Functional μ-opioid-galanin receptor heteromers in the ventral tegmental area

The neuropeptide galanin has been shown to interact with the opioid system. More specifically, galanin counteracts the behavioral effects of the systemic administration of μ-opioid receptor (MOR) agonists. Yet the mechanism responsible for this galanin-opioid interaction has remained elusive. Using biophysical techniques in mammalian transfected cells, we found evidence for selective heteromerization of MOR and the galanin receptor subtype Gal1 (Gal1R). Also in transfected cells, a synthetic peptide selectively disrupted MOR-Gal1R heteromerization as well as specific interactions between MOR and Gal1R ligands: a negative cross talk, by which galanin counteracted MAPK activation induced by the endogenous MOR agonist endomorphin-1, and a cross-antagonism, by which a MOR antagonist counteracted MAPK activation induced by galanin. These specific interactions, which represented biochemical properties of the MOR-Gal1R heteromer, could then be identified in situ in slices of rat ventral tegmental area (VTA) with MAPK activation and two additional cell signaling pathways, AKT and CREB phosphorylation. Furthermore, in vivo microdialysis experiments showed that the disruptive peptide selectively counteracted the ability of galanin to block the dendritic dopamine release in the rat VTA induced by local infusion of endomorphin-1, demonstrating a key role of MOR-Gal1R heteromers localized in the VTA in the direct control of dopamine cell function and their ability to mediate antagonistic interactions between MOR and Gal1R ligands. The results also indicate that MOR-Gal1R heteromers should be viewed as targets for the treatment of opioid use disorders

Cross-communication between Gi and Gs in a G-protein-coupled receptor heterotetramer guided by a receptor C-terminal domain

BACKGROUND: G-protein-coupled receptor (GPCR) heteromeric complexes have distinct properties from homomeric GPCRs, giving rise to new receptor functionalities. Adenosine receptors (A1R or A2AR) can form A1R-A2AR heteromers (A1-A2AHet), and their activation leads to canonical G-protein-dependent (adenylate cyclase mediated) and -independent (β-arrestin mediated) signaling. Adenosine has different affinities for A1R and A2AR, allowing the heteromeric receptor to detect its concentration by integrating the downstream Gi- and Gs-dependent signals. cAMP accumulation and β-arrestin recruitment assays have shown that, within the complex, activation of A2AR impedes signaling via A1R. RESULTS: We examined the mechanism by which A1-A2AHet integrates Gi- and Gs-dependent signals. A1R blockade by A2AR in the A1-A2AHet is not observed in the absence of A2AR activation by agonists, in the absence of the C-terminal domain of A2AR, or in the presence of synthetic peptides that disrupt the heteromer interface of A1-A2AHet, indicating that signaling mediated by A1R and A2AR is controlled by both Gi and Gs proteins. CONCLUSIONS: We identified a new mechanism of signal transduction that implies a cross-communication between Gi and Gs proteins guided by the C-terminal tail of the A2AR. This mechanism provides the molecular basis for the operation of the A1-A2AHet as an adenosine concentration-sensing device that modulates the signals originating at both A1R and A2AR

Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer

Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A2AR agonists, but also A2AR antagonists, decrease the affinity and intrinsic efficacy of D2R agonists and the affinity of D2R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A2AR-D2R heteromers as heterotetramers, constituted by A2AR and D2R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A2AR antagonists behaved as A2AR agonists and decreased D2R function in the brain

Interactions between intracellular domains as key determinants of the quaternary structure and function of receptor heteromers

G protein-coupled receptor (GPCR) heteromers are macromolecular complexes with unique functional properties different from those of its individual protomers. Little is known about what determines the quaternary structure of GPCR heteromers resulting in their unique functional properties. In the present study, using Resonance Energy Transfer (RET) techniques in experiments with mutated receptors, we provide for the first time clear evidence for a key role of intracellular domains in the determination of the quaternary structure of GPCR heteromers between adenosine A2A, cannabinoid CB1 and dopamine D2 receptors. In these interactions, arginine-rich epitopes form salt bridges with phosphorylated serine or threonine residues from CK1/2 consensus sites. Each receptor (A2A, CB1 and D2) was found to include two evolutionary conserved intracellular domains to establish selective electrostatic interactions with intracellular domains of the other two receptors, indicating that these particular electrostatic interactions constitute a general mechanism for receptor heteromerization. Mutation experiments indicated that the interactions of the intracellular domains of the CB1 receptor with A2A and D2 receptors are fundamental for the correct formation of the quaternary structure needed for the function (mitogen-activated protein kinase, MAPK, signaling) of the A2A-CB1-D2 receptor heteromers. Analysis of MAPK signaling in striatal slices of CB1 receptor KO mice and wild-type littermates supported the existence of A1-CB1-D2 receptor heteromer in the brain. These findings allowed us to propose the first molecular model of the quaternary structure of a receptor heteromultime

