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Journal of Molecular Modeling Jan 2022We have developed two ligand- and receptor-based computational approaches to study the physicochemical properties relevant to the biological activity of vasopressin V2...
We have developed two ligand- and receptor-based computational approaches to study the physicochemical properties relevant to the biological activity of vasopressin V2 receptor (V2R) antagonist and eventually to predict the expected binding mode to V2R. The obtained quantitative structure activity relationship (QSAR) model showed a correlation of the antagonist activity with the hydration energy (E), the polarizability (P), and the calculated partial charge on atom N7 (q6) of the common substructure. The first two descriptors showed a positive contribution to antagonist activity, while the third one had a negative contribution. V2R was modeled and further relaxed on a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocoline (POPC) membrane by molecular dynamics simulations. The receptor antagonist complexes were guessed by molecular docking, and the stability of the most relevant structures was also evaluated by molecular dynamics simulations. As a result, amino acid residues Q96, W99, F105, K116, F178, A194, F307, and M311 were identified with the probably most relevant antagonist-receptor interactions on the studied complexes. The proposed QSAR model could explain the molecular properties relevant to the antagonist activity. The contributions to the antagonist-receptor interaction appeared also in agreement with the binding mode of the complexes obtained by molecular docking and molecular dynamics. These models will be used in further studies to look for new V2R potential antagonist molecules.
Topics: Algorithms; Amino Acid Sequence; Antidiuretic Hormone Receptor Antagonists; Binding Sites; Chemical Phenomena; Cluster Analysis; Ligands; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Protein Binding; Quantitative Structure-Activity Relationship; Receptors, Vasopressin; Structure-Activity Relationship
PubMed: 34997307
DOI: 10.1007/s00894-021-05022-6 -
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 -
International Journal of Molecular... May 2021Tolvaptan is a recently available diuretic that blocks arginine vasopressin receptor 2 in the renal collecting duct. Its diuretic mechanism involves selective water... (Review)
Review
Tolvaptan is a recently available diuretic that blocks arginine vasopressin receptor 2 in the renal collecting duct. Its diuretic mechanism involves selective water reabsorption by affecting the water reabsorption receptor aquaporin 2. Given that liver cirrhosis patients exhibit hyponatremia due to their pseudo-aldosteronism and usage of natriuretic agents, a sodium maintaining agent, such as tolvaptan, is physiologically preferable. However, large scale studies indicating the patients for whom this would be effective and describing management under its use have been insufficient. The appropriate management of cirrhosis patients treated with tolvaptan should be investigated. In the present review, we collected articles investigating the effectiveness of tolvaptan and factors associated with survival and summarized their management reports. Earlier administration of tolvaptan before increasing the doses of natriuretic agents is recommended because this may preserve effective arterial blood volume.
Topics: Humans; Liver Cirrhosis; Tolvaptan
PubMed: 34070416
DOI: 10.3390/ijms22115582 -
Handbook of Clinical Neurology 2021Diabetes insipidus (DI) is a syndrome characterized by the persistent excretion of abnormally large volumes of dilute urine. It can be caused by any of four... (Review)
Review
Diabetes insipidus (DI) is a syndrome characterized by the persistent excretion of abnormally large volumes of dilute urine. It can be caused by any of four fundamentally different abnormalities: deficient production of the antidiuretic hormone, arginine vasopressin (AVP) by magnocellular neurons that form the posterior pituitary (hypothalamic DI); impaired renal effects of AVP (nephrogenic DI); reduced AVP secretion due to excessive water intake (primary polydipsia); or degradation of AVP by placental vasopressinase (gestational DI). Each type of DI can be caused or potentiated by other disorders. Hypothalamic and nephrogenic DI can also be caused by mutation of the gene that encodes the AVP prohormone, the AVP-2 receptors in the kidney, or the aquaporin-2 water channels that mediate antidiuresis. Familial hypothalamic DI is usually transmitted in an autosomal dominant mode, but autosomal recessive or X-linked recessive forms also exist. Familial nephrogenic DI is usually transmitted in an X-linked recessive mode but can also be autosomal recessive or dominant. Hence the mode of inheritance does not always indicate the type of DI. Indirect methods of differential diagnosis are also unreliable and the pituitary MRI signal is diminished in both types of familial DI. Thus the determination of plasma AVP and/or the response to desmopressin therapy plus gene sequencing provides the best basis for effective management and family counseling.
