Functions of arginine vasopressin and its receptors: importance of human molecular genetics studies in bidirectional translational research.
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ABSTRACT:
SUBMITTER: Kreek MJ
PROVIDER: S-EPMC3762586 | biostudies-literature | 2011 Sep
REPOSITORIES: biostudies-literature
Publications
Functions of arginine vasopressin and its receptors: importance of human molecular genetics studies in bidirectional translational research.
Kreek Mary Jeanne MJ Zhou Yan Y Levran Orna O
Biological psychiatry 20110901 6
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Project description:The focus of this review is primarily on recent developments in bidirectional translational research on the addictions, within the Laboratory of the Biology of Addictive Diseases at The Rockefeller University. This review is subdivided into major interacting aspects, including (a) Investigation of neurobiological and molecular adaptations (e.g., in genes for the opioid receptors or endogenous neuropeptides) in response to cocaine or opiates, administered under laboratory conditions modeling chronic patterns of human self-exposure (e.g., chronic escalating "binge"). (b) The impact of such drug exposure on the hypothalamic-pituitary-adrenal (HPA) axis and interacting neuropeptidergic systems (e.g., opioid, orexin and vasopressin). (c) Molecular genetic association studies using candidate gene and whole genome approaches, to define particular systems involved in vulnerability to develop specific addictions, and response to pharmacotherapy. (d) Neuroendocrine challenge studies in normal volunteers and current addictive disease patients along with former addicts in treatment, to investigate differential pharmacodynamics and responsiveness of molecular targets, in particular those also investigated in the experimental and molecular genetic approaches as described above.
| S-EPMC2741728 | biostudies-literature
Project description:The blood-brain barrier (BBB) plays a significant pathophysiological role in multiple sclerosis (MS). Vasopressin (AVP) is released after brain injury and contributes to the inflammatory response. We propose that AVP may be modulating BBB permeability and hence affecting EAE clinical signs. Female Lewis rats were immunized s.c. with guinea-pig brain extract suspended in complete Freund's adjuvant. Prior to that, animals were subjected to Neurointermediate pituitary lobectomy (NIL) or treated with AVP receptor antagonist (conivaptan). BBB permeability assays were performed. Western blot for claudin-5 and histological analysis were performed in conivaptan treated EAE rats. EAE increase in BBB permeability to Evans blue was reverted by the NIL surgery. AVP receptor blockade reverted the EAE BBB hyperpermeability to Evans blue and 10-kDa FITC-dextran in almost all brain regions. Both, AVP low levels and AVP receptor blockade attenuated EAE clinical signs. Conivaptan reduced perivascular cuffs in EAE rats. A decrease in claudin-5 expression was observed in EAE rats and conivaptan treatment partially restored normal levels. Our data indicate that V1a and V2 AVP receptors can modulate BBB permeability and consequently are involved in the CNS inflammatory process during EAE. Future research is required to characterize the utility of vasopressin antagonist in MS treatment.
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Project description:Oxytocin (OXT) and arginine-vasopressin (AVP) play a key regulatory part in social and affiliative behaviors; two aspects highly compromised in Autism Spectrum Disorder (ASD). Furthermore, variants in the adjacent oxytocin-vasopressin gene regions have been found to be associated with ASD diagnosis and endophenotypes. This review focuses mainly on common OXTr single nucleotide polymorphisms (SNPs), AVPR1a microsatellites and AVPR1b polymorphisms in relation to the development of autism. Although these genes did not surface in genome-wide association studies, evidence supports the hypothesis that these receptors and their polymorphisms are widely involved in the regulation of social behavior, and in modulating neural and physiological pathways contributing to the etiology of ASD. With a specific focus on variants considered to be among the most prevalent in the development of ASD, these issues will be discussed in-depth and suggestions to approach inconsistencies in the present literature will be provided. Translational implications and future directions are deliberated from a short-term and a forward-looking perspective. While the scientific community has made significant progress in enhancing our understanding of ASD, more research is required for the ontology of this disorder to be fully elucidated. By supplementing information related to genetics, highlighting the differences across male and female sexes, this review provides a wider view of the current state of knowledge of OXTr and AVPr mechanisms of functioning, eventually addressing future research in the identification of further risk factors, to build new strategies for early interventions.
