The Experts below are selected from a list of 4701 Experts worldwide ranked by ideXlab platform
Susan R. George - One of the best experts on this subject based on the ideXlab platform.
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Δ-Tetrahydrocannabinol Increases Dopamine D1-D2 Receptor Heteromer and Elicits Phenotypic Reprogramming in Adult Primate Striatal Neurons.
iScience, 2019Co-Authors: Ahmed Hasbi, Bertha K. Madras, Jack Bergman, Stephen J. Kohut, Zhicheng Lin, Sarah L. Withey, Susan R. GeorgeAbstract:Long-term cannabis users manifest deficits in dopaminergic functions, reflecting Δ9-tetrahydrocannabinol (THC)-induced neuroadaptive dysfunctional dopamine signaling, similar to those observed upon dopamine D1-D2 Heteromer activation. The molecular mechanisms remain largely unknown. We show evolutionary and regional differences in D1-D2 Heteromer abundance in mammalian striatum. Importantly, chronic THC increased the number of D1-D2 Heteromer-expressing neurons, and the number of Heteromers within individual neurons in adult monkey striatum. The majority of these neurons displayed a phenotype co-expressing the characteristic markers of both striatonigral and striatopallidal neurons. Furthermore, THC increased D1-D2-linked calcium signaling markers (pCaMKIIα, pThr75-DARPP-32, BDNF/pTrkB) and inhibited cyclic AMP signaling (pThr34-DARPP-32, pERK1/2, pS845-GluA1, pGSK3). Cannabidiol attenuated most but not all of these THC-induced neuroadaptations. Targeted pathway analyses linked these changes to neurological and psychological disorders. These data underline the importance of the D1-D2 receptor Heteromer in cannabis use-related disorders, with THC-induced changes likely responsible for the reported adverse effects observed in heavy long-term users.
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d5 dopamine receptor carboxyl tail involved in d5 d2 Heteromer formation
Biochemical and Biophysical Research Communications, 2013Co-Authors: Brian F Odowd, Susan R. George, Tuan V. NguyenAbstract:We have demonstrated that D5 and D2 dopamine receptors exist as Heteromers in cells, and determined these receptor interact through amino acids in the cytoplasmic regions of each receptor. Specifically involved in Heteromer formation we identified in the carboxyl tail of the D5 receptor three adjacent glutamic acid residues, and in intracellular loop 3 of the D2 receptor two adjacent arginine residues. Any pairing of these three D5 receptor glutamic acids were sufficient for Heteromer formation. These identified residues in D5 and D2 receptors are oppositely charged and likely interact by electrostatic interactions.
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D5 dopamine receptor carboxyl tail involved in D5–D2 Heteromer formation
Biochemical and biophysical research communications, 2013Co-Authors: Brian F. O'dowd, Tuan V. Nguyen, Susan R. GeorgeAbstract:We have demonstrated that D5 and D2 dopamine receptors exist as Heteromers in cells, and determined these receptor interact through amino acids in the cytoplasmic regions of each receptor. Specifically involved in Heteromer formation we identified in the carboxyl tail of the D5 receptor three adjacent glutamic acid residues, and in intracellular loop 3 of the D2 receptor two adjacent arginine residues. Any pairing of these three D5 receptor glutamic acids were sufficient for Heteromer formation. These identified residues in D5 and D2 receptors are oppositely charged and likely interact by electrostatic interactions.
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Disruption of the mu-delta opioid receptor Heteromer.
Biochemical and biophysical research communications, 2012Co-Authors: Brian F. O'dowd, Paul B. O’dowd, Tuan V. Nguyen, Susan R. GeorgeAbstract:Abstract The crystal structure of the mu and kappa opioid receptors has revealed dimeric structural arrangements. Mu–delta receptors Heteromers also exist and we have identified discrete cytoplasmic regions in each receptor required for oligomer formation. In the carboxyl tail of the delta receptor we identified three glycine residues (-GGG), substitution of any of these residues prevented Heteromer formation. In intracellular loop 3 of both mu and delta receptors we identified three residues (-SVR), substitution of any of these residues prevented Heteromer formation.