Topics: Diabetes Insipidus; Diabetes Insipidus, Nephrogenic; Diabetes Mellitus; Diagnosis, Differential; Female; Humans; Placenta; Pregnancy; Receptors, Vasopressin
PubMed: 34238460
DOI: 10.1016/B978-0-12-820683-6.00017-8 -
Frontiers in Endocrinology 2020The identification of structurally related hypothalamic hormones that regulate blood pressure and diuresis (vasopressin, VP; CYFQNCPRG-NH) or lactation and uterine... (Comparative Study)
Comparative Study Review
The identification of structurally related hypothalamic hormones that regulate blood pressure and diuresis (vasopressin, VP; CYFQNCPRG-NH) or lactation and uterine contraction (oxytocin, OT; CYIQNCPLG-NH) was a major advance in neuroendocrinology, recognized in the award of the Nobel Prize for Chemistry in 1955. Furthermore, the discovery of central actions of VP and OT as regulators of reproductive and social behavior in humans and other mammals has broadened interest in these neuropeptides beyond physiology into psychology. VP/OT-type neuropeptides and their G-protein coupled receptors originated in a common ancestor of the Bilateria (Urbilateria), with invertebrates typically having a single VP/OT-type neuropeptide and cognate receptor. Gene/genome duplications followed by gene loss gave rise to variety in the number of VP/OT-type neuropeptides and receptors in different vertebrate lineages. Recent advances in comparative transcriptomics/genomics have enabled discovery of VP/OT-type neuropeptides in an ever-growing diversity of invertebrate taxa, providing new opportunities to gain insights into the evolution of VP/OT-type neuropeptide function in the Bilateria. Here we review the comparative physiology of VP/OT-type neuropeptides in invertebrates, with roles in regulation of reproduction, feeding, and water/salt homeostasis emerging as common themes. For example, we highlight recent reports of roles in regulation of oocyte maturation in the sea-squirt , extraoral feeding behavior in the starfish and energy status and dessication resistance in ants. Thus, VP/OT-type neuropeptides are pleiotropic regulators of physiological processes, with evolutionarily conserved roles that can be traced back to Urbilateria. To gain a deeper understanding of the evolution of VP/OT-type neuropeptide function it may be necessary to not only determine the actions of the peptides but also to characterize the transcriptomic/proteomic/metabolomic profiles of cells expressing VP/OT-type precursors and/or VP/OT-type receptors within the framework of anatomically and functionally identified neuronal networks. Furthermore, investigation of VP/OT-type neuropeptide function in a wider range of invertebrate species is now needed if we are to determine how and when this ancient signaling system was recruited to regulate diverse physiological and behavioral processes in different branches of animal phylogeny and in contrasting environmental contexts.
Topics: Animals; Evolution, Molecular; Humans; Invertebrates; Neuropeptides; Oxytocin; Vasopressins
PubMed: 32362874
DOI: 10.3389/fendo.2020.00225 -
Comparative Biochemistry and... Aug 2021The authors recently reported the presence and distribution of oxytocin/vasopressin-like peptide in Portunus pelagicus as well as demonstrated its function to inhibit...
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.
Topics: Animals; Brachyura; Central Nervous System; Female; Gene Expression Profiling; Ovary; Oxytocin; Peptides; Phylogeny; RNA, Messenger; Receptors, Peptide; Receptors, Vasopressin; Vasopressins
PubMed: 34004320
DOI: 10.1016/j.cbpa.2021.110983 -
European Journal of Pharmacology Aug 2020The vasopressin V receptor belongs to the superfamily of G protein-coupled receptors (GPCRs) and is a potential drug target for water balance disorders such as...
The vasopressin V receptor belongs to the superfamily of G protein-coupled receptors (GPCRs) and is a potential drug target for water balance disorders such as polycystic kidney disease. Traditionally, the discovery of novel agents for the vasopressin V receptor has been guided by evaluating their receptor affinity, largely ignoring the binding kinetics. However, the latter is receiving increasing attention in the drug research community and has been proved to be a more complete descriptor of the dynamic process of ligand-receptor interaction. Herein we aim to revisit the molecular basis of ligand-vasopressin V receptor interaction from the less-investigated kinetic perspective. A homogenous time-resolved fluorescence resonance energy transfer (TR-FRET) assay was set up and optimized, which enabled accurate kinetic profiling of unlabeled vasopressin V receptor ligands. Receptor occupancy profiles of two representative antagonists with distinct target residence time were simulated. Their functional effects were further explored in cAMP assays. Our results showed that the antagonist with longer receptor residence time (lixivaptan) displayed sustained target occupancy than the antagonist with shorter receptor residence time (mozavaptan). In accordance, lixivaptan displayed insurmountable antagonism and wash-resistant inhibitory effect on the cellular cAMP level, while not so for mozavaptan. Together, our data provide evidence that binding kinetics, next to their affinity, offers additional information for the dynamic process of ligand-receptor interaction. Hopefully, this study may lead to more kinetics-directed medicinal chemistry efforts and aid the design and discovery of different-in-class of vasopressin V receptor ligands for clinical applications.
