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Molecular and Cellular Neurosciences Jun 2024The axons containing arginine vasopressin (AVP) from the hypothalamus innervate a variety of structures including the cerebral cortex, thalamus, hippocampus and...
The axons containing arginine vasopressin (AVP) from the hypothalamus innervate a variety of structures including the cerebral cortex, thalamus, hippocampus and amygdala. A plethora amount of evidence indicates that activation of the V subtype of the vasopressin receptors facilitates anxiety-like and fear responses. As an essential structure involved in fear and anxiety responses, the amygdala, especially the lateral nucleus of amygdala (LA), receives glutamatergic innervations from the auditory cortex and auditory thalamus where high density of V receptors have been detected. However, the roles and mechanisms of AVP in these two important areas have not been determined, which prevents the understanding of the mechanisms whereby V activation augments anxiety and fear responses. Here, we used coronal brain slices and studied the effects of AVP on neuronal activities of the auditory cortical and thalamic neurons. Our results indicate that activation of V receptors excited both auditory cortical and thalamic neurons. In the auditory cortical neurons, AVP increased neuronal excitability by depressing multiple subtypes of inwardly rectifying K (Kir) channels including the Kir2 subfamily, the ATP-sensitive K channels and the G protein-gated inwardly rectifying K (GIRK) channels, whereas activation of V receptors excited the auditory thalamic neurons by depressing the Kir2 subfamily of the Kir channels as well as activating the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and a persistent Na channel. Our results may help explain the roles of V receptors in facilitating fear and anxiety responses. Categories: Cell Physiology.
PubMed: 38942186
DOI: 10.1016/j.mcn.2024.103951 -
Cureus May 2024Vasopressin infusion is commonly used in intensive care settings during states of advanced vasodilatory shock for its vasoconstrictive properties. Vasopressin also acts...
Vasopressin infusion is commonly used in intensive care settings during states of advanced vasodilatory shock for its vasoconstrictive properties. Vasopressin also acts on renal tubular cell receptors in the collecting ducts of kidneys to allow for water reabsorption. The sudden discontinuation of vasopressin infusion can lead to the development of transient diabetes insipidus (DI) with classic findings of polyuria, dilute urine, and hypernatremia. We report the case of a 59-year-old male who underwent an emergent bedside cricothyrotomy procedure secondary to papillary carcinoma of the thyroid and subsequently developed septic shock requiring initiation of vasopressin infusion for hemodynamic support. He remained on vasopressin for five days before the infusion was discontinued after clinical improvement. Within 12 hours of vasopressin discontinuation, the patient developed polyuria (> 3 L/day urine output) with volumes as high as 1 L per hour. His serum sodium levels increased more than 10 mmol/L from 137 to 149 mmol/L. This case is unique from prior reports, as our patient was without any neurological or neurosurgical comorbidities that would predispose him to an organic central cause of DI. Furthermore, the patient's large-volume diuresis and serum abnormalities spontaneously self-improved within 24 hours without significant medical intervention. In conclusion, this case adds to a growing number of reports of transient DI following vasopressin withdrawal, demonstrating the need to formally recognize this occurrence as a potential consequence of vasopressin use in intensive care settings.
PubMed: 38939271
DOI: 10.7759/cureus.61253 -
International Journal of Molecular... Jun 2024The neuropeptide vasopressin is known for its regulation of osmotic balance in mammals. Arginine vasotocin (AVT) is a non-mammalian homolog of this neuropeptide that is...
