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PloS One 2017Pharmacoperones are small molecules that diffuse into cells and rescue misfolded, mistrafficked protein mutants, restoring their function. These substances act with high...
Pharmacoperones are small molecules that diffuse into cells and rescue misfolded, mistrafficked protein mutants, restoring their function. These substances act with high target specificity, serving as templates to fold (or refold) receptors, enzymes, ion channels or other proteins and enable them to pass the scrutiny of the cellular quality control system ("rescue"). In the present study we demonstrate that a rescued mutant (L83Q) of the vasopressin type 2 receptor (V2R), shows a strong bias for Gs coupling unlike the WT V2 receptor, which couples to both Gs and Gq/11. Failure of the mutant to couple to Gq/11 was not due to a limiting quantity of G-proteins since other Gq/11-coupled receptors (WT V2R, histamine receptor and muscarinic receptor) responded appropriately to their ligands. Transfection with DNA encoding Gq enabled the V2 receptor mutant to couple to this G protein, but only modestly compared with the WT receptor. Fourteen V2R mutant pharmacoperones, of multiple chemical classes, obtained from a high throughput screen of a 660,000 structure library, and one V2R peptidomimetic antagonist rescues L83Q. The rescued mutant shows similar bias with all pharmacoperones identified, suggesting that the bias is intrinsic to the mutant protein's structure, rather than due to the chemical class of the pharmacoperone. In the case of V2R mutant Y128S, rescue with a pharmacoperone revealed constitutive activity, also with bias for Gs, although both IP and cAMP were produced in response to agonist. These results suggest that particular rescued receptor mutants show functional characteristics that differ from the WT receptor; a finding that may be important to consider as pharmacoperones are developed as therapeutic agents.
Topics: Antidiuretic Hormone Receptor Antagonists; Cyclic AMP; GTP-Binding Protein alpha Subunits, Gq-G11; HeLa Cells; High-Throughput Screening Assays; Humans; Models, Molecular; Morpholines; Mutation; Receptors, Vasopressin; Small Molecule Libraries; Spiro Compounds
PubMed: 28767678
DOI: 10.1371/journal.pone.0181830 -
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 -
The Journal of International Medical... Apr 2018Sepsis is one of the most frequent causes of death among patients in intensive care units. Many therapeutic strategies have been assessed without the desired success... (Review)
Review
Sepsis is one of the most frequent causes of death among patients in intensive care units. Many therapeutic strategies have been assessed without the desired success rates. A key risk factor for death is hypotension due to vasodilatation with vascular hyposensitivity. However, the pathways underlying this process remain unclear. Endotoxemia induces inflammatory mediators, and this is followed by vasoplegia and decreased cardiac contractility. Although inhibition of these mediators diminishes mortality rates in animal models, this phenomenon has not been confirmed in humans. Downregulation of vasoconstrictive receptors such as angiotensin receptors, adrenergic and vasopressin receptors is seen in sepsis, which is associated with a hyporesponsiveness to vasoconstrictive mediators. Animal studies have verified that receptor downregulation is linked to the above-mentioned inflammatory mediators. Anti-inflammatory therapy with glucocorticoids reportedly improves responsiveness to catecholamines with higher survival in rats, although this has not been shown to be clinically significant in humans. Hence, there is an urgent need for in-depth studies investigating the underlying mechanisms of vasoplegia to allow for development of effective therapeutic strategies for the treatment of sepsis.
Topics: Animals; Humans; Inflammation Mediators; Shock, Septic; Vasoconstriction; Vasoplegia
PubMed: 29332515
DOI: 10.1177/0300060517743836 -
Journal of Cardiology Jul 2019Modulating neurohormonal imbalance is the cornerstone of successful therapy in patients with chronic heart failure with reduced ejection fraction (HFrEF). Plasma... (Review)
Review
Modulating neurohormonal imbalance is the cornerstone of successful therapy in patients with chronic heart failure with reduced ejection fraction (HFrEF). Plasma arginine vasopressin (AVP) levels are elevated in HFrEF and may contribute to disease progression by excess signaling at either the V1a or V2 receptors. The effects of V1a receptor antagonism are almost completely unexplored, but V1a signaling is closely related to that for angiotensin II and blocking that receptor deserves further study. Interfering with V2 signaling causes free water diuresis and improves congestion without worsening renal function when added to loop diuretics but alone did not improve outcomes when carried into the post-acute phase in one large study. Outcomes in chronic HFrEF are quite good while outcomes in acute HF remain poor. Therefore, further study of V2 or combined V1/V2 blockade of the effects of AVP would most likely yield positive results in patients with acute HF, perhaps especially as alternative, not adjunctive therapy to loop diuretics.
