin antagonist) treatment showed an opposite effect to atosiban, increasing tachycardic responses to restraint. Thus, this provides evidence that oxytocin secreted to the periphery attenuates tachycardic responses evoked by restraint via increased parasympathetic activity, promoting cardioprotection by reducing the stress-evoked heart rate increase.

Objective Childhood onset aggression can cause major suffering to affected families and is associated with many negative outcomes in the child's later life, including poor academic performance, adolescent delinquency, drug abuse, depression and antisocial personality disorder. Currently available prevention and intervention strategies have limited efficacy, but a better understanding of underlying genetic and neurobiological factors can lead to more effective prevention and treatment strategies, through genetic screening programs and novel therapies. Method This study examined the RS1 (n = 299 aggression, n = 192 controls) and RS3 (n = 291 aggression, n = 189 controls) microsatellite repeats within the promoter region of the vasopressin receptor 1A gene (AVPR1A) and their association with extreme childhood aggression, as assessed by the Child Behavior Checklist (CBCL), as well as the Teacher Report Form (TRF) and Youth Self Report (YSR). Binary logistic regression was used to model the relationship between microsatellite length and childhood aggression. Age and sex were used as covariates. Results Logistic regression revealed a nominally significant association between one specific RS3 repeat and non-aggressive status. No association was found for any of the RS1 repeats. In a separate model, grouping repeats into short and long, carriers of long RS3 repeats were nominally significantly associated with non-aggressive status. Conclusions These findings suggest a role for AVPR1A and its RS3 microsatellite in extreme childhood aggression and could lead to a better understanding of the biological pathways of aggressive behavior. However, independent replication and further research into the functionality of studied genetic variants is required.

To detect potential variant in a male neonate affected with congenital nephrogenic diabetes insipidus (CNDI).Clinical data of the patient was collected. Genomic DNA was extracted from peripheral blood samples from the child and his parents. The whole coding regions of the arginine vasopressin V2 receptor (AVPR2) gene were amplified by PCR and subjected to Sanger sequencing.The patient presented recurrent fever and polyuria after birth. Multiple blood gas analyses indicated hypernatremia. Ultrasound showed bilateral hydronephrosis and hydroureter. The patient was partially responsive to hydrochlorothiazide. DNA analysis identified a hemizygous frameshift variant c.890-899delACCCGGAGGC in exon 2 of the AVPR2 gene in the proband. His mother was heterozygous for the same variant.The c.890-899delACCCGGAGGC variant of the AVPR2 gene probably underlies the CNDI in the child. Above discovery has enriched to spectrum of CNDI associated variants.

Depression is an independent nontraditional risk factor for cardiovascular disease and mortality. The chronic unpredictable mild stress (CMS) rat model is a validated model of depression. Within the paraventricular nucleus (PVN), vasopressin (VP) via V

Background: Patients with autosomal dominant polycystic kidney disease (ADPKD) are treated with a vasopressin V2 receptor antagonist (V2RA) to slow disease progression. This drug increases vasopressin considerably in these patients with already elevated baseline levels. Vasopressin is known to stimulate the hypothalamic-pituitary-adrenal (HPA) axis through V1 and V3 receptor activation. It is unknown whether this increase in vasopressin during V2RA treatment affects glucocorticoid production. Methods: Twenty-seven ADPKD patients were studied on and off treatment with a V2RA and compared to age- and sex-matched healthy controls and IgA nephropathy patients, the latter also matched for kidney function. Vasopressin was measured by its surrogate copeptin. Twenty-four-hour urinary excretions of cortisol, cortisone, tetrahydrocortisone, tetrahydrocortisol, allotetrahydrocortisol, and the total glucocorticoid pool were measured. Results: At baseline, ADPKD patients demonstrated a higher copeptin concentration in comparison with healthy controls, while urinary excretion of cortisol and cortisone was lower (medians of 0.23 vs. 0.34 μmol/24 h, p = 0.007, and 0.29 vs. 0.53 μmol/24 h, p < 0.001, respectively). There were no differences in cortisol and cortisone excretion compared to IgA nephropathy patients. Cortisol, cortisone, and total glucocorticoid excretions correlated with kidney function (R = 0.37, 0.58, and 0.19, respectively; all p < 0.05). Despite that V2RA treatment resulted in a 3-fold increase in copeptin, only cortisone excretion increased (median of 0.44 vs. baseline 0.29 μmol/24 h, p < 0.001), whereas no changes in cortisol or total glucocorticoid excretion were observed. Conclusions: Increased concentration of vasopressin in ADPKD patients at baseline and during V2RA treatment does not result in activation of the HPA axis. The impaired glucocorticoid production in these patients is related to their degree of kidney function impairment.