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Two amino acids in each of D1 and D2 dopamine receptor cytoplasmic regions are involved in D1-D2 Heteromer formation.
Biochemical and biophysical research communications, 2011Co-Authors: Brian F. O'dowd, Tuan V. Nguyen, Susan R. GeorgeAbstract:D(1) and D(2) dopamine receptors exist as Heteromers in cells and brain tissue and are dynamically regulated and separated by agonist concentrations at the cell surface. We determined that these receptor pairs interact primarily through discrete amino acids in the cytoplasmic regions of each receptor, with no evidence of any D(1)-D(2) receptor transmembrane interaction found. Specifically involved in Heteromer formation we identified, in intracellular loop 3 of the D(2) receptor, two adjacent arginine residues. Substitution of one of the arginine pair prevented Heteromer formation. Also involved in Heteromer formation we identified, in the carboxyl tail of the D(1) receptor, two adjacent glutamic acid residues. Substitution of one of the glutamic acid pair prevented Heteromer formation. These amino acid pairs in D(1) and D(2) receptors are oppositely charged, and presumably interact directly by electrostatic interactions.
Sergi Ferre - One of the best experts on this subject based on the ideXlab platform.
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functional μ opioid galanin receptor Heteromers in the ventral tegmental area
The Journal of Neuroscience, 2017Co-Authors: Estefania Moreno, César Quiroz, Josefa Mallol, Carme Lluis, Antoni Cortes, Vicent Casado, Enric I. Canela, Sergi FerreAbstract: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. SIGNIFICANCE STATEMENT The μ-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel in vitro experiments in mammalian transfected cells and in situ and in vivo experiments in rat VTA, we demonstrate that a significant population of these MORs form functional Heteromers with the galanin receptor subtype Gal1 (Gal1R), which modulate the activity of the VTA dopaminergic neurons. The MOR-Gal1R Heteromer can explain previous results showing antagonistic galanin–opioid interactions and offers a new therapeutic target for the treatment of opioid use disorder.
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allosteric mechanisms within the adenosine a2a dopamine d2 receptor heterotetramer
Neuropharmacology, 2016Co-Authors: Sergi Ferre, Estefania Moreno, Carme Lluis, Gemma Navarro, Jordi Bonaventura, Antonio Cortes, Vicent Casado, Dardo Tomasi, Nora D VolkowAbstract:Abstract The structure constituted by a G protein coupled receptor (GPCR) homodimer and a G protein provides a main functional unit and oligomeric entities can be viewed as multiples of dimers. For GPCR Heteromers, experimental evidence supports a tetrameric structure, comprised of two different homodimers, each able to signal with its preferred G protein. GPCR homomers and Heteromers can act as the conduit of allosteric interactions between orthosteric ligands. The well-known agonist/agonist allosteric interaction in the adenosine A2A receptor (A2AR)–dopamine D2 receptor (D2R) Heteromer, by which A2AR agonists decrease the affinity of D2R agonists, gave the first rationale for the use of A2AR antagonists in Parkinson's disease. We review new pharmacological findings that can be explained in the frame of a tetrameric structure of the A2AR–D2R Heteromer: first, ligand-independent allosteric modulations by the D2R that result in changes of the binding properties of A2AR ligands; second, differential modulation of the intrinsic efficacy of D2R ligands for G protein-dependent and independent signaling; third, the canonical antagonistic Gs–Gi interaction within the frame of the Heteromer; and fourth, the ability of A2AR antagonists, including caffeine, to also exert the same allosteric modulations of D2R ligands than A2AR agonists, while A2AR agonists and antagonists counteract each other's effects. These findings can have important clinical implications when evaluating the use of A2AR antagonists. They also call for the need of monitoring caffeine intake when evaluating the effect of D2R ligands, when used as therapeutic agents in neuropsychiatric disorders or as probes in imaging studies. This article is part of the Special Issue entitled ‘Purines in Neurodegeneration and Neuroregeneration’.
