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The Journal of Physical Chemistry. B Jan 2015Vasopressin and oxytocin are intrinsically disordered cyclic nonapeptides belonging to a family of neurohypophysial hormones. Although unique in their functions, these...
Vasopressin and oxytocin are intrinsically disordered cyclic nonapeptides belonging to a family of neurohypophysial hormones. Although unique in their functions, these peptides differ only by two residues and both feature a tocin ring formed by the disulfide bridge between first and sixth cysteine residues. This sequence and structural similarity are experimentally linked to oxytocin agonism at vasopressin receptors and vasopressin antagonism at oxytocin receptors. Yet single- or double-residue mutations in both peptides have been shown to have drastic impacts on their activities at either receptor, and possibly the ability to bind to their neurophysin carrier protein. In this study we perform molecular dynamics simulations of the unbound native and mutant sequences of the oxytocin and vasopressin hormones to characterize their structural ensembles. We classify the subpopulations of these structural ensembles on the basis of the distributions of radius of gyration and secondary structure and hydrogen-bonding features of the canonical tocin ring and disordered tail region. We then relate the structural changes observed in the unbound form of the different hormone sequences to experimental information about peptide receptor binding, and more indirectly, carrier protein binding affinity, receptor activity, and protease degradation. This study supports the hypothesis that the structural characteristics of the unbound form of an IDP can be used to predict structural or functional preferences of its functional bound form.
Topics: Hydrogen Bonding; Isomerism; Molecular Dynamics Simulation; Mutation; Oxytocin; Protein Conformation; Vasopressins
PubMed: 25231121
DOI: 10.1021/jp505902m -
Endocrinology Aug 2021Arginine vasopressin (AVP) and oxytocin (OXY) are released by magnocellular neurosecretory cells that project to the posterior pituitary. While AVP and OXY currently... (Review)
Review
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.
Topics: Animals; Arginine Vasopressin; Blood Pressure; Blood Volume; Cardiovascular Diseases; Cardiovascular System; Humans; Hypothalamo-Hypophyseal System; Natriuresis; Oxytocin; Receptors, Oxytocin; Receptors, Vasopressin; Sex Characteristics
PubMed: 33891015
DOI: 10.1210/endocr/bqab082 -
Continence (Amsterdam, Netherlands) Jun 2022The main goal of this study was to determine the effects of arginine vasopressin (AVP) and desmopressin on bladder contractility and to examine whether the effects of...
PURPOSE
The main goal of this study was to determine the effects of arginine vasopressin (AVP) and desmopressin on bladder contractility and to examine whether the effects of these vasopressin receptor (VR) agonists differ in young versus aged animals. These aims were addressed using urinary bladders from young (3 months) and aged (24 month) female Fischer 344 rats that were isolated and dissected into strips for isometric tension recordings. Bladder strips were exposed to AVP and desmopressin through the perfusate, and tension changes recorded.
RESULTS
In young rat bladders, AVP, an agonist at both vasopressin-1 receptors (VRs) and vasopressin-2 receptor (VRs), concentration-dependently caused contraction of bladder strips with a sensitivity that was greater in young versus aged bladder strips. Removal of the mucosa did not alter the sensitivity of young bladder strips to AVP yet enhanced the AVP sensitivity of aged bladder strips. The differential sensitivity to AVP between young denuded and aged denuded bladder strips was similar. In contrast to AVP, desmopressin (VR selective agonist) relaxed bladder strips. This response was reduced by removal of the mucosa in young, but not aged, bladder strips.
CONCLUSION
These findings support a direct role for VRs in regulating detrusor tone with VRs causing contraction and VRs relaxation. In aged bladders, the contractile response to VR activation is attenuated due to release of a mucosal factor that attenuates VR-induced contractions. Also in aged bladders, the relaxation response to VR activation is attenuated by lack of release of a mucosal factor that contributes to VR-induced relaxation. Thus age-associated changes in the bladder mucosa impair the effects of VRs on bladder tone. Because the VR signaling system is impaired in the older bladder, administering an exogenous VR agonist (e.g., desmopressin) could counteract this defect. Thus, desmopressin could potentially increase nighttime bladder capacity through detrusor relaxation in concert with decreased urine production, reducing nocturnal voiding frequency.