| S-EPMC5816822 | biostudies-literature
Project description:Background & aimsAcetaminophen-related acute liver injury and liver failure (ALF) result from ingestion of supratherapeutic quantities of this analgesic, frequently in association with other forms of substance abuse including alcohol, opioids, and cocaine. Thus, overdosing represents a unique high-risk behavior associated with other forms of drug use disorder.MethodsWe examined a series of 21 single nucleotide polymorphisms (SNPs) in 9 genes related to impulsivity and/or stress responsivity that may modify response to stress. Study subjects were 229 white patients admitted to tertiary care liver centers for ALF that was determined to be due to acetaminophen toxicity after careful review of historical and biochemical data. Identification of relevant SNPs used Sanger sequencing, TaqMan, or custom microarray. Association tests were carried out to compare genotype frequencies between patients and healthy white controls.ResultsThe mean age was 37 years, and 75.6% were female, with similar numbers classified as intentional overdose or unintentional (without suicidal intent, occurring for a period of several days, usually due to pain). There was concomitant alcohol abuse in 30%, opioid use in 33.6%, and use of other drugs of abuse in 30.6%. The genotype frequencies of 2 SNPs were found to be significantly different between the cases and controls, specifically SNP rs2282018 in the arginine vasopressin gene (AVP, odds ratio 1.64) and SNP rs11174811 in the AVP receptor 1A gene (AVPR1A, odds ratio 1.89), both of which have been previously linked to a drug use disorder diagnosis.ConclusionsPatients who develop acetaminophen-related ALF have increased frequency of gene variants that may cause altered stress responsivity, which has been shown to be associated with other unrelated substance use disorders.
| S-EPMC5404026 | biostudies-literature
Project description:In the last several decades, sophisticated experimental techniques have been used to determine the neurobiology of the oxytocin and vasopressin systems in rodents. Using a suite of methodologies, including electrophysiology, site-specific selective pharmacology, receptor autoradiography, in vivo microdialysis, and genetic and optogenetic manipulations, we have gained unprecedented knowledge about how these neuropeptides engage neural circuits to regulate behaviour, particularly social behaviour. Based on this foundation of information from rodent studies, we have started generating new hypotheses and frameworks about how the oxytocin and vasopressin systems could be acting in humans to influence social cognition. However, despite the recent inundation of publications using intranasal oxytocin in humans, we still know very little about the neurophysiology of the oxytocin system in primates more broadly. Furthermore, the design and analysis of these human studies have remained largely uninformed of the potential neurobiological mechanisms underlying their findings. Although the methods available for studying the oxytocin and vasopressin systems in humans are incredibly limited as a result of practical and ethical considerations, there is great potential to fill the gaps in our knowledge by developing better nonhuman primate models of social functioning. Behavioural pharmacology and receptor autoradiography have been used to study the oxytocin and vasopressin systems in nonhuman primates, and there is now great potential to broaden our understanding of the neurobiology of these systems. In this review, we discuss comparative findings in receptor distributions in rodents and primates, with perspectives on the functionality of conserved regions of expression in these distinct mammalian clades. We also identify specific ways that established technologies can be used to answer basic research questions in primates. Finally, we highlight areas of future research in nonhuman primates that are experimentally poised to yield critical insights into the anatomy, physiology and behavioural effects of the oxytocin system, given its remarkable translational potential.