The neuropeptide vasopressin is known for its regulation of osmotic balance in mammals. Arginine vasotocin (AVT) is a non-mammalian homolog of this neuropeptide that is present in fish. Limited information suggested that vasopressin and its homologs may also influence reproductive function. In the present study, we investigated the direct effect of AVT on spermatogenesis, using zebrafish as a model organism. Results demonstrate that AVT and its receptors (, , , and ) are expressed in the zebrafish brain and testes. The direct action of AVT on spermatogenesis was investigated using an ex vivo culture of mature zebrafish testes for 7 days. Using histological, morphometric, and biochemical approaches, we observed direct actions of AVT on zebrafish testicular function. AVT treatment directly increased the number of spermatozoa in an androgen-dependent manner, while reducing mitotic cells and the proliferation activity of type B spermatogonia. The observed stimulatory action of AVT on spermiogenesis was blocked by flutamide, an androgen receptor antagonist. The present results support the novel hypothesis that AVT stimulates short-term androgen-dependent spermiogenesis. However, its prolonged presence may lead to diminished spermatogenesis by reducing the proliferation of spermatogonia B, resulting in a diminished turnover of spermatogonia, spermatids, and spermatozoa. The overall findings offer an insight into the physiological significance of vasopressin and its homologs in vertebrates as a contributing factor in the multifactorial regulation of male reproduction.
Topics: Animals; Zebrafish; Male; Spermatogenesis; Vasotocin; Testis; Receptors, Vasopressin; Zebrafish Proteins; Spermatozoa; Cell Proliferation; Spermatogonia
PubMed: 38928267
DOI: 10.3390/ijms25126564 -
Psychiatry and Clinical Neurosciences Jun 2024Vasopressin or arginine-vasopressin (AVP) is a neuropeptide molecule known for its antidiuretic effects and serves to regulate plasma osmolality and blood pressure. The...
Vasopressin or arginine-vasopressin (AVP) is a neuropeptide molecule known for its antidiuretic effects and serves to regulate plasma osmolality and blood pressure. The existing literature suggests that AVP plays a multifaceted-though less well-known-role in the central nervous system (CNS), particularly in relation to the pathophysiology and treatment of mood disorders. Animal models have demonstrated that AVP is implicated in regulating social cognition, affiliative and prosocial behaviors, and aggression, often in conjunction with oxytocin. In humans, AVP is implicated in mood disorders through its effects on the hypothalamic-pituitary-adrenal (HPA) axis as well as on the serotoninergic and glutamatergic systems. Measuring plasma AVP has yielded interesting but mixed results in mood and stress-related disorders. Recent advances have led to the development of copeptin as a stable and reliable surrogate biomarker for AVP. Another interesting but relatively unexplored issue is the interaction between the osmoregulatory system and mood disorder pathophysiology, given that psychotropic medications often cause dysregulation of AVP receptor expression or signaling that can subsequently lead to clinical syndromes like syndrome of inappropriate diuresis and diabetes insipidus. Finally, pharmaceutical trials of agents that act on V1a and V1b receptor antagonists are still underway. This narrative review summarizes: (1) the neurobiology of the vasopressinergic system in the CNS; (2) the interaction between AVP and the monoaminergic and glutamatergic pathways in the pathophysiology and treatment of mood disorders; (3) the iatrogenic AVP dysregulation caused by psychotropic medications; and (4) the pharmaceutical development of AVP receptor antagonists for the treatment of mood disorders.
PubMed: 38923665
DOI: 10.1111/pcn.13703 -
Science Signaling Jun 2024The stabilization of different active conformations of G protein-coupled receptors is thought to underlie the varying efficacies of biased and balanced agonists. Here,...
The stabilization of different active conformations of G protein-coupled receptors is thought to underlie the varying efficacies of biased and balanced agonists. Here, profiling the activation of signal transducers by angiotensin II type 1 receptor (ATR) agonists revealed that the extent and kinetics of β-arrestin binding exhibited substantial ligand-dependent differences, which were lost when receptor internalization was inhibited. When ATR endocytosis was prevented, even weak partial agonists of the β-arrestin pathway acted as full or near-full agonists, suggesting that receptor conformation did not exclusively determine β-arrestin recruitment. The ligand-dependent variance in β-arrestin translocation was much larger at endosomes than at the plasma membrane, showing that ligand efficacy in the β-arrestin pathway was spatiotemporally determined. Experimental investigations and mathematical modeling demonstrated how multiple factors concurrently shaped the effects of agonists on endosomal receptor-β-arrestin binding and thus determined the extent of functional selectivity. Ligand dissociation rate and G protein activity had particularly strong, internalization-dependent effects on the receptor-β-arrestin interaction. We also showed that endocytosis regulated the agonist efficacies of two other receptors with sustained β-arrestin binding: the V vasopressin receptor and a mutant β-adrenergic receptor. In the absence of endocytosis, the agonist-dependent variance in β-arrestin2 binding was markedly diminished. Our results suggest that endocytosis determines the spatiotemporal bias in GPCR signaling and can aid in the development of more efficacious, functionally selective compounds.