PubMed: 35789681
DOI: 10.1016/j.cont.2022.100032 -
Science Advances Jul 2020The peptide hormone oxytocin modulates socioemotional behavior and sexual reproduction via the centrally expressed oxytocin receptor (OTR) across several species. Here,...
The peptide hormone oxytocin modulates socioemotional behavior and sexual reproduction via the centrally expressed oxytocin receptor (OTR) across several species. Here, we report the crystal structure of human OTR in complex with retosiban, a nonpeptidic antagonist developed as an oral drug for the prevention of preterm labor. Our structure reveals insights into the detailed interactions between the G protein-coupled receptor (GPCR) and an OTR-selective antagonist. The observation of an extrahelical cholesterol molecule, binding in an unexpected location between helices IV and V, provides a structural rationale for its allosteric effect and critical influence on OTR function. Furthermore, our structure in combination with experimental data allows the identification of a conserved neurohypophyseal receptor-specific coordination site for Mg that acts as potent, positive allosteric modulator for agonist binding. Together, these results further our molecular understanding of the oxytocin/vasopressin receptor family and will facilitate structure-guided development of new therapeutics.
Topics: Binding Sites; Humans; Oxytocin; Protein Binding; Receptors, Oxytocin
PubMed: 32832646
DOI: 10.1126/sciadv.abb5419 -
Behavior Genetics Mar 2017Polymorphisms of the arginine vasopressin receptor 1a (AVPR1a) gene have been linked to various measures related to human social behavior, including sibling conflict and...
Polymorphisms of the arginine vasopressin receptor 1a (AVPR1a) gene have been linked to various measures related to human social behavior, including sibling conflict and agreeableness. In chimpanzees, AVPR1a polymorphisms have been associated with traits important for social interactions, including sociability, joint attention, dominance, conscientiousness, and hierarchical personality dimensions named low alpha/stability, disinhibition, and negative emotionality/low dominance. We examined associations between AVPR1a and six personality domains and hierarchical personality dimensions in 129 chimpanzees (Pan troglodytes) living in Japan or in a sanctuary in Guinea. We fit three linear and three animal models. The first model included genotype, the second included sex and genotype, and the third included genotype, sex, and sex × genotype. All personality phenotypes were heritable. Chimpanzees possessing the long form of the allele were higher in conscientiousness, but only in models that did not include the other predictors; however, additional analyses suggested that this may have been a consequence of study design. In animal models that included sex and sex × genotype, chimpanzees homozygous for the short form of the allele were higher in extraversion. Taken with the findings of previous studies of chimpanzees and humans, the findings related to conscientiousness suggest that AVPR1a may be related to lower levels of impulsive aggression. The direction of the association between AVPR1a genotype and extraversion ran counter to what one would expect if AVPR1a was related to social behaviors. These results help us further understand the genetic basis of personality in chimpanzees.
Topics: Aggression; Alleles; Animals; Arginine; Behavior, Animal; Genotype; Models, Animal; Pan troglodytes; Personality; Phenotype; Polymorphism, Genetic; Receptors, Vasopressin; Social Behavior
PubMed: 27804047
DOI: 10.1007/s10519-016-9822-2 -
EMBO Reports Nov 2020β-arrestins (βarr1 and βarr2) are ubiquitous regulators of G protein-coupled receptor (GPCR) signaling. Available data suggest that β-arrestins dock to different...
