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Frontiers in Neuroscience 2024
PubMed: 38352043
DOI: 10.3389/fnins.2024.1372140 -
Journal of Neuroendocrinology Jul 2023Parenting induces many neurological and behavioral changes that enable parents to rear offspring. Vasopressin plays an important role in this process via its effects on...
Parenting induces many neurological and behavioral changes that enable parents to rear offspring. Vasopressin plays an important role in this process via its effects on cognition, affect, and neuroplasticity, and in some cases, via interactions with decreased parental androgens. Thus far, the role of these hormones has been primarily studied in rodents. To address this gap, we explored vasopressin receptors and androgens in titi monkeys, a pair-bonding and biparental primate species. In Studies 1 and 2, we used receptor autoradiography to correlate arginine vasopressin receptor 1a (AVPR1a) binding in the hippocampus (Study 1, n = 10) and the rest of the forebrain (Study 2, n = 23) with parental status, parental experience, parity, infant carrying, and pair affiliation. We found that parents exhibited lower AVPR1a binding than non-parents throughout most brain regions assessed, with especially strong effects in the hippocampus (β = -.61), superior colliculus (β = -.88), lateral septum (β = -.35), and medial preoptic area (β = -.29). The other measures of parental experience also tended to be negatively associated with AVPR1a binding across different brain regions. In Study 3 (n = 44), we compared pre- and postpartum urinary androgen levels in parents and non-parents and found that mothers exhibited a sustained androgen decrease across 3-4 months postpartum (relative to 3 months prepartum; β ranged from -.72 to -.62 for different comparisons). For males, we found that multiparous fathers exhibited decreased androgen levels at 1-2 weeks postpartum (β = -.25) and at 3-4 months postpartum (β = -.40) compared to the prepartum, indicating both immediate and long-term reductions with subsequent paternal experience. Together, the results of this study suggest that decreases in AVPR1a binding and circulating androgens are associated with parental behavior and physiology in titi monkeys.
Topics: Male; Humans; Animals; Pregnancy; Female; Receptors, Vasopressin; Androgens; Callicebus; Brain; Postpartum Period
PubMed: 37267441
DOI: 10.1111/jne.13304 -
Kidney360 Dec 2023In a analysis, short-term reduction in spot urine osmolality (Uosm) was associated with decreased kidney volume growth in autosomal dominant polycystic kidney disease...
KEY POINTS
In a analysis, short-term reduction in spot urine osmolality (Uosm) was associated with decreased kidney volume growth in autosomal dominant polycystic kidney disease for both tolvaptan and instruction to increase hydration alone. For the same spot Uosm reduction, however, the kidney volume benefit was greater with tolvaptan, possibly because of greater cumulative 24-hour Uosm suppression by tolvaptan.
BACKGROUND
In addition to decreasing water excretion and increasing urinary concentration, the antidiuretic hormone vasopressin plays a role in the pathophysiology of autosomal dominant polycystic kidney disease. It has been hypothesized that by suppressing vasopressin release, drinking large amounts of water might exert therapeutic effects in autosomal dominant polycystic kidney disease similar to those of tolvaptan, an antagonist of the vasopressin type 2 receptor, but evidence is lacking. We analyzed data from tolvaptan clinical trials to evaluate relationships among water intake, urine osmolality (Uosm), and change in total kidney volume (TKV).
METHODS
Analysis of the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 clinical trial in which participants were randomized to tolvaptan or placebo and instructed to drink large amounts of water. The relationship between change in spot Uosm from baseline to week 3 and change in TKV to month 12 was assessed using linear regression modeling. Two short-term tolvaptan trials were analyzed to explore relationships between intermittent Uosm sampling and 24-hour Uosm suppression.
RESULTS
With both tolvaptan and placebo (, mandated high water intake alone), Uosm reduction at week 3 was associated with reduction in TKV growth at month 12. However, for the same decrease in spot Uosm, the corresponding reduction in TKV growth was greater for tolvaptan (, a −250 mOsm/kg reduction in Uosm at week 3 was associated with a −1% change in TKV at month 12 for tolvaptan versus +4.5% for placebo). In short-term trials, similar reductions in spot or trough Uosm values were achievable with tolvaptan and high water intake, but cumulative 24-hour suppression was greater with tolvaptan.
CONCLUSIONS
This analysis supports a relationship between effects on Uosm and inhibition of disease progression by tolvaptan and high water intake alone. The findings further suggest that 24-hour Uosm measurement is superior to spot Uosm for assessing suppression of vasopressin activity by tolvaptan.
