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Current Neuropharmacology 2024Major depressive disorder (MDD) is a stress-related mental disorder with a lifetime prevalence of 20% and, thus, is one of the most prevalent mental health disorders...
Major depressive disorder (MDD) is a stress-related mental disorder with a lifetime prevalence of 20% and, thus, is one of the most prevalent mental health disorders worldwide. Many studies with a large number of patients support the notion that abnormalities of the hypothalamus-pituitaryadrenal (HPA) axis are crucial for the development of MDD. Therefore, a number of strategies and drugs have been investigated to target different components of the HPA axis: 1) corticotrophinreleasing hormone (CRH) 1 receptor antagonists; 2) vasopressin V receptor antagonists, 3) glucocorticoid receptor antagonists, and 4) FKBP5 antagonists. Until now, V receptor antagonists and GR antagonists have provided the most promising results. Preclinical data also support antagonists of FKBP5, which seem to be partly responsible for the effects exerted by ketamine. However, as HPA axis alterations occur only in a subset of patients, specific treatment approaches that target only single components of the HPA axis will be effective only in this subset of patients. Companion tests that measure the function of the HPA axis and identify patients with an impaired HPA axis, such as the dexamethasone-corticotrophin-releasing hormone (dex-CRH) test or the molecular dexamethasonesuppression (mDST) test, may match the patient with an effective treatment to enable patient-tailored treatments in terms of a precision medicine approach.
Topics: Humans; Depressive Disorder, Major; Depression; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Corticotropin-Releasing Hormone
PubMed: 37581323
DOI: 10.2174/1570159X21666230811141557 -
Structure (London, England : 1993) Nov 2023Arrestin-dependent G protein-coupled receptor (GPCR) signaling pathway is regulated by the phosphorylation state of GPCR's C-terminal domain, but the molecular bases of...
Arrestin-dependent G protein-coupled receptor (GPCR) signaling pathway is regulated by the phosphorylation state of GPCR's C-terminal domain, but the molecular bases of arrestin:receptor interaction are to be further illuminated. Here we investigated the impact of phosphorylation on the conformational features of the C-terminal region from three rhodopsin-like GPCRs, the vasopressin V2 receptor (V2R), the growth hormone secretagogue or ghrelin receptor type 1a (GHSR), and the β2-adernergic receptor (β2AR). Using phosphomimetic variants, we identified pre-formed secondary structure elements, or short linear motifs (SLiMs), that undergo specific conformational transitions upon phosphorylation. Of importance, such conformational transitions appear to favor arrestin-2 binding. Hence, our results suggest a model in which the phosphorylation-dependent structuration of the GPCR C-terminal regions would modulate arrestin binding and therefore signaling outcomes in arrestin-dependent pathways.
Topics: Arrestin; Phosphorylation; Receptors, G-Protein-Coupled; Signal Transduction; Rhodopsin
PubMed: 37669668
DOI: 10.1016/j.str.2023.08.011 -
Comprehensive Psychoneuroendocrinology Nov 2023In this article, I am going through my scientific and personal journey using my work on oxytocin as a compass. I recount how my scientific questions were shaped over the... (Review)
Review
In this article, I am going through my scientific and personal journey using my work on oxytocin as a compass. I recount how my scientific questions were shaped over the years, and how I studied them through the lens of different fields ranging from linguistics and neuroscience to comparative and population genomics in a wide range of vertebrate species. I explain how my evolutionary findings and proposal for a universal gene nomenclature in the oxytocin-vasotocin ligand and receptor families have impacted relevant fields, and how my studies in the oxytocin and vasotocin system in songbirds, humans and non-human primates have led me to now be testing intranasal oxytocin as a candidate treatment for speech deficits. I also discuss my projects on the neurobiology of dance and where oxytocin fits in the picture of studying speech and dance in parallel. Lastly, I briefly communicate the challenges I have been facing as a woman and an international scholar in science and academia, and my personal ways to overcome them.
PubMed: 38108035
DOI: 10.1016/j.cpnec.2023.100193 -
British Journal of Pharmacology Aug 2023Autism spectrum disorders (ASDs) are diagnosed in 1/100 children worldwide, based on two core symptoms: deficits in social interaction and communication, and stereotyped... (Review)
Review
Autism spectrum disorders (ASDs) are diagnosed in 1/100 children worldwide, based on two core symptoms: deficits in social interaction and communication, and stereotyped behaviours. G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors that transduce extracellular signals to convergent intracellular signalling and downstream cellular responses that are commonly dysregulated in ASD. Despite hundreds of GPCRs being expressed in the brain, only 23 are genetically associated with ASD according to the Simons Foundation Autism Research Initiative (SFARI) gene database: oxytocin OTR; vasopressin V and V ; metabotropic glutamate mGlu and mGlu ; GABA ; dopamine D , D and D ; serotoninergic 5-HT ; β -adrenoceptor; cholinergic M ; adenosine A and A ; angiotensin AT ; cannabinoid CB ; chemokine CX CR1; orphan GPR37 and GPR85; and olfactory OR1C1, OR2M4, OR2T10 and OR52M1. Here, we review the therapeutic potential of these 23 GPCRs, as well as 5-HT and 5-HT , for ASD. For each GPCR, we discuss its genetic association, genetic and pharmacological manipulation in animal models, pharmacopoeia for core symptoms of ASD and rank them based on these factors. Among these GPCRs, we highlight D , 5-HT , CB , OTR and V as the more promising targets for ASD. We discuss that the dysregulation of GPCRs and their signalling is a convergent pathological mechanism of ASD. Their therapeutic potential has only begun as multiple GPCRs could mitigate ASD.