Topics: Antidiuretic Hormone Receptor Antagonists; Chronic Disease; Disease Progression; Female; Heart Failure; Humans; Male; Neurophysins; Protein Precursors; Receptors, Vasopressin; Sodium Potassium Chloride Symporter Inhibitors; Stroke Volume; Vasopressins
PubMed: 30904236
DOI: 10.1016/j.jjcc.2019.03.001 -
Hormones and Behavior Aug 2020Behavioral neuroendocrinology has a rich history of using diverse model organisms to elucidate general principles and evolution of hormone-brain-behavior relationships.... (Comparative Study)
Comparative Study
Behavioral neuroendocrinology has a rich history of using diverse model organisms to elucidate general principles and evolution of hormone-brain-behavior relationships. The oxytocin and vasopressin systems have been studied in many species, revealing their role in regulating social behaviors. Oxytocin and vasopressin receptors show remarkable species and individual differences in distribution in the brain that have been linked to diversity in social behaviors. New technologies allow for unprecedented interrogation of the genes and neural circuitry regulating behaviors, but these approaches often require transgenic models and are most often used in mice. Here we discuss seminal findings relating the oxytocin and vasopressin systems to social behavior with a focus on non-traditional animal models. We then evaluate the potential of using CRISPR/Cas9 genome editing to examine the roles of genes and enable circuit dissection, manipulation and activity monitoring of the oxytocin and vasopressin systems. We believe that it is essential to incorporate these genetic and circuit level techniques in comparative behavioral neuroendocrinology research to ensure that our field remains innovative and attractive for the next generation of investigators and funding agencies.
Topics: Animals; Animals, Genetically Modified; Biobehavioral Sciences; Brain; CRISPR-Cas Systems; Gene Editing; History, 21st Century; Mice; Oxytocin; Receptors, Oxytocin; Receptors, Vasopressin; Social Behavior; Vasopressins
PubMed: 32544402
DOI: 10.1016/j.yhbeh.2020.104780 -
Clinical and Experimental Nephrology Oct 2021Congenital nephrogenic diabetes insipidus (NDI) is primarily caused by loss-of-function mutations in the vasopressin type 2 receptor (V2R). Renal unresponsiveness to the... (Review)
Review
BACKGROUND
Congenital nephrogenic diabetes insipidus (NDI) is primarily caused by loss-of-function mutations in the vasopressin type 2 receptor (V2R). Renal unresponsiveness to the antidiuretic hormone vasopressin impairs aquaporin-2 (AQP2) water channel activity and water reabsorption from urine, resulting in polyuria. Currently available symptomatic treatments inadequately reduce patients' excessive amounts of urine excretion, threatening their quality of life. In the past 25 years, vasopressin/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) has been believed to be the most important signaling pathway for AQP2 activation. Although cAMP production without vasopressin is the reasonable therapeutic strategy for congenital NDI caused by V2R mutations, the efficacy of candidate drugs on AQP2 activation is far less than that of vasopressin.
RESULTS
Intracellular distribution and activity of PKA are largely controlled by its scaffold proteins, A-kinase anchoring proteins (AKAPs). Dissociating the binding of AKAPs and PKA significantly increased PKA activity in the renal collecting ducts and activated AQP2 phosphorylation and trafficking. Remarkably, the AKAPs-PKA disruptor FMP-API-1 increased transcellular water permeability in isolated renal collecting ducts to the same extent as vasopressin. Moreover, derivatives of FMP-API-1 possessed much more high potency. FMP-API-1/27 is the first low-molecular-weight compound to be discovered that can phosphorylate AQP2 more effectively than preexisting drug candidates.
CONCLUSION
AKAP-PKA disruptors are a promising therapeutic target for congenital NDI. In this article, we shall discuss the pathophysiological roles of PKA and novel strategies to activate PKA in renal collecting ducts.
Topics: A Kinase Anchor Proteins; Aminophenols; Animals; Aquaporin 2; Cell Membrane Permeability; Cyclic AMP-Dependent Protein Kinases; Diabetes Insipidus, Nephrogenic; Humans; Loss of Function Mutation; Phosphorylation; Receptors, Vasopressin; Signal Transduction; Vasopressins; Water
PubMed: 34224008
DOI: 10.1007/s10157-021-02108-6 -
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 -
Peptides Jun 2022The Avpr1a (V1a) and Avpr1b (V1b) receptor selective, vasopressin (AVP) analogue, Ac3IV has been shown to improve metabolism and pancreatic islet structure in diabetes...
