The zinc binding receptor GPR39 interacts with 5-HT1A and GalR(1) to form dynamic heteroreceptor complexes with signaling diversity

GPR39 is a class A G protein-coupled receptor involved in zinc binding and glucose homeostasis regulation, among other physiological processes. GPR39 was originally thought to be the receptor for obestatin peptide but this view has been challenged. However, activation of this receptor by zinc has been clearly established. Recent studies suggest that low GPR39 expression, due to deficient zinc levels, is involved in major depressive disorder. We have previously reported that zinc can alter receptor-receptor interactions and favor specific receptor interactions. In order to unravel the effect of zinc on specific G protein-coupled receptor association processes, we have performed FRET and co-immunopurification studies with GPR39 and 5-HT1A and GalR(1) which have been shown to dimerize. Our results suggest that zinc can modulate the formation of specific 5-HT1A-GPR39 and GalR(1)-5-HT1A-GPR39 heteroreceptor complexes under our experimental conditions.; We have analyzed the differences in signaling between the mono-homomeric receptors 5-HT1A, GalR(1) and GPR39 and the heteroreceptor complexes between them Our results show that the GPR39-5-HT1A heterocomplex has additive functionalities when compared to the monomeric-homomeric receptors upon receptor activation. In addition, the heterocomplex including also GalR(1) shows a different behavior, upon exposure to the same agonists. Furthermore, these processes appear to be regulated by zinc. These findings provide a rationale for the antidepressive effect widely described for zinc because pro-depressive heterocomplexes are predominant at low zinc concentration levels. (C) 2015 Elsevier B.V. All rights reserved.Peer ReviewedPostprint (author's final draft

Influence of limb dominance on body and jump asymmetries in elite female handball.

Handball is a team sport subjected to asymmetric actions that require high physical capacity demands on players. The development of large asymmetries could negatively affect sports performance. However, few studies have analyzed body composition and the force asymmetries in elite female handball players. The aim of this study was to analyze the presence of asymmetries based on limb dominance in body composition parameters and lower limb power in jumping performances in an elite women’s handball team. An entire elite women’s handball team, comprised by of 14 players, was analyzed. Dual X-ray Absorptiometry (DXA) and bioimpedance were used to analyze body composition. Force plates were used to evaluate jump performance. Results show the presence of differences between all the players in the different parameters of the CMJ jump. In addition, an asymmetry between the power of the dominant and non-dominant lower limb was observed between the players. The results show differences in muscle mass between the upper limbs, but not in the lower limbs in terms of both muscle and fat mass. However, there were no crossed asymmetries or significant differences between members based on dominance. The results suggest that the presence of asymmetries does not have to be one of the main parameters to be taken into account by coaches in elite athletes and to highlight the importance of including specific analyzes of body composition and sports performance in an individualized way. © 2023, The Author(s).No hubo financiación extern

A Role for Galanin N-Terminal Fragment (1–15) in Anxiety- and Depression-Related Behaviors in Rats.

Galanin (GAL) plays a role in mood regulation. In this study we analyzed the action of the active N-terminal fragment [GAL(1–15)] in anxiety- and depression-related behavioral tests in rats. Methods: The effect of GAL(1–15) was analyzed in the forced swimming test, tail suspension test, open field test, and light/dark test. The proximity of GAL1 and GAL2 receptors was examined with the proximity ligation assay (PLA). We tested the GAL receptors involved in GAL(1–15) effects with the GAL2 receptor antagonist M871 and with an in vivo model of siRNA GAL2 receptor knockdown or siRNA GAL1 receptor knockdown rats. The effects of GAL(1–15) were also studied in the cell line RN33B. Results: GAL(1–15) induced strong depression-like and anxiogenic-like effects in all the tests. These effects were stronger than the ones induced by GAL. The involvement of the GAL2 receptor was demonstrated with M871 and with the siRNA GAL2 receptor knockdown rats. The PLA indicated the possible existence of GAL1 and GAL2 heteroreceptor complexes in the dorsal hippocampus and especially in the dorsal raphe nucleus. In the siRNA GAL1 receptor knockdown rats the behavioral actions of GAL(1–15) disappeared, and in the siRNA GAL2 receptor knockdown rats the reductions of the behavioral actions of GAL(1–15) was linked to a disappearance of PLA. In the cell line RN33B, GAL(1–15) decreased 5-HT immunoreactivity more strongly than GAL. Conclusions: Our results indicate that GAL(1–15) exerts strong depression-related and anxiogenic-like effects and may give the basis for the development of drugs targeting GAL1 and GAL2 heteroreceptor complexes in the raphe-limbic system for the treatment of depression and anxiety

Galanin receptor 2-neuropeptide Y Y1 receptor interactions in the dentate gyrus are related with antidepressant-like effects.