| S-EPMC4886472 | biostudies-literature
Project description:There is a great deal of interest in personalized, individualized, or precision interventions for disease and health-risk mitigation. This is as true of nutrition-based intervention and prevention strategies as it is for pharmacotherapies and pharmaceutical-oriented prevention strategies. Essentially, technological breakthroughs have enabled researchers to probe an individual's unique genetic, biochemical, physiological, behavioral, and exposure profile, allowing them to identify very specific and often nuanced factors that an individual might possess, which may make it more or less likely that he or she responds favorably to a particular intervention (e.g., nutrient supplementation) or disease prevention strategy (e.g., specific diet). However, as compelling and intuitive as personalized nutrition might be in the current era in which data-intensive biomedical characterization of individuals is possible, appropriately and objectively vetting personalized nutrition strategies is not trivial and requires novel study designs and data analytical methods. These designs and methods must consider a very integrated use of the multiple contemporary biomedical assays and technologies that motivate them, which adds to their complexity. Single-subject or N-of-1 trials can be used to assess the utility of personalized interventions and, in addition, can be crafted in such a way as to accommodate the necessarily integrated use of many emerging biomedical technologies and assays. In this review, we consider the motivation, design, and implementation of N-of-1 trials in translational nutrition research that are meant to assess the utility of personalized nutritional strategies. We provide a number of example studies, discuss appropriate analytical methods given the complex data they generate and require, and consider how such studies could leverage integration of various biomarker assays and clinical end points. Importantly, we also consider the development of strategies and algorithms for matching nutritional needs to individual biomedical profiles and the issues surrounding them. Finally, we discuss the limitations of personalized nutrition studies, possible extensions of N-of-1 nutritional intervention studies, and areas of future research.
| S-EPMC6383767 | biostudies-literature
Project description:ObjectiveThe study aims to know the effect of electroacupuncture (EA) in maintenance of the homeostasis of the neuroendocrine system in hepatectomy rats and the involvement of arginine vasopressin (AVP) signaling in hypothalamus after EA was observed.Materials and methodsRats were randomly assigned to four groups, including the intact group, model group, sham-EA group, and EA group. EA was given during the perioperative period at the Zusanli (ST36) and Sanyinjiao (SP6) points after hepatectomy. The serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels were detected via radioimmunoassay. The expression of AVP, arginine vasopressin receptor 1a (AVPR1a), arginine vasopressin receptor 1b (AVPR1b), and glucocorticoid receptor (GR) was detected by Western blot after surgery.ResultsCompared with the intact group, the ACTH and CORT levels in the serum of model group were increased, whereas the ACTH and CORT levels were decreased in the EA group compared with the model group. Moreover, AVP and AVPR1b protein levels in the pituitary gland were increased in the model group and decreased in the EA group. Further, a distinct increase in the AVP and AVPR1a protein levels was observed in the model group, whereas they were significantly decreased in the EA group. Blockade of AVPR1b by nelivaptan reduced the increase of ACTH and CORT. D [Leu(4) , Lys(8) ] vasopressin can inhibit the effect of EA in rectification of the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis.ConclusionsEA application at ST36 and SP6 can ameliorate the hyperactivity of the HPA axis via AVP signaling during the perioperative period.