Tabanque : revista pedagógica

Resumen tomado de la publicaciónResumen y palabras clave disponibles en español y en inglésEl Ayuntamiento de Zafra, a través de su Universidad Popular, lleva desde 1999 hasta la actualidad, trabajando por la integración e inclusión social de la población inmigrante, la sensibilización de la población acogedora, la educación en valores y la interculturalidad, con una metodología práctica, funcional, innovadora, realizada por sus verdaderos protagonistas: la ciudadanía; y con unos excelentes resultados. Aun así, todavía la propia Universidad Popular de Zafra sigue marcándose nuevos retos y objetivos que vienen regidos por las propias necesidades que presentan las personas, tanto las que son de aquí como las que provienen de allí, para que aprendamos de otras culturas y costumbres, y para enseñar y compartir las nuestras, en una sociedad globalizada, con muchas diferencias, con muchos problemas… Se trata de aprender en conjunto a ser mejores en el siglo que nos ha tocado vivir, el s. XXI.ES

Definition of Intervention Contexts in Social Casework Practice: Predictor Variables

[eng] The main objective of the present study is to examine the set of predictor variables which facilitate a greater level of intervention in the definition of the context of change in Social Casework Practice. We have based our research on the level of interventions shown by the sample of Community Social Services Social Workers on the Island of Mallorca in the scope of the Inventory for the Analysis of the Relation of Help between the Social Worker and the Client during the Phase of Study and Evaluation of the Analysis of the Problem Situation ( Cardona, 2008). In this study, we have examined an intentional non-probabilistic sample of 73.04 per cent of the total number of social workers who work on projects involving direct contact with the individual or family (N = 84). Ratings for the two aspects under analysis (importance and accomplishment) have been obtained, the lineal relationship has been tested through Spearman's lineal correlation coefficient and the Z conformity test for proportions has been carried out, as well as analysis of variance. Finally, we have undertaken an analysis of regression models in seven areas of study, with the aim of identifying the predictor variables showing greatest levels of accomplishment linked to the characteristics of the professionals, the characteristics of the services and context features. Additionally, an analysis of co-linearity between variables has been carried out with the aim of refining the variables which show constant correlations. The increases in the levels of intervention do not depend on the organisation of the social services, nor are they determined by the working rules of the said services. Data show that the increase in the levels of intervention are related to the behaviour of three characteristics of the professionals: postgraduate training and/or updating professional qualifications, the development of reflective practice based on case discussion in their work team and, finally, the professionals' expectations of self-efficacy

Integration in the Fourier domain for restoration of a function from its slope : comparison of four methods

Altres ajuts: European Community project CTB556-01-4175.In some measurement techniques the profile, f(x), of a function should be obtained from the data on measured slope f'(x) by integration. The slope is measured in a given set of points, and from these data we should obtain the profile with the highest possible accuracy. Most frequently, the integration is carried out by numerical integration methods [Press et al., Numerical Recipes: The Art of Scientific Computing (Cambridge U. Press, Cambridge, 1987)] that assume different kinds of polynomial approximation of data between sampling points. We propose the integration of the function in the Fourier domain, by which the most-accurate interpolation is automatically carried out. Analysis of the integration methods in the Fourier domain permits us to easily study and compare the methods' behavior

Influence of the incident angle in the performance of Liquid Crystal on Silicon displays

In this paper we experimentally analyze the performance of a twisted nematic liquid crystal on silicon (LCoS) display as a function of the angle of incidence of the incoming beam. These are reflective displays that can be configured to produce amplitude or phase modulation by properly aligning external polarization elements. But we demonstrate that the incident angle plays an important role in the selection of the polarization configuration. We performed a Mueller matrix polarimetric analysis of the display that demonstrates that the recently reported depolarization effect observed in this type of displays is also dependant on the incident angle.We acknowledge financial support from Spanish Ministerio de Educación y Ciencia (FIS2006-13037-C02-01 and 02) and Generalitat de Catalunya (2006PIV00011). C. Iemmi acknowledges support from Univ. Buenos Aires and CONICET (Argentina)

Anamorphic and spatial frequency dependent phase modulation on liquid crystal displays: optimization of the modulation diffraction efficiency

In this work we present experimental evidence of an anamorphic and spatial frequency dependent phase modulation in commercially available twisted nematic liquid crystal spatial light modulators. We have found that the phase modulation depth depends on the magnitude of the local spatial frequency component along the horizontal direction. Along the vertical direction the phase modulation depth does not depend on the spatial frequency. This phenomenon is related with the electronics driving the device and in no way related to liquid crystal physics. It causes a reduction of the optical efficiency of a diffractive optical element displayed onto this type of modulator. We present an algorithm to correct this effect and more efficiently display a diffractive optical element. We apply it to the particular case of a Fresnel lens. Experimental results that confirm the improvements in the efficiency of the displayed diffractive lens are presented.This work was supported by Ministerio de Ciencia y Tecnología, Spain (projects BFM2003-06273-C02-01/FIS and BFM2003-06273-C02-02/FIS). C. Iemmi acknowledges the support of Universidad de Buenos Aires and CONICET (Argentina), and Generalitat de Catalunya, project ACI 2003-42 (Spain)