Galanin (GAL) and the NPYY1 agonist play a role in mood regulation and both neuropeptides interact in several central functions. The present study examined the interaction between Galanin receptor 2 (GALR2) and Neuropeptide Y Y1 receptor (NPYY1R) in the dentate gyrus (DG) of the Hippocampus in relation to depression-like behavior. Using receptor autoradiography, in situ hybridization and in situ proximity ligation assay an interaction between GALR and NPYY1R was demonstrated in the DG probably involving the formation of GALR2-NPYY1R heteroreceptor complexes. These complexes were specifically observed in the polymorphic and subgranular subregions of the DG, where both receptors were found to colocalize. Moreover, this GALR2/NPYY1R interaction was linked to an enhancement of the antidepressive-like behavior mediated by NPYY1R in the forced swimming test. Specific cells populations within DG subregions may be involved in this behavioral effect since the coactivation of GALR2 and NPYY1R enhances the NPYY1R-mediated reduction in the number of c-Fos immunoreactive nuclei in the polymorphic region. These results indicate that GALR2/NPYY1R interactions can provide a novel integrative mechanism in DG in depression-related behavior and may give the basis for the development of drugs targeting GALR2/NPYY1R heteroreceptor complexes in the DG of the hippocampus for the treatment of depression

Long- term enhancements in antidepressant efficacy and neurogenesis: Effects of intranasal co- administration of neuropeptide Y 1 receptor (NPY1R) and galanin receptor 2 (GALR2) agonists in the ventral hippocampus

This study evaluates the sustained antidepressant- like effects and neurogenic potential of a 3- day intranasal co- administration regimen of galanin receptor 2 (GALR2) agonist M1145 and neuropeptide Y Y1 receptor (NPY1R) agonist [Leu31, Pro34]NPY in the ventral hippocampus of adult rats, with outcomes ana-lyzed 3 weeks post- treatment. Utilizing the forced swimming test (FST), we found that this co- administration significantly enhances antidepressant- like behaviors, an effect neutralized by the GALR2 antagonist M871, highlighting the syner-gistic potential of these neuropeptides in modulating mood- related behaviors. In situ proximity ligation assay (PLA) indicated a significant increase in GALR2/NPYY1R heteroreceptor complexes in the ventral hippocampal dentate gyrus, suggesting a molecular basis for the behavioral outcomes observed. Moreover, proliferating cell nuclear antigen (PCNA) immunolabeling revealed increased cell proliferation in the subgranular zone of the dentate gyrus, specifically in neuroblasts as evidenced by co- labeling with doublecortin (DCX), without affect-ing quiescent neural progenitors or astrocytes. The study also noted a significant uptick in the number of DCX- positive cells and alterations in dendritic morphol-ogy in the ventral hippocampus, indicative of enhanced neuronal differentiation and maturation.Funding for open access charge: Universidad de Málaga/CBU

Galanin receptor 2-neuropeptide Y Y1 receptor interactions in the amygdala lead to increased anxiolytic actions

Galanin (GAL) and Neuropeptide Y (NPY) are neuropeptides involved in behaviors associated with anxiety. Both neuropeptides interact in several central functions. However, the potential behavioral and cellular interactions between them in anxiety are unknown. GAL was found to act through GAL receptor 2 (GALR2) to enhance NPYY1 receptor (NPYY1R) mediated anxiolytic behaviors in rats. Using receptor autoradiography, c-fos expression and in situ proximity ligation assay, the medial paracapsular intercalated nuclei of the amygdala were determined to be a key area in the interaction probably involving the formation of GALR2/NPYY1R heteroreceptor complexes. In cell cultures co-stimulation of GALR2 and NPYY1R induced changes in the functions of these receptors. The changes involved a potentiation of the decrease in the phosphorylation of CREB induced by NPYY1R and a delay in the internalization of NPYY1R. These results indicate that GALR2/NPYY1R interactions can provide a novel integrative amygdaloid mechanism in anxiety

Enhancement of neurogenesis and cognition through intranasal co-delivery of galanin receptor 2 (GALR2) and neuropeptide Y receptor 1 (NPY1R) agonists: a potential pharmacological strategy for cognitive dysfunctions.