Topics: Humans; Tolvaptan; Polycystic Kidney, Autosomal Dominant; Drinking; Antidiuretic Hormone Receptor Antagonists; Benzazepines
PubMed: 37986188
DOI: 10.34067/KID.0000000000000302 -
Neuroscience Jul 2023The nonapeptide system modulates a diversity of social behaviors, including aggression, parental care, affiliation, sexual behavior, and pair bonding. Such social...
The nonapeptide system modulates a diversity of social behaviors, including aggression, parental care, affiliation, sexual behavior, and pair bonding. Such social behaviors are regulated through oxytocin and vasopressin activation of the oxytocin receptor (OXTR) and vasopressin V1a receptor (AVPR1A) in the brain. Nonapeptide receptor distributions have been mapped for several species, however, studies have demonstrated that there is substantial variation across species. Mongolian gerbils (Meriones unguiculatus) are an excellent organism for studying family dynamics, social development, pair bonding, and territorial aggression. Although an increasing number of studies are examining the neural mechanisms of social behavior in Mongolian gerbils, nonapeptide receptor distributions have yet to be characterized for this species. Here we conducted receptor autoradiography to map distributions of OXTR and AVPR1A binding throughout the basal forebrain and midbrain of female and male Mongolian gerbils. Further, we assessed whether gonadal sex influenced binding densities in brain regions important for social behavior and reward, however, we observed no effects of sex on OXTR or AVPR1A binding densities. These findings provide mapping distributions of nonapeptide receptors in male and female Mongolian gerbils, laying a foundation for future studies that seek to manipulate the nonapeptide system to examine nonapeptide-mediated social behavior.
Topics: Animals; Male; Female; Receptors, Oxytocin; Gerbillinae; Basal Forebrain; Vasopressins; Mesencephalon; Receptors, Vasopressin; Oxytocin; Social Behavior; DNA-Binding Proteins
PubMed: 37172688
DOI: 10.1016/j.neuroscience.2023.05.004 -
Biochemical and Biophysical Research... Nov 2023Many insects produce the cyclic neuropeptide inotocin (CLITNCPRGamide), which is the insect orthologue of the mammalian neuropeptides oxytocin and vasopressin. These...
Many insects produce the cyclic neuropeptide inotocin (CLITNCPRGamide), which is the insect orthologue of the mammalian neuropeptides oxytocin and vasopressin. These insects also have one inotocin G protein-coupled receptor (GPCR), which is the orthologue of the mammalian oxytocin and vasopressin receptors. The tick Ixodes scapularis belongs to the subphylum Chelicerata, an arthropod taxon different from insects, to which also spiders, scorpions, and mites belong. I. scapularis is an ectoparasite and a health risk for humans, because it transfers pathogenic microorganisms to its human host during a blood meal, thereby causing serious neurological diseases, among them Lyme disease and tick-borne encephalitis (TBE). By annotating the genomic sequence of I. scapularis, we previously found one presumed tick inotocin preprohormone gene and, in contrast to insects, three genes coding for presumed inotocin GPCRs. We now find that these GPCR genes cluster on one genomic contig, suggesting that they originated by recent gene duplications. Closely located on the same contig are also four adipokinetic hormone/corazonin-related peptide (ACP) GPCR genes, and one crustacean cardioactive peptide (CCAP) GPCR gene, suggesting evolutionary relationships. These evolutionary relationships are confirmed by phylogenetic tree analyses of their gene products. We also cloned the tick inotocin preprohormone, which has a structural organization closely resembling mammalian oxytocin and vasopressin preprohormones, including the presence of a conserved neurophysin sequence, having seven cystine bridges. This neurophysin sequence has two cystine-knot domains, but in contrast to mammalian neurophysins, the tick neurophysin contains a canonical prohormone convertase cleavage signal and a peptide C-terminal amidation sequence (GKR), suggesting cleavage into two biologically active cystine-knot peptides. This cleavage/amidation sequence occurs in neurophysins from most hard tick species, but not in other chelicerates. Mature tick inotocin is different from insect inotocin and has the sequence CFITNCPPGamide. Finally, we cloned and stably expressed the three tick inotocin receptors in Chinese Hamster Ovary cells and found that each of them was activated by nanomolar concentrations of tick inotocin (EC for ITR1 = 1.6 × 10 M; EC for ITR2 = 5.8 × 10 M; EC for ITR3 = 9.3 × 10 M), thereby establishing that they are genuine tick inotocin receptors.