The Avpr1a (V1a) and Avpr1b (V1b) receptor selective, vasopressin (AVP) analogue, Ac3IV has been shown to improve metabolism and pancreatic islet structure in diabetes and insulin resistance. The present study further investigates these actions by assessing the ability of Ac3IV to protect against pancreatic islet architectural disturbances induced by hydrocortisone (HC) treatment in transgenic Ins1;Rosa26-eYFP mice, that possess beta-cell lineage tracing capabilities. HC intervention increased (p < 0.001) energy intake but reduced (p < 0.01) body weight gain, with no impact of Ac3IV. All HC mice had reduced (p < 0.05) circulating glucose, but plasma insulin and glucagon concentrations remained unchanged. However, HC mice presented with increased (p < 0.001) pancreatic insulin content, which was further augmented by Ac3IV. In addition, Ac3IV treatment countered HC-induced increases in islet-, beta- and alpha-cell areas (p < 0.01), as well as promoting islet number towards control levels. This was accompanied by reduced (p < 0.05) beta-cell growth, but enhanced (p < 0.001) alpha-cell proliferation. There were no changes in islet cell apoptotic rates in any of the groups of HC mice, but co-expression of CK19 with insulin in pancreatic ductal cells was reduced by Ac3IV. Assessment of beta-cell lineage revealed that Ac3IV partially protected against HC-mediated de-differentiation of mature beta-cells, whilst also decreasing (p < 0.01) beta- to alpha-cell transdifferentiation. Our data indicate that sustained activation of V1a and V1b receptors exerts positive islet cell transition effects to help retain beta-cell identity in HC mice.
Topics: Animals; Cell Lineage; Diabetes Mellitus, Experimental; Hydrocortisone; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Mice; Receptors, Vasopressin; Vasopressins
PubMed: 35202749
DOI: 10.1016/j.peptides.2022.170772 -
Current Opinion in Psychiatry Jul 2019The aim of this study was to provide an update on medication development efforts for alcohol use disorder (AUD) by reviewing recently published (past 2 years) human... (Review)
Review
PURPOSE OF REVIEW
The aim of this study was to provide an update on medication development efforts for alcohol use disorder (AUD) by reviewing recently published (past 2 years) human studies that evaluated medications' effects on alcohol-related outcomes.
RECENT FINDINGS
Forty-five publications were found suitable for this review. A variety of compounds have been tested in the past 2 years as potential pharmacological options for AUD, including medications that act on multiple targets (topiramate, aripiprazole, quetiapine), calcium channels (gabapentin), gamma-Aminobutyric acid receptors (baclofen, diazepam), glutamate receptors (ifenprodil, memantine, glycine), nicotinic acetylcholine receptors (varenicline, mecamylamine), α1 adrenergic receptors (prazosin, doxazosin), neuroendocrine pathways (oxytocin, a vasopressin receptor 1b antagonist, a ghrelin receptor inverse agonist) and others (samidorphan, ibudilast, N-acetylcysteine, citoline). Important findings and limitations regarding the effects of these medications on alcohol-related outcomes are discussed.
SUMMARY
There is a critical need to increase the armamentarium of medications for AUD. Human laboratory studies may help screen and prioritize promising targets and compounds before running large clinical trials. Given the complexity of AUD and the heterogeneity of afflicted patients, future studies should also investigate potential moderators and predictors of response to each pharmacological intervention.
Topics: Adrenergic alpha-1 Receptor Antagonists; Alcohol-Related Disorders; Cholinergic Agonists; GABA Modulators; GABA-B Receptor Agonists; Humans; Nicotinic Agonists; Treatment Outcome
PubMed: 31107292
DOI: 10.1097/YCO.0000000000000519 -
International Journal of Molecular... Nov 2017Under physiological conditions, excessive loss of water through the urine is prevented by the release of the antidiuretic hormone arginine-vasopressin (AVP) from the... (Review)
Review
Under physiological conditions, excessive loss of water through the urine is prevented by the release of the antidiuretic hormone arginine-vasopressin (AVP) from the posterior pituitary. In the kidney, AVP elicits a number of cellular responses, which converge on increasing the osmotic reabsorption of water in the collecting duct. One of the key events triggered by the binding of AVP to its type-2 receptor (AVPR2) is the exocytosis of the water channel aquaporin 2 (AQP2) at the apical membrane the principal cells of the collecting duct. Mutations of either AVPR2 or AQP2 result in a genetic disease known as nephrogenic diabetes insipidus, which is characterized by the lack of responsiveness of the collecting duct to the antidiuretic action of AVP. The affected subject, being incapable of concentrating the urine, presents marked polyuria and compensatory polydipsia and is constantly at risk of severe dehydration. The molecular bases of the disease are fully uncovered, as well as the genetic or clinical tests for a prompt diagnosis of the disease in newborns. A real cure for nephrogenic diabetes insipidus (NDI) is still missing, and the main symptoms of the disease are handled with s continuous supply of water, a restrictive diet, and nonspecific drugs. Unfortunately, the current therapeutic options are limited and only partially beneficial. Further investigation in vitro or using the available animal models of the disease, combined with clinical trials, will eventually lead to the identification of one or more targeted strategies that will improve or replace the current conventional therapy and grant NDI patients a better quality of life. Here we provide an updated overview of the genetic defects causing NDI, the most recent strategies under investigation for rescuing the activity of mutated AVPR2 or AQP2, or for bypassing defective AVPR2 signaling and restoring AQP2 plasma membrane expression.
Topics: Aquaporin 2; Arginine Vasopressin; Diabetes Insipidus, Nephrogenic; Exocytosis; Humans; Mutation; Receptors, Vasopressin
PubMed: 29125546
DOI: 10.3390/ijms18112385