Background: Spatial memory deficits and reduced neuronal survival contribute to cognitive decline seen in the aging process. Current treatments are limited, emphasizing the need for innovative therapeutic strategies. This research explored the combined effects of intranasally co‑administered galanin receptor 2 (GALR2) and neuropeptide Y1 receptor (NPY1R) agonists, recognized for their neural benefits, on spatial memory, neuronal survival, and differentiation in adult rats. After intranasal co‑delivery of the GALR2 agonist M1145 and a NPY1R agonist to adult rats, spatial memory was tested with the object‑in‑place task 3 weeks later. We examined neuronal survival and differentiation by assessing BrdUIR profiles and doublecortin (DCX) labeled cells, respectively. We also used the GALR2 antagonist M871 to confirm GALR2’s crucial role in promoting cell growth. Results: Co‑administration improved spatial memory and increased the survival rate of mature neurons. The positive effect of GALR2 in cell proliferation was confirmed by the nullifying effects of its antagonist. The treatment boosted DCX‑labeled newborn neurons and altered dendritic morphology, increasing cells with mature dendrites. Conclusions: Our results show that intranasal co‑delivery of GALR2 and NPY1R agonists improves spatial memory, boosts neuronal survival, and influences neuronal differentiation in adult rats. The significant role of GALR2 is emphasized, suggesting new potential therapeutic strategies for cognitive decline.UMA18‑FEDERJA‑100 and ProyExcel_00613, Junta de Andalucía, Spain, to MN. Funding for open access charge: Universidad de Málaga. Cátedra Imbrain: Neurociencia integrada y bienestar to MN. The Swedish Medical Research Council, Sweden (62X‑00715‑50‑3) to KF, by Stiftelsen Olle Engkvist Byggmästare to KF, and by Hjärnfonden, Sweden (F02018‑0286), Hjärnfonden, Sweden (F02019‑0296), EMERGIA 2020‑39318 (Plan Andaluz de Investigación, Desarrollo e Innovación 2020), and CONSOLIDACION INVESTIGADORA (CNS2022‑136008, Programa Estatal para Desarrollar, Atraer y Retener Talento, del Plan Estatal de Investigación Científica, Técnica y de Innovación 20212023) and Karolinska Institutet Forskningsstiftelser, Sweden, to D.B.‑E

Unveiling the Synergistic Interplay of Neuropeptides for Novel Therapeutic Approaches in Neurodegenerative and Depressive Disorders.

The intricate relationship between hippocampal neurogenesis dysregulation and neurodegenerative diseases such as Alzheimer's, as well as depression, has sparked an urgent call for innovative therapeutic strategies. Our groundbreaking study delves into the interaction of Neuropeptide Y (NPY) and galanin (GAL) agonists, two neuromodulatory systems with a substantial presence in the limbic system, and their potential neurogenic impact on both the dorsal and ventral hippocampus. Through meticulous examination of the subchronic e"ects of NPY Y1 (Y1R) and GAL2 (GALR2) agonists on hippocampal cell proliferation, survival, and neuroprotective factor expression, we reveal a fascinating cascade of cellular responses. These include increased cell proliferation (PCNA), enhanced hippocampal cell survival (BrdU), and induction of neuroprotective factors (BDNF). Our functional assessment showcases the resulting improvements in spatial memory performance in the object-in-place task and antidepressant-like e"ects in the forced swimming test. These outcomes are attributed to the synergistic interaction between Y1R and GALR2 receptors, which promote neuronal survival and neurite outgrowth in hippocampal cells. This pioneering research paves the way for the development of heterobivalent agonist pharmacophores that target Y1R-GALR2 heterocomplexes. By acting on neuronal precursor cells in the dentate gyrus of the dorsal hippocampus, these novel compounds hold immense promise as transformative therapies for cognitive and a"ective impairments in neurodegenerative and depressive diseases.Supported by the Proy_Excel_2021_0613 (Junta de Andalucía) and Proyecto Puente (B4-2021) (UMA), Spain to MN. Swedish Medical Research Council, Sweden (62X-00715-50-3), to KF, by Stiftelsen Olle Engkvist Byggmästare to KF, and by Hjärnfonden, Sweden (F02018-0286), Hjärnfonden, Sweden (F02019-0296) and EMERGIA2020 (Junta de Andalucía), to DOBE. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Differential expression of muscarinic acetylcholine receptor subtypes in Jurkat cells and their signaling

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The M-5 muscarinic acetylcholine receptor third intracellular loop regulates receptor function and oligomerization

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