Topics: Animals; Antidiuretic Hormone Receptor Antagonists; CHO Cells; Cricetulus; Cyclic AMP; HEK293 Cells; Humans; Kinetics; Ligands; Protein Binding; Receptors, Vasopressin
PubMed: 32360346
DOI: 10.1016/j.ejphar.2020.173157 -
Acta Medica Indonesiana Jul 2022This is a literature review of the use of aquaretic in patients with acute decompensated heart failure (ADHF), including the physiologic function of vasopressin and its... (Review)
Review
This is a literature review of the use of aquaretic in patients with acute decompensated heart failure (ADHF), including the physiologic function of vasopressin and its mechanism of action in heart failure patients, and aquaretic drugs with their respective risks and benefits.Vasopressin is one of several hormones that can cause hyponatremia and worsen congestion in ADHF patients. Aquaretics are a class of drugs that have an antagonistic effect on vasopressin receptors, especially V2R. Aquaretics use in ADHF patients can provide relief for congestive symptoms with no serious adverse effects. In-depth additional understanding regarding aquaretics may be useful for clinical judgments in treating ADHF patients.
Topics: Acute Disease; Heart Failure; Humans; Receptors, Vasopressin; Vasopressins
PubMed: 36156485
DOI: No ID Found -
Brain Structure & Function Mar 2023The nonapeptide system modulates numerous social behaviors through oxytocin and vasopressin activation of the oxytocin receptor (OXTR) and vasopressin receptor (AVPR1A)...
The nonapeptide system modulates numerous social behaviors through oxytocin and vasopressin activation of the oxytocin receptor (OXTR) and vasopressin receptor (AVPR1A) in the brain. OXTRs and AVPR1As are widely distributed throughout the brain and binding densities exhibit substantial variation within and across species. Although OXTR and AVPR1A binding distributions have been mapped for several rodents, this system has yet to be characterized in the spiny mouse (Acomys cahirinus). Here we conducted receptor autoradiography and in situ hybridization to map distributions of OXTR and AVPR1A binding and Oxtr and Avpr1a mRNA expression throughout the basal forebrain and midbrain of male and female spiny mice. We found that nonapeptide receptor mRNA is diffuse throughout the forebrain and midbrain and does not always align with OXTR and AVPR1A binding. Analyses of sex differences in brain regions involved in social behavior and reward revealed that males exhibit higher OXTR binding densities in the lateral septum, bed nucleus of the stria terminalis, and anterior hypothalamus. However, no association with gonadal sex was observed for AVPR1A binding. Hierarchical clustering analysis further revealed that co-expression patterns of OXTR and AVPR1A binding across brain regions involved in social behavior and reward differ between males and females. These findings provide mapping distributions and sex differences in nonapeptide receptors in spiny mice. Spiny mice are an excellent organism for studying grouping behaviors such as cooperation and prosociality, and the nonapeptide receptor mapping here can inform the study of nonapeptide-mediated behavior in a highly social, large group-living rodent.
Topics: Animals; Female; Male; Receptors, Oxytocin; RNA, Messenger; Basal Forebrain; Mesencephalon; Oxytocin; Receptors, Vasopressin; Vasopressins; Social Behavior; Murinae
PubMed: 36271259
DOI: 10.1007/s00429-022-02581-z -
Annual Review of Pharmacology and... Jan 2020The ability to regulate water movement is vital for the survival of cells and organisms. In addition to passively crossing lipid bilayers by diffusion, water transport... (Review)
Review
The ability to regulate water movement is vital for the survival of cells and organisms. In addition to passively crossing lipid bilayers by diffusion, water transport is also driven across cell membranes by osmotic gradients through aquaporin water channels. There are 13 aquaporins in human tissues, and of these, aquaporin-2 (AQP2) is the most highly regulated water channel in the kidney: The expression and trafficking of AQP2 respond to body volume status and plasma osmolality via the antidiuretic hormone, vasopressin (VP). Dysfunctional VP signaling in renal epithelial cells contributes to disorders of water balance, and research initially focused on regulating the major cAMP/PKA pathway to normalize urine concentrating ability. With the discovery of novel and more complex signaling networks that regulate AQP2 trafficking, promising therapeutic targets have since been identified. Several strategies based on data from preclinical studies may ultimately translate to the care of patients with defective water homeostasis.
Topics: Animals; Aquaporin 2; Cell Membrane; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Humans; Kidney; Neurophysins; Protein Precursors; Signal Transduction; Vasopressins; Water; Water-Electrolyte Balance; Water-Electrolyte Imbalance
PubMed: 31561739
DOI: 10.1146/annurev-pharmtox-010919-023654