β-arrestins (βarr1 and βarr2) are ubiquitous regulators of G protein-coupled receptor (GPCR) signaling. Available data suggest that β-arrestins dock to different receptors in different ways. However, the structural characterization of GPCR-arrestin complexes is challenging and alternative approaches to study GPCR-arrestin complexes are needed. Here, starting from the finger loop as a major site for the interaction of arrestins with GPCRs, we genetically incorporate non-canonical amino acids for photo- and chemical crosslinking into βarr1 and βarr2 and explore binding topologies to GPCRs forming either stable or transient complexes with arrestins: the vasopressin receptor 2 (rhodopsin-like), the corticotropin-releasing factor receptor 1, and the parathyroid hormone receptor 1 (both secretin-like). We show that each receptor leaves a unique footprint on arrestins, whereas the two β-arrestins yield quite similar crosslinking patterns. Furthermore, we show that the method allows defining the orientation of arrestin with respect to the GPCR. Finally, we provide direct evidence for the formation of arrestin oligomers in the cell.
Topics: Arrestin; Arrestins; Receptors, G-Protein-Coupled; Signal Transduction; beta-Arrestins
PubMed: 32929862
DOI: 10.15252/embr.202050437 -
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 -
European Journal of Endocrinology Jan 2016Recently, imbalance in the vasopressin (AVP) system, measured as elevated levels of copeptin (the C-terminal part of the AVP pro-hormone) in plasma, was linked to the...
OBJECTIVE
Recently, imbalance in the vasopressin (AVP) system, measured as elevated levels of copeptin (the C-terminal part of the AVP pro-hormone) in plasma, was linked to the development of abdominal obesity and diabetes mellitus (DM). Here, we aim to investigate if the genetic variation of the human AVP receptor 1b gene (AVPR1B) is associated with measures of obesity and DM.
DESIGN
Malmö Diet and Cancer study (MDC) is a population-based prospective cohort examined 1991-1996.
METHODS
Four tag single nucleotide polymorphisms (SNPs: rs35810727, rs28373064, rs35439639, rs35608965) of AVPR1B were genotyped in the cardiovascular cohort (n=6103) of MDC (MDC-CC) and associated with measures of obesity and DM. Significant SNPs were replicated in another 24 344 MDC individuals (MDC replication cohort).
RESULTS
In MDC-CC, the major allele of rs35810727 was associated with elevated BMI (β-coefficient ± s.e.m.; 0.30 ± 0.14, P=0.03) and waist (0.78 ± 0.36, P=0.03) after age and gender adjustment. The association with BMI was replicated in the MDC replication cohort (0.21 ± 0.07, P=0.003), whereas that with waist was not significant. In MDC-CC there was no association between the major allele of rs35810727 and DM, but in the complete MDC cohort (n=30 447) the major allele of rs35810727 was associated with DM (OR (95% CI); 1.10 (1.00-1.20), P=0.04).
CONCLUSIONS
Genetic variance of AVPR1B contributes to overweight. Furthermore, our data indicate a link between AVPR1B variance and DM development. Our data point at a relationship between the disturbance of the pharmacologically modifiable AVP system and the body weight regulation.