Arginine-vasopressin (AVP) is a neurohypophyseal peptide that plays a critical role in the regulation of social behavior in mammals. Neuronal AVP regulates male-specific social signaling processes, such as exocrine urinary scent deposition and marking behavior in mice. In the periphery, AVP is transported to the portal bloodstream and acts as an antidiuretic hormone. These AVP dynamics imply that the central role of AVP in the stimulation of urinary marking is dissociated with the peripheral role of AVP in the retention of osmotic conditions. Using male BALB/c mice as subjects, peripheral injection of AVP decreased urinary marking and urination. In contrast, a central infusion of AVP facilitated urinary marking with no effect on urination, while an antagonist of the AVP 1a receptor inhibited marking. Centrally AVP-injected mice also exhibited typical behaviors, such as hiccough/sneeze-like reactions and flash scratching, particularly when confronted with a stimulus mouse through a wire mesh screen. Significant expression of these typical reactions in these mice resulted in the disruption of marking deposition. Further analysis of AVP synthesis illustrated that AVP levels increased in the midbrain but not in the circulation immediately after the test, particularly when confronted with a stimulus mouse. The central AVP regulates urinary marking and other typical behaviors in a dose- and situation-dependent manner. The sequential process implies that centrally synthesized AVP may be secreted into the circulation following immediate neuronal processes, and then peripheral AVP acts as an antidiuretic hormone on urinary marking behavior.

The V2 vasopressin receptor (V2R) is a class A G protein-coupled receptor (GPCR) and plays a vital role in controlling water homeostasis upon stimulation by the natural peptide arginine vasopressin (AVP). Thus, V2R has attracted intense interest as a drug target for diabetes insipidus, nocturia, and hyponatremia. However, how AVP recognizes and activates V2R remains elusive. Here, we report the 2.6 Å resolution structure of V2R bound to AVP and the stimulatory G protein Gs, determined by cryo-electron microscopy (cryo-EM). In this complex, AVP presents a unique cyclic conformation formed by an intramolecular disulfide bond and engages the orthosteric binding pocket of V2R in a ligand-specific mode. Comparison of the AVP–V2R–Gscomplex to previously reported Gs-coupled class A GPCRs reveals distinct structural features, including a smaller outward movement of TM5 and TM6 and the concomitant shift of Gsprotein. Our detailed structural analysis provides a framework for understanding AVP recognition and V2R activation, thereby offering a structural template for drug design targeting V2R.

Autism spectrum disorder is a neurodevelopmental disease with increasing occurrence. Recent studies focus on the development of novel V