Topics: Endocytosis; Humans; Signal Transduction; Receptor, Angiotensin, Type 1; beta-Arrestins; HEK293 Cells; Receptors, Vasopressin; Receptors, Adrenergic, beta-2; Endosomes; Receptors, G-Protein-Coupled; Animals; Ligands; Protein Binding; Protein Transport
PubMed: 38917219
DOI: 10.1126/scisignal.adi0934 -
Proceedings of the National Academy of... Jun 2024Oxytocin plays a critical role in regulating social behaviors, yet our understanding of its function in both neurological health and disease remains incomplete....
Oxytocin plays a critical role in regulating social behaviors, yet our understanding of its function in both neurological health and disease remains incomplete. Real-time oxytocin imaging probes with spatiotemporal resolution relevant to its endogenous signaling are required to fully elucidate oxytocin's role in the brain. Herein, we describe a near-infrared oxytocin nanosensor (nIROXT), a synthetic probe capable of imaging oxytocin in the brain without interference from its structural analogue, vasopressin. nIROXT leverages the inherent tissue-transparent fluorescence of single-walled carbon nanotubes (SWCNT) and the molecular recognition capacity of an oxytocin receptor peptide fragment to selectively and reversibly image oxytocin. We employ these nanosensors to monitor electrically stimulated oxytocin release in brain tissue, revealing oxytocin release sites with a median size of 3 µm in the paraventricular nucleus of C57BL/6 mice, which putatively represents the spatial diffusion of oxytocin from its point of release. These data demonstrate that covalent SWCNT constructs, such as nIROXT, are powerful optical tools that can be leveraged to measure neuropeptide release in brain tissue.
Topics: Animals; Oxytocin; Mice; Optical Imaging; Vasopressins; Nanotubes, Carbon; Brain; Mice, Inbred C57BL; Male; Receptors, Oxytocin; Spectroscopy, Near-Infrared
PubMed: 38905241
DOI: 10.1073/pnas.2314795121 -
Acta Pharmacologica Sinica Jun 2024The vasopressin V receptor (VR) is a validated therapeutic target for autosomal dominant polycystic kidney disease (ADPKD), with tolvaptan being the first FDA-approved...
The vasopressin V receptor (VR) is a validated therapeutic target for autosomal dominant polycystic kidney disease (ADPKD), with tolvaptan being the first FDA-approved antagonist. Herein, we used Gaussian accelerated molecular dynamics simulations to investigate the spontaneous binding of tolvaptan to both active and inactive VR conformations at the atomic-level. Overall, the binding process consists of two stages. Tolvaptan binds initially to extracellular loops 2 and 3 (ECL2/3) before overcoming an energy barrier to enter the pocket. Our simulations result highlighted key residues (e.g., R181, Y205, F287, F178) involved in this process, which were experimentally confirmed by site-directed mutagenesis. This work provides structural insights into tolvaptan-VR interactions, potentially aiding the design of novel antagonists for VR and other G protein-coupled receptors.
PubMed: 38902502
DOI: 10.1038/s41401-024-01325-5 -
PloS One 2024Arginine vasopressin (AVP) and oxytocin (OT) are well-known as neuropeptides that regulate various social behaviors in mammals. However, little is known about their role...