PubMed: 37716155
DOI: 10.1016/j.bbrc.2023.09.009 -
Autonomic Neuroscience : Basic &... Feb 2024The sensitization and hypertonicity of visceral afferents are highly relevant to the development and progression of cardiovascular and respiratory disease states. In... (Review)
Review
The sensitization and hypertonicity of visceral afferents are highly relevant to the development and progression of cardiovascular and respiratory disease states. In this review, we described the evidence that the inflammatory process regulates visceral afferent sensitivity and tonicity, affecting the control of the cardiovascular and respiratory system. Some inflammatory mediators like nitric oxide, angiotensin II, endothelin-1, and arginine vasopressin may inhibit baroreceptor afferents and contribute to the baroreflex impairment observed in cardiovascular diseases. Cytokines may act directly on peripheral afferent terminals that transmit information to the central nervous system (CNS). TLR-4 receptors, which recognize lipopolysaccharide, were identified in the nodose and petrosal ganglion and have been implicated in disrupting the blood-brain barrier, which can potentiate the inflammatory process. For example, cytokines may cross the blood-brain barrier to access the CNS. Additionally, pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α and some of their receptors have been identified in the nodose ganglion and carotid body. These pro-inflammatory cytokines also sensitize the dorsal root ganglion or are released in the nucleus of the solitary tract. In cardiovascular disease, pro-inflammatory mediators increase in the brain, heart, vessels, and plasma and may act locally or systemically to activate/sensitize afferent nervous terminals. Recent evidence demonstrated that the carotid body chemoreceptor cells might sense systemic pro-inflammatory molecules, supporting the novel proposal that the carotid body is part of the afferent pathway in the central anti-inflammatory reflexes. The exact mechanisms of how pro-inflammatory mediators affects visceral afferent signals and contribute to the pathophysiology of cardiovascular diseases awaits future research.
Topics: Humans; Cardiovascular Diseases; Solitary Nucleus; Inflammation; Cytokines; Inflammation Mediators
PubMed: 38104365
DOI: 10.1016/j.autneu.2023.103137 -
European Journal of Pharmacology Sep 2023Interstitial cells of Cajal generate slow wave gastric electrical activity, initiating spontaneous muscle contractions. This becomes dysrhythmic during nausea when...
BACKGROUND
Interstitial cells of Cajal generate slow wave gastric electrical activity, initiating spontaneous muscle contractions. This becomes dysrhythmic during nausea when [Arg]-vasopressin (AVP) is also released. In human stomach AVP increased spontaneous contraction activity and muscle tone, not neuronally-mediated contractions. Rodents cannot vomit, releasing the related hormone, oxytocin (OT) instead. We hypothesised that rat stomach would behave differently.
EXPERIMENTAL APPROACH
Spontaneous and electrically-evoked (EFS) contractions were measured in rat forestomach and antrum circular muscle. Custom software defined spontaneous contractions by analysing eight motility parameters.
RESULTS
The forestomach was quiescent. Irregular antrum contractions became regular adjacent to the pylorus (1.7 ± 0.4 mN; 1.2 ± 0.1 contractions/min, n = 12). These were unaffected by tetrodotoxin (10 M), atropine (10 M) and L-NAME (3 × 10 M). In both regions, AVP (pEC∼9.0) and OT (∼0.5 log-unit less potent) caused contraction (greater in antrum), competitively antagonized by, respectively, SR49059 (pK∼9.5) and L371257 (pK∼9.0), reduced by tetrodotoxin but unaffected by atropine. In the antrum, AVP and OT (∼2 log-units less potent/efficacious) regularized and increased spontaneous contraction amplitude, frequency, rates of contraction/decay. In both regions, EFS-evoked contractions, abolished by atropine/tetrodotoxin, were reduced by AVP and OT, with AVP more potent and efficacious, particularly in forestomach.
CONCLUSION
Irregular spontaneous contractions of gastric antrum suggest variable ICC-muscle coupling. AVP and less potently, OT, enhanced frequency and force of contractions via V and OT receptors. Compared with human, differences in contraction regularity, potency and ability of AVP/OT to affect neuronal function suggests caution when using rat stomach to model ICC functions and nauseagenic stimuli.