| S-EPMC5063097 | biostudies-literature
Project description:We describe the synthesis, pharmacological properties, and structures of antidiuretic agonists, arginine vasopressin (AVP) and [D-Arg(8)]-vasopressin (DAVP), and their inverso analogues. The structures of the peptides are studied based on micellar and liposomic models of cell membranes using CD spectroscopy. Additionally, three-dimensional structures in mixed anionic-zwitterionic micelles are obtained using NMR spectroscopy and molecular dynamics simulations. NMR data have shown that AVP and DAVP tend to adopt typical of vasopressin-like peptides β-turns: in the 2-5 and 3-6 fragments. The inverso-analogues also adopt β-turns in the 3-6 fragments. For this reason, their inactivity seems to be due to the difference in side chains orientations of Tyr(2), Phe(3), and Arg(8), important for interactions with the receptors. Again, the potent antidiuretic activity of DAVP can be explained by CD data suggesting differences in mutual arrangement of the aromatic side chains of Tyr(2) and Phe(3) in this peptide in liposomes rather than of native AVP. In the presence of liposomes, the smallest conformational changes of the peptides are noticed with DPPC and the largest with DPPG liposomes. This suggests that electrostatic interactions are crucial for the peptide-membrane interactions. We obtained similar, probably active, conformations of the antidiuretic agonists in the mixed DPC/SDS micelles (5:1) and in the mixed DPPC/DPPG (7:3) liposomes. Thus it can be speculated that the anionic-zwitterionic liposomes as well as the anionic-zwitterionic micelles, mimicking the eukaryotic cell membrane environment, partially restrict conformational freedom of the peptides and probably induce conformations resembling those of biologically relevant ones.
| S-EPMC4628624 | biostudies-literature
Project description:"Discovery" research about molecular markers for diagnosis, prognosis, or prediction of response to therapy has frequently produced results that were not reproducible in subsequent studies. What are the reasons, and can observational cohorts be cultivated to provide strong and reliable answers to those questions? ExperimentalSelected examples are used to illustrate: (i) what features of research design provide strength and reliability in observational studies about markers of diagnosis, prognosis, and response to therapy? (ii) How can those design features be cultivated in existing observational cohorts, for example, within randomized controlled clinical trial (RCT), other existing observational research studies, or practice settings like health maintenance organization (HMOs)?Examples include a study of RNA expression profiles of tumor tissue to predict prognosis of breast cancer, a study of serum proteomics profiles to diagnose ovarian cancer, and a study of stool-based DNA assays to screen for colon cancer. Strengths and weaknesses of observational study design features are discussed, along with lessons about how features that help assure strength might be "cultivated" in the future.By considering these examples and others, it may be possible to develop a process of "cultivating cohorts" in ongoing RCTs, observational cohort studies, and practice settings like HMOs that have strong features of study design. Such an effort could produce sources of data and specimens to reliably answer questions about the use of molecular markers in diagnosis, prognosis, and response to therapy.
| S-EPMC4378958 | biostudies-other
Project description:PURPOSE: Recently, arginine vasopressin (AVP) has been revealed to have diverse functional roles in nervous tissues beyond that of a vasoconstrictor. Several previous studies have indicated the existence of AVP in the retina, but the source of AVP has not been determined. The objective of the present study was to address the question of whether retinal cells have the ability to synthesize endogenous AVP to act in a paracrine or autocrine manner. METHODS: We used AVP-eGFP transgenic rats to find endogenous AVP-positive cells in the retina by immunohistochemistry with an AVP antibody and a GFP antibody. We also examined AVP mRNA and AVP receptor genes by reverse transcriptase (RT)-PCR of dissociated GFP-positive cells and whole retinas. RESULTS: Endogenous AVP-positive cells were found in the ganglion cell layer and inner nuclear layer of the retina of AVP-eGFP transgenic rats by immunohistochemistry. As indicated by the results of RT-PCR of dissociated GFP-positive cells, these cells have the ability to synthesize endogenous AVP, as well as transgenic AVP-eGFP. In addition, the V1a and V1b AVP receptors were found in the wild-type rat retina by whole retina RT-PCR, but the V2 receptor was not detectable. In dissociated AVP-eGFP-positive cells, no AVP receptor was detected by RT-PCR. Moreover, AVP secretion was not detected by stimulation with a high potassium (50 mM) solution. CONCLUSIONS: In the rat retina, we found retinal cells that have the ability to synthesize endogenous AVP, and that the retina possesses V1a and V1b AVP receptors. Taken together, these results suggest that the retina has an intrinsic AVP-synthesizing and -receiving mechanism that can operate in a paracrine manner via V1a and V1b receptors.
| S-EPMC3244476 | biostudies-literature