Topics: Aged; Body Mass Index; Cohort Studies; Diabetes Mellitus; Female; Genetic Variation; Genotype; Glycopeptides; Humans; Male; Middle Aged; Obesity; Obesity, Abdominal; Overweight; Polymorphism, Single Nucleotide; Prospective Studies; Receptors, Vasopressin; Sweden
PubMed: 26503846
DOI: 10.1530/EJE-15-0781 -
International Journal of Molecular... Jan 2024The present review draws attention to the specific role of angiotensin peptides [angiotensin II (Ang II), angiotensin-(1-7) (Ang-(1-7)], vasopressin (AVP), and insulin... (Review)
Review
The present review draws attention to the specific role of angiotensin peptides [angiotensin II (Ang II), angiotensin-(1-7) (Ang-(1-7)], vasopressin (AVP), and insulin in the regulation of the coronary blood flow and cardiac contractions. The interactions of angiotensin peptides, AVP, and insulin in the heart and in the brain are also discussed. The intracardiac production and the supply of angiotensin peptides and AVP from the systemic circulation enable their easy access to the coronary vessels and the cardiomyocytes. Coronary vessels and cardiomyocytes are furnished with AT1 receptors, AT2 receptors, Ang (1-7) receptors, vasopressin V1 receptors, and insulin receptor substrates. The presence of some of these molecules in the same cells creates good conditions for their interaction at the signaling level. The broad spectrum of actions allows for the engagement of angiotensin peptides, AVP, and insulin in the regulation of the most vital cardiac processes, including (1) cardiac tissue oxygenation, energy production, and metabolism; (2) the generation of the other cardiovascular compounds, such as nitric oxide, bradykinin (Bk), and endothelin; and (3) the regulation of cardiac work by the autonomic nervous system and the cardiovascular neurons of the brain. Multiple experimental studies and clinical observations show that the interactions of Ang II, Ang(1-7), AVP, and insulin in the heart and in the brain are markedly altered during heart failure, hypertension, obesity, and diabetes mellitus, especially when these diseases coexist. A survey of the literature presented in the review provides evidence for the belief that very individualized treatment, including interactions of angiotensins and vasopressin with insulin, should be applied in patients suffering from both the cardiovascular and metabolic diseases.
Topics: Humans; Angiotensin II; Arginine Vasopressin; Diabetes Mellitus; Insulin; Obesity; Receptors, Angiotensin; Receptors, Vasopressin; Vasopressins
PubMed: 38279313
DOI: 10.3390/ijms25021310 -
PloS One 2021Recently, we reported that the chemokine (C-X-C motif) receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) heteromerize with α1A/B/D-adrenoceptors (ARs) and...
Recently, we reported that the chemokine (C-X-C motif) receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) heteromerize with α1A/B/D-adrenoceptors (ARs) and arginine vasopressin receptor 1A (AVPR1A) in recombinant systems and in rodent and human vascular smooth muscle cells (hVSMCs). In these studies, we observed that heteromerization between two receptor partners may depend on the presence and the expression levels of other partnering receptors. To test this hypothesis and to gain initial insight into the formation of these receptor heteromers in native cells, we utilized proximity ligation assays in hVSMCs to visualize receptor-receptor proximity and systematically studied how manipulation of the expression levels of individual protomers affect heteromerization patterns among other interacting receptor partners. We confirmed subtype-specific heteromerization between endogenously expressed α1A/B/D-ARs and detected that AVPR1A also heteromerizes with α1A/B/D-ARs. siRNA knockdown of CXCR4 and of ACKR3 resulted in a significant re-arrangement of the heteromerization patterns among α1-AR subtypes. Similarly, siRNA knockdown of AVPR1A significantly increased heteromerization signals for seven of the ten receptor pairs between CXCR4, ACKR3, and α1A/B/D-ARs. Our findings suggest plasticity of seven transmembrane helix (7TM) receptor heteromerization in native cells and could be explained by a supramolecular organization of these receptors within dynamic clusters in the plasma membrane. Because we previously observed that recombinant CXCR4, ACKR3, α1a-AR and AVPR1A form hetero-oligomeric complexes composed of 2-4 different protomers, which show signaling properties distinct from individual protomers, re-arrangements of receptor heteromerization patterns in native cells may contribute to the phenomenon of context-dependent GPCR signaling. Furthermore, these findings advise caution in the interpretation of functional consequences after 7TM receptor knockdown in experimental models. Alterations of the heteromerization patterns among other receptor partners may alter physiological and pathological responses, in particular in more complex systems, such as studies on the function of isolated organs or in in vivo experiments.
Topics: Cell Line; Gene Expression Regulation; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Promoter Regions, Genetic; Protein Multimerization; Protein Structure, Secondary; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 34166476
DOI: 10.1371/journal.pone.0253821