PubMed: 37574491
DOI: 10.1111/bph.16216 -
ELife Oct 2023The vasopressin type 2 receptor (VR) is an essential G protein-coupled receptor (GPCR) in renal regulation of water homeostasis. Upon stimulation, the VR activates Gα...
The vasopressin type 2 receptor (VR) is an essential G protein-coupled receptor (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 imply 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.
Topics: beta-Arrestins; Receptors, Vasopressin; Arrestins; beta-Arrestin 1; Endosomes; GTP-Binding Proteins; Vasopressins
PubMed: 37855711
DOI: 10.7554/eLife.87754 -
Frontiers in Endocrinology 2023
PubMed: 37854180
DOI: 10.3389/fendo.2023.1279895 -
Turkish Journal of Anaesthesiology and... Aug 2023Vasoplegic syndrome (VS) is defined as low systemic vascular resistance, normal or high cardiac output, and resistant hypotension unresponsive to vasopressor agents and...
Vasoplegic syndrome (VS) is defined as low systemic vascular resistance, normal or high cardiac output, and resistant hypotension unresponsive to vasopressor agents and intravenous volume. VS is a frequently encountered complication in cardiovascular and transplantation surgery, burns, trauma, pancreatitis, and sepsis. The basis of the pathophysiology is associated with an imbalance of vasodilator and vasoconstrictive structure in vascular smooth muscle cells and is highly complex. The pathogenesis of VS has several mechanisms, including overproduction of iNO, stimulation of ATP-dependent K+ channels and NF-κB, and vasopressin receptor 1A (V1A-receptor) down-regulation. Available treatments involve volume and inotropes administration, vasopressin, methylene blue, hydroxocobalamin, Ca++, vitamin C, and thiamine, and should also restore vascular tone and improve vasoplegia. Other treatments could include angiotensin II, corticosteroids, NF-κB inhibitor, ATP-dependent K+ channel blocker, indigo carmine, and hyperbaric oxygen therapy. Despite modern advances in treatment, the mortality rate is still 30-50%. It is challenging for an anaesthesiologist to consider this syndrome's diagnosis and manage its treatment. Our review aims to review the diagnosis, predisposing factors, pathophysiology, treatment, and anaesthesia approach of VS during anaesthesia and to suggest a treatment algorithm.
PubMed: 37587654
DOI: 10.4274/TJAR.2023.221093 -
The Journal of Physiology Dec 2023Aquaporin-2 (AQP2) water channels are proteins that are recycled between intracellular vesicles and the apical plasma membrane in renal collecting ducts....
Aquaporin-2 (AQP2) water channels are proteins that are recycled between intracellular vesicles and the apical plasma membrane in renal collecting ducts. Lipopolysaccharide-responsive beige-like anchor protein (LRBA) is a protein kinase A (PKA) anchoring protein that creates compartmentalized PKA signalling responsible for AQP2 phosphorylation. In response to increased plasma osmolality, vasopressin/cyclic adenosine monophosphate (cAMP)/PKA signalling phosphorylates AQP2, promoting AQP2 trafficking into the apical plasma membrane and increasing water reabsorption from urine. However, the molecular mechanisms by which LRBA mediates vasopressin-induced AQP2 phosphorylation remain unknown. To investigate AQP2 intracellular localization and phosphorylation status in vivo, a density gradient ultracentrifugation technique was combined with an in situ proximity ligation assay, super-resolution structured illumination microscopy and immunoelectron microscopy. Most of the AQP2 was localized on the recycling endosome in the presence of tolvaptan, a vasopressin type 2 receptor (V2R) antagonist. Desmopressin, a V2R agonist, phosphorylated AQP2, translocating it from the recycling endosome to the apical plasma membrane. In contrast, LRBA was constitutively localized at the recycling endosome. Therefore, LRBA and AQP2 were well colocalized in the absence of vasopressin stimulation. The loss of LRBA/PKA signalling by Lrba knockout impaired vasopressin-induced AQP2 phosphorylation, resulting in AQP2 retention at the recycling endosome. Defective AQP2 trafficking caused low urinary concentrating ability in Lrba mice. The LRBA-PKA complex created compartmentalized PKA signalling at the recycling endosome, which facilitated AQP2 phosphorylation in response to vasopressin. KEY POINTS: Membrane proteins are continuously internalized into the endosomal system via endocytosis, after which they are either recycled back to the plasma membrane or degraded at the lysosome. In T cells, lipopolysaccharide-responsive beige-like anchor protein (LRBA) binds directly to the cytotoxic T lymphocyte antigen 4 (CTLA-4), a checkpoint immune molecule, to prevent CTLA-4 lysosomal degradation and promote its vesicle recycling. LRBA has different physiological functions in renal collecting ducts. LRBA and aquaporin-2 (AQP2) water channels were colocalized on the recycling endosome in vivo in the absence of the anti-diuretic hormone vasopressin. LRBA promoted vasopressin-induced AQP2 trafficking, increasing water reabsorption from urine via AQP2. LRBA determined renal responsiveness to vasopressin at recycling endosomes. LRBA is a ubiquitously expressed anchor protein. LRBA signalosomes might regulate membrane trafficking of several constitutively recycled proteins at recycling endosomes.