Cyclophosphamide (CP) is a chemotherapeutic agent which is extensively used in the treatment of multiple neoplastic and nonneoplastic diseases like breast cancer, lymphomas, systemic lupus erythematosus, and multiple sclerosis. Dose-limiting side effects, mainly nephrotoxicity is a major problem hindering its use in the clinical practice. CP induces nephrogenic syndrome of inappropriate antidiuresis mostly via the activation of arginine vasopressin V2 receptors. Moreover, CP produces reactive metabolites which is responsible for augmentation of lipid peroxidation and oxidative stress. Tolvaptan (TOL) is a selective vasopressin V2 receptor antagonist used in the treatment of clinically significant hyponatremia, volume overload in heart failure, and liver cirrhosis with edema. The present study aimed to investigate the potential protective effect of TOL in CP-induced nephrotoxicity. Twenty-four adult male albino rats were randomly divided into four groups: the control group, TOL group that treated daily with tolvaptan (10 mg/kg/d, orally), CP group where CP was administered intraperitoneally 75 mg/kg on days 3, 4, 5, 19, 20, and 21 of study, and the CP + TOL group where animals were treated with TOL daily with (10 mg/kg/d, orally) for 22 days with concomitant administration of CP as described before. Coadministration of TOL with CP induces significant improvement in the level of urine volume, serum Na+, serum osmolarity, urinary creatinine, and free water clearance in addition to significant reduction of body weight, serum creatinine, urea, serum K+, blood pressure, urine osmolarity, and the fractional excretion of sodium as compared to CP-treated group. In addition, coadministration of TOL significantly reduced MDA, the marker of lipid peroxidation, and different pro-inflammatory cytokines. Histopathological changes showed improvement in the signs of nephrotoxicity with the coadministration of TOL. Also, co-treatment with TOL significantly decreased the level of markers of apoptosis as caspase-3 and Bax with increased expression of antiapoptotic Bcl-2 in renal tissue as compared to CP-treated group.

Pulmonary hypertension (PH) in newborns and adults is a disease that can lead to right heart failure and result in a shorter lifespan. PH was induced by maintaining pregnant rats in a hypoxic chamber for 4 h twice a day, from days 7–21 of pregnancy. Hypoxia was confirmed by a decrease in the partial pressure of oxygen (PaO2) and the oxygen saturation (SaO2) of arterial blood in the aorta. The body weight of newborns from hypoxic rats was ~20% decreased compared with the control newborns of normoxic rats. The vascular wall thickness/vascular diameter values of hypoxia treated pubs were increased compared with that of control newborns 7 days after birth; however, it decreased to similar levels than in the control group after 3 months, and then further decreased to significantly lower levels than in the control group at 6 months after birth. At birth, the lung tissues of newborns from hypoxic rats exhibited an increase in the levels of mRNA and proteins associated with PH such as HIF-1α, HIF-2α, V2R, TGF-β, TNF-α, Ang-2 and α-SMA. At 3 and 6 months after birth, the levels of both V2R mRNA and protein in offspring from hypoxic rats were at least 2-fold higher, whereas the expression of all other factors decreased compared with the control offspring. By contrast, HIF-2α and Ang-2 expression levels were significantly increased in the 6-month-old control offspring from normoxic rats. V2R overexpression in pups induced by hypoxia in maternal rats was sustained until their adulthood. V2R may be a marker for detecting PH.

International audience; Rationale: MQ1, a snake toxin which targets with high nanomolar affinity and absolute selectivity for the type 2 vasopressin receptor (V2R), is a drug candidate for renal diseases and a molecular probe for imaging cells or organs expressing V2R. Methods: MQ1's pharmacological properties were characterized and applied to a rat model of hyponatremia. Its PK/PD parameters were determined as well as its therapeutic index. Fluorescently and radioactively labeled MQ1 were chemically synthesized and associated with moderate loss of affinity. MQ1's dynamic biodistribution was monitored by positron emission tomography. Confocal imaging was used to observe the labeling of three cancer cell lines. Results: The inverse agonist property of MQ1 very efficiently prevented dDAVP-induced hyponatremia in rats with low nanomolar/kg doses and with a very large therapeutic index. PK (plasma MQ1 concentrations) and PD (diuresis) exhibited a parallel biphasic decrease. The dynamic biodistribution showed that MQ1 targets the kidneys and then exhibits a blood and kidney biphasic decrease. Whatever the approach used, we found a T1/2α between 0.9 and 3.8 h and a T1/2β between 25 and 46 h and demonstrated that the kidneys were able to retain MQ1. Finally, the presence of functional V2R expressed at the membrane of cancer cells was, for the first time, demonstrated with a specific fluorescent ligand. Conclusion: As the most selective V2 binder, MQ1 is a new promising drug for aquaresis-related diseases and a molecular probe to visualize in vitro and in vivo V2R expressed physiologically or under pathological conditions.