Topics: Animals; Rats; Arginine; Arginine Vasopressin; Atropine; Oxytocin; Receptors, Oxytocin; Receptors, Vasopressin; Stomach; Tetrodotoxin; Vasopressins
PubMed: 37429518
DOI: 10.1016/j.ejphar.2023.175906 -
BioRxiv : the Preprint Server For... Aug 2023The vasopressin type 2 receptor (VR) is an essential GPCR in renal regulation of water homeostasis. Upon stimulation, the VR activates Gα and Gα, which is followed by...
The vasopressin type 2 receptor (VR) is an essential GPCR in renal regulation of water homeostasis. Upon stimulation, the VR activates Gα and Gα, which is followed by robust recruitment of β-arrestins and receptor internalization into endosomes. Unlike canonical GPCR signaling, the β-arrestin association with the VR does not terminate Gα activation, and thus, Gα-mediated signaling is sustained while the receptor is internalized. Here, we demonstrate that this VR ability to co-interact with G protein/β-arrestin and promote endosomal G protein signaling is not restricted to Gα, but also involves Gα. Furthermore, our data implies that β-arrestins potentiate Gα/Gα activation at endosomes rather than terminating their signaling. Surprisingly, we found that the VR internalizes and promote endosomal G protein activation independent of β-arrestins to a minor degree. These new observations challenge the current model of endosomal GPCR signaling and suggest that this event can occur in both β-arrestin-dependent and -independent manners.
PubMed: 37034816
DOI: 10.1101/2023.04.01.535208 -
Journal of Personalized Medicine Jul 2023The clinical impact of vasopressin in hemorrhagic shock remains largely unknown.
BACKGROUND
The clinical impact of vasopressin in hemorrhagic shock remains largely unknown.
OBJECTIVE
This systematic review and meta-analysis was designed to investigate the effects of vasopressin receptor agonists during the resuscitation of hemorrhagic shock.
METHODS
A systematic search of PubMed (MEDLINE), Scopus, and PubMed Central was conducted for relevant articles. Experimental (animal) and clinical studies were included. The primary objective was to investigate the correlation of vasopressin receptor agonist use with mortality and various hemodynamic parameters.
RESULTS
Data extraction was possible in thirteen animal studies and two clinical studies. Differences in risk of mortality between patients who received a vasopressin receptor agonist were not statistically significant when compared to those who were not treated with such agents [RR (95% CI): 1.17 (0.67, 2.08); = 0.562; I = 50%]. The available data were insufficient to conduct a meta-analysis assessing the effect of vasopressin receptor agonists on hemodynamics. Drawing safe conclusions from animal studies was challenging, due to significant heterogeneity in terms of species and dosage of vasopressin receptor agonists among studies.
CONCLUSIONS
Differences in risk of mortality between patients who received a vasopressin receptor agonist were not statistically significant when compared to those who were not treated with such agents after hemorrhagic shock. More data are needed to deduce certain conclusions.
PubMed: 37511756
DOI: 10.3390/jpm13071143 -
BioRxiv : the Preprint Server For... Jul 2023The small size and flexibility of G protein-coupled receptors (GPCRs) have long posed a significant challenge to determining their structures for research and...
The small size and flexibility of G protein-coupled receptors (GPCRs) have long posed a significant challenge to determining their structures for research and therapeutic applications. Single particle cryogenic electron microscopy (cryoEM) is often out of reach due to the small size of the receptor without a signaling partner. Crystallization of GPCRs in lipidic cubic phase (LCP) often results in crystals that may be too small and difficult to analyze using X-ray microcrystallography at synchrotron sources or even serial femtosecond crystallography at X-ray free electron lasers. Here, we determine the previously unknown structure of the human vasopressin 1B receptor (V1BR) using microcrystal electron diffraction (MicroED). To achieve this, we grew V1BR microcrystals in LCP and transferred the material directly onto electron microscopy grids. The protein was labeled with a fluorescent dye prior to crystallization to locate the microcrystals using cryogenic fluorescence microscopy, and then the surrounding material was removed using a plasma-focused ion beam to thin the sample to a thickness amenable to MicroED. MicroED data from 14 crystalline lamellae were used to determine the 3.2 Å structure of the receptor in the crystallographic space group 1. These results demonstrate the use of MicroED to determine previously unknown GPCR structures that, despite significant effort, were not tractable by other methods.
PubMed: 37461729
DOI: 10.1101/2023.07.05.547888