Topics: Mice; Animals; Aquaporin 2; CTLA-4 Antigen; Lipopolysaccharides; Protein Transport; Vasopressins; Endosomes; Antidiuretic Hormone Receptor Antagonists; Cyclic AMP-Dependent Protein Kinases; Water; Phosphorylation; Kidney Tubules, Collecting
PubMed: 37860942
DOI: 10.1113/JP285188 -
Endocrine Nov 2023Tolvaptan, a selective vasopressin V2-receptor antagonist, is approved for the treatment of SIADH-related hyponatremia, but its use is limited. The starting dose is...
PURPOSE
Tolvaptan, a selective vasopressin V2-receptor antagonist, is approved for the treatment of SIADH-related hyponatremia, but its use is limited. The starting dose is usually 15 mg/day, but recent clinical experience suggests a lower starting dose (<15 mg/day) to reduce the risk of sodium overcorrection. However, long-term low-dose efficacy and safety has not been explored, so far. Aim of our study is to characterize safety and efficacy of long-term SIADH treatment with low-dose Tolvaptan.
METHODS
We retrospectively evaluated 11 patients receiving low-dose Tolvaptan (<15 mg/day) for chronic SIADH due to neurological, idiopathic and neoplastic causes. Plasma sodium levels were measured before and 1, 3, 5, 15 and 30 days after starting Tolvaptan and then at 3-month intervals. Anamnestic and clinical data were collected.
RESULTS
Mean time spanned 27.3 ± 29.8 months (range 6 months-7 years). Mean plasma sodium levels were within normal range 1, 3 and 6 months after starting Tolvaptan as well as after 1, 2, 3, 5 and 7 years of therapy. Neither osmotic demyelination syndrome nor overcorrection were observed. Plasma sodium levels normalization was associated with beneficial clinical effects. Neurological patients obtained seizures disappearance, improvement in neurological picture and good recovery from rehabilitation. Neoplastic patients were able to start chemotherapy and improved their general condition. Patients did not show hypernatremia during long-term follow-up and reported mild thirst and pollakiuria.
CONCLUSIONS
The present study shows that long-term low-dose Tolvaptan is safe and effective in SIADH treatment. No cases of overcorrection were documented and mild side effects were reported.
Topics: Humans; Tolvaptan; Inappropriate ADH Syndrome; Antidiuretic Hormone Receptor Antagonists; Retrospective Studies; Benzazepines; Hyponatremia; Sodium
PubMed: 37507553
DOI: 10.1007/s12020-023-03457-w -
Clinical Kidney Journal Aug 2023Despite its discovery more than 150 years ago, the cause of primary hypertension remains unknown. Most studies suggest that hypertension involves genetic, congenital or... (Review)
Review
Despite its discovery more than 150 years ago, the cause of primary hypertension remains unknown. Most studies suggest that hypertension involves genetic, congenital or acquired risk factors that result in a relative inability of the kidney to excrete salt (sodium chloride) in the kidneys. Here we review recent studies that suggest there may be two phases, with an initial phase driven by renal vasoconstriction that causes low-grade ischemia to the kidney, followed by the infiltration of immune cells that leads to a local autoimmune reaction that maintains the renal vasoconstriction. Evidence suggests that multiple mechanisms could trigger the initial renal vasoconstriction, but one way may involve fructose that is provided in the diet (such as from table sugar or high fructose corn syrup) or produced endogenously. The fructose metabolism increases intracellular uric acid, which recruits NADPH oxidase to the mitochondria while inhibiting AMP-activated protein kinase. A drop in intracellular ATP level occurs, triggering a survival response. Leptin levels rise, triggering activation of the sympathetic central nervous system, while vasopressin levels rise, causing vasoconstriction in its own right and stimulating aldosterone production via the vasopressin 1b receptor. Low-grade renal injury and autoimmune-mediated inflammation occur. High-salt diets can amplify this process by raising osmolality and triggering more fructose production. Thus, primary hypertension may result from the overactivation of a survival response triggered by fructose metabolism. Restricting salt and sugar and hydrating with ample water may be helpful in the prevention of primary hypertension.
PubMed: 37529651
DOI: 10.1093/ckj/sfad058