As a rare hereditary disease, congenital nephrogenic diabetes insipidus (NDI) is clinically characterized by polyuria with hyposthenuria and polydipsia. NDI results from collecting duct principal cell hyporesponsiveness or insensitivity to the antidiuretic action of arginine vasopressin (AVP). The principal cell-specific water channel aquaporin-2 (AQP2) plays an essential role in water reabsorption along osmotic gradients. The capacity to accumulate AQP2 in the apical plasma membrane in response to decreased fluid volume or increased plasma osmolality is critically regulated by the antidiuretic hormone AVP and its receptor 2 (AVPR2). Mutations in AVPR2 result in X-linked recessive NDI, the most common form of inherited NDI. Genetic defects in AQP2 cause autosomal recessive or dominant NDI. In this review, we provide an updated overview of the genetic and molecular mechanisms of congenital NDI, with a focus on the potential disease-causing mutations in AVPR2 and AQP2, the molecular defects in the AVPR2 and AQP2 mutants, post-translational modifications (i.e., phosphorylation, ubiquitination, and glycosylation) and various protein-protein interactions that regulate phosphorylation, ubiquitination, tetramerization, trafficking, stability, and degradation of AQP2.

Nephrogenic diabetes insipidus (NDI) is characterized by renal resistance to the antidiuretic hormone arginine vasopressin (AVP), which leads to polyuria, plasma hyperosmolarity, polydipsia, and impaired quality of living. Inherited forms are caused by X-linked loss-of-function mutations in the gene encoding the vasopressin 2 receptor (V2R) or autosomal recessive/dominant mutations in the gene encoding aquaporin 2 (AQP2). A common acquired form is lithium-induced NDI. AVP facilitates reabsorption of water through increased abundance and insertion of AQP2 in the apical membrane of principal cells in the collecting ducts. In X-linked NDI, V2R is dysfunctional, which leads to impaired water reabsorption. These patients have functional AQP2, and thus the challenge is to achieve AQP2 membrane insertion independently of V2R. The current treatment is symptomatic and is based on distally acting diuretics (thiazide or amiloride) and cyclooxygenase inhibitors (indomethacin). This mini-review covers published data from trials in preclinical in vivo models and a few human intervention studies to improve NDI by more causal approaches. Promising effects on NDI in preclinical studies have been demonstrated by the use of pharmacological approaches with secretin, Wnt5a, protein kinase A agonist, fluconazole, prostaglandin E2 EP2 and EP4 agonists, statins, metformin, and soluble prorenin receptor agonists. In patients, only casuistic reports have evaluated the effect of statins, phosphodiesterase inhibitors (rolipram and sildenafil), and the guanylate cyclase stimulator riociguat without amelioration of symptoms. It is concluded that there is currently no established intervention that causally improves symptoms or quality of life in patients with NDI. There is a need to collaborate to improve study quality and conduct formal trials.

Aims: Arginine vasopressin (AVP) mediates deleterious effects via vascular V1a and renal V2 receptors in heart failure (HF). Despite positive short-term decongestive effects in phase II HF studies, selective V2 receptor antagonism has shown no long-term mortality benefit, potentially related to unopposed V1a receptor activation. We compared the novel dual V1a/V2 receptor antagonist pecavaptan with the selective V2 receptor antagonist tolvaptan in pre-clinical HF models. Methods and results: In vitro IC50 determination in recombinant cell lines revealed similar receptor selectivity profiles (V2:V1a) of tolvaptan and pecavaptan for human and dog AVP receptors, respectively. Two canine models were used to compare haemodynamic and aquaretic effects: (i) anaesthetised dogs with tachypacing-induced HF, and (ii) conscious telemetric dogs with a non-invasive cardiac output (CO) monitor. Tolvaptan and pecavaptan exhibited no differences in urinary output. In HF dogs, pecavaptan counteracted the AVP-induced increase in afterload and decrease in CO (pecavaptan: 1.83 ± 0.31 L/min; vs. tolvaptan: 1.46 ± 0.07 L/min, P < 0.05). In conscious telemetric animals, pecavaptan led to a significant increase in CO (+0.26 ± 0.17 L/min, P = 0.0086 vs. placebo), in cardiac index (+0.58 ± 0.39 L/min/m², P = 0.009 vs. placebo) and a significant decrease in total peripheral resistance (−5348.6 ± 3601.3 dyn × s/cm⁵, P < 0.0001 vs. placebo), whereas tolvaptan was without any significant effect. Conclusions: Simultaneous blockade of vascular V1a and renal V2 receptors efficiently induces aquaresis and counteracts AVP-mediated haemodynamic aggravation in HF models. Dual V1a/V2 antagonism may lead to improved outcomes in HF.