Arginine vasopressin (AVP) and oxytocin (OT) are well-known as neuropeptides that regulate various social behaviors in mammals. However, little is known about their role in mouse female sexual behavior. Thus, we investigated the role of AVP (v1a and v1b) and OT receptors on female sexual behavior. First, we devised a new apparatus, the bilevel chamber, to accurately observe female mouse sexual behavior. This apparatus allowed for a more precisely measurement of lordosis as receptivity and rejection-like behavior (newly defined in this study), a reversed expression of proceptivity. To address our research question, we evaluated female sexual behavior in mice lacking v1a (aKO), v1b (bKO), both v1a and v1b (dKO), and OT (OTRKO) receptors. aKO females showed decreased rejection-like behavior but a normal level of lordosis, whereas bKO females showed almost no lordosis and no change in rejection-like behavior. In addition, dKO females showed normal lordosis levels, suggesting that the v1b receptor promotes lordosis, but not necessarily, while the v1a receptor latently suppresses it. In contrast, although OTRKO did not influence lordosis, it significantly increased rejection-like behavior. In summary, the present results demonstrated that the v1a receptor inhibits proceptivity and receptivity, whereas the v1b and OT receptors facilitate receptivity and proceptivity, respectively.
Topics: Animals; Female; Receptors, Vasopressin; Receptors, Oxytocin; Sexual Behavior, Animal; Mice; Mice, Knockout; Male; Oxytocin; Mice, Inbred C57BL; Arginine Vasopressin
PubMed: 38900750
DOI: 10.1371/journal.pone.0304703 -
Structure (London, England : 1993) Jun 2024Arrestins interact with phosphorylated G protein-coupled receptors (GPCRs) and regulate the homologous desensitization and internalization of GPCRs. The gate loop in...
Arrestins interact with phosphorylated G protein-coupled receptors (GPCRs) and regulate the homologous desensitization and internalization of GPCRs. The gate loop in arrestins is a critical region for both stabilization of the basal state and interaction with phosphorylated receptors. We investigated the roles of specific residues in the gate loop (K292, K294, and H295) using β-arrestin-1 and phosphorylated C-tail peptide of vasopressin receptor type 2 (V2Rpp) as a model system. We measured the binding affinity of V2Rpp and analyzed conformational dynamics of β-arrestin-1. Our results suggest that K294 plays a critical role in the interaction with V2Rpp without influencing the overall conformation of the V2Rpp-bound state. The residues K292 and H295 contribute to the stability of the polar core in the basal state and form a specific conformation of the finger loop in the V2Rpp-bound state.
PubMed: 38889722
DOI: 10.1016/j.str.2024.05.014 -
BioRxiv : the Preprint Server For... Mar 2024The arginine vasopressin 1b receptor (Avpr1b) plays an important role in social behaviors including social learning, memory, and aggression, and is known to be a...
The arginine vasopressin 1b receptor (Avpr1b) plays an important role in social behaviors including social learning, memory, and aggression, and is known to be a specific marker for the cornu ammonis area 2 (CA2) regions of the hippocampus. The fasciola cinereum (FC) is an anatomical region in which Avpr1b expressing neurons are prominent, but the functional roles of the FC have yet to be investigated. Surprisingly, the FC is absent in the inbred BTBR T+tf/J (BTBR) mouse strain used to study core behavioral deficits of autism. Here, we characterized and compared transcriptomic expression profiles using single nucleus RNA sequencing and identified 7 different subpopulations and heterogeneity within the dorsal CA2 (dCA2) and FC. involved in autism spectrum disorder, is more highly expressed in the FC. Using Hiplex hybridization, we examined the neuroanatomical locations of these subpopulations in the proximal and distal regions of the hippocampus. Anterograde tracing of Avpr1b neurons specific for the FC showed projections to the IG, dCA2, lacunosum molecular layer of CA1, dorsal fornix, septofibrial nuclei, and intermediate lateral septum (iLS). In contrast to the dCA2, inhibition of Avpr1b neurons in the FC by the inhibitory DREADD system during behavioral testing did not impair social memory. We performed single nucleus RNA sequencing in the dCA2 region and compared between wildtype (WT) and BTBR mice. We found that transcriptomic profiles of dCA2 neurons between BTBR and WT mice are very similar as they did not form any unique clusters; yet, we found there were differentially expressed genes between the dCA2s of BTBR and WT mice. Overall, this is a comprehensive study of the comparison of Avpr1b neuronal subpopulations between the FC and dCA2. The fact that FC is absent in BTBR mice, a mouse model for autism spectrum disorder, suggests that the FC may play a role in understanding neuropsychiatric disease.
PubMed: 38883723
DOI: 10.1101/2024.03.21.586108