Family context and co-parent rapport alter caregiving and shape epigenetic modification in the brain and behavior of offspring., Although it is well appreciated that the early-life social environment asserts subsequent long-term consequences on offspring brain and behavior, the specific mechanisms that account for this relationship remain poorly understood. Using a novel assay that forced biparental pairs or single mothers to prioritize caring for offspring or themselves, we investigated the impact of parental variation on adult expression of nonapeptide-modulated behaviors in prairie voles. We demonstrated that single mothers compensate for the lack of a co-parent. Moreover, mothers choose to invest in offspring over themselves when faced with a tradeoff, whereas fathers choose to invest in themselves. Furthermore, our study suggests a pathway whereby variation in parental behavior (specifically paternal care) may lead to alterations in DNA methylation within the vasopressin receptor 1a gene and gene expression in the lateral septum. These differences are concomitant with changes in social approach, a behavior closely associated with septal vasopressin receptor function.

Luteolin, a flavonoid widely distributed in the plant kingdom, contains two benzene rings and hydroxyl groups, and this structural specificity contributes to its diverse biological activities. However, no previous studies have simultaneously investigated the therapeutic potency of luteolin isolated from a plant as an antipsychotic and antidepressant. Here, luteolin exhibited selective inhibition of hMAO-A (IC

Significance G protein-coupled receptors (GPCRs) are targeted by a large fraction of approved drugs and regulate many important cellular processes. Association of GPCRs with heterotrimeric G proteins in response to agonist activation is thought to invariably lead to G protein activation. We find instead that G12 heterotrimers can associate with agonist-bound receptors in a manner that does not lead to activation. These unproductive agonist–receptor-G protein ternary complexes sequester G12 heterotrimers and thus inhibit rather than support G12 signaling. These findings reveal a mechanism whereby agonist activation of GPCRs can inhibit as well as promote G protein signaling., G proteins are activated when they associate with G protein-coupled receptors (GPCRs), often in response to agonist-mediated receptor activation. It is generally thought that agonist-induced receptor-G protein association necessarily promotes G protein activation and, conversely, that activated GPCRs do not interact with G proteins that they do not activate. Here we show that GPCRs can form agonist-dependent complexes with G proteins that they do not activate. Using cell-based bioluminescence resonance energy transfer (BRET) and luminescence assays we find that vasopressin V2 receptors (V2R) associate with both Gs and G12 heterotrimers when stimulated with the agonist arginine vasopressin (AVP). However, unlike V2R-Gs complexes, V2R-G12 complexes are not destabilized by guanine nucleotides and do not promote G12 activation. Activating V2R does not lead to signaling responses downstream of G12 activation, but instead inhibits basal G12-mediated signaling, presumably by sequestering G12 heterotrimers. Overexpressing G12 inhibits G protein receptor kinase (GRK) and arrestin recruitment to V2R and receptor internalization. Formyl peptide (FPR1 and FPR2) and Smoothened (Smo) receptors also form complexes with G12 that are insensitive to nucleotides, suggesting that unproductive GPCR-G12 complexes are not unique to V2R. These results indicate that agonist-dependent receptor-G protein association does not always lead to G protein activation and may in fact inhibit G protein activation.