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Allosteric Mechanisms in the Adenosine A2A-Dopamine D2 Receptor Heteromer
Current Topics in Neurotoxicity, 2015Co-Authors: Sergi Ferre, Estefania Moreno, Carme Lluis, Gemma Navarro, Jordi Bonaventura, Nora D Volkow, Vicent CasadoAbstract:The pentameric structure constituted by one G protein coupled receptor (GPCR) homodimer and one heterotrimeric G protein provides a main functional unit and oligomeric entities can be viewed as multiples of dimers. For GPCR Heteromers, experimental evidence supports a tetrameric structure, comprised of two different homodimers, each able to signal with their preferred G protein. GPCR homomers and Heteromers can act as the conduit of allosteric interactions of orthosteric ligands. One ligand binding to one of the receptor units (protomer) modulates the properties of the same or another orthosteric ligand binding to another protomer. The agonist/agonist interaction in the adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) Heteromer, by which A2AR agonists decrease the affinity of D2R agonists, constitutes a well-known example and gave the first rationale for the use of A2AR antagonists in Parkinson’s disease. We review most recent studies that extend those findings to, first, ligand-independent allosteric modulations of the D2R protomer that result in changes of the binding properties of A2AR ligands in the A2AR-D2R Heteromer; second, the differential modulation of the intrinsic efficacy of D2R ligands for G protein-dependent and independent signaling; and third, the existence of the canonical antagonistic Gs-Gi interaction within the frame of the A2AR-D2R Heteromer. These studies support the heterotetrameric structure of GPCR Heteromers.
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G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives.
Pharmacological Reviews, 2014Co-Authors: Sergi Ferre, Vicent Casado, Marta Filizola, Lakshmi Devi, Ralf Jockers, Martin Lohse, Graeme Milligan, Jean-philippe Pin, Xavier GuitartAbstract:Most evidence indicates that, as for family C G protein-coupled receptors (GPCRs), family A GPCRs form homo- and Heteromers. Homodimers seem to be a predominant species, with potential dynamic formation of higher-order oligomers, particularly tetramers. Although monomeric GPCRs can activate G proteins, the pentameric structure constituted by one GPCR homodimer and one heterotrimeric G protein may provide a main functional unit, and oligomeric entities can be viewed as multiples of dimers. It still needs to be resolved if GPCR Heteromers are preferentially heterodimers or if they are mostly constituted by Heteromers of homodimers. Allosteric mechanisms determine a multiplicity of possible unique pharmacological properties of GPCR homomers and Heteromers. Some general mechanisms seem to apply, particularly at the level of ligand-binding properties. In the frame of the dimer-cooperativity model, the two-state dimer model provides the most practical method to analyze ligand-GPCR interactions when considering receptor homomers. In addition to ligand-binding properties, unique properties for each GPCR oligomer emerge in relation to different intrinsic efficacy of ligands for different signaling pathways (functional selectivity). This gives a rationale for the use of GPCR oligomers, and particularly Heteromers, as novel targets for drug development. Herein, we review the functional and pharmacological properties of GPCR oligomers and provide some guidelines for the application of discrete direct screening and high-throughput screening approaches to the discovery of receptor-Heteromer selective compounds.
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prime time for g protein coupled receptor Heteromers as therapeutic targets for cns disorders the dopamine d1 d3 receptor Heteromer
Cns & Neurological Disorders-drug Targets, 2010Co-Authors: Sergi Ferre, Carme Lluis, Jose L Lanciego, Rafael FrancoAbstract:A number of G-protein-coupled receptors (GPCRs) are currently under consideration as potential therapeutic targets for drugs acting in the central nervous system (CNS). Attempts to discover new medications have operated under the assumption that GPCRs are monomers and that a specific drug activates one single receptor coupled to one single signal transduction mechanism. In the neuronal membrane, GPCRs are now known to be arranged into homo- and hetero-oligomers; drugs acting on a single receptor within a specific Heteromer context are thought to induce a particular downstream signaling. However, there is recent evidence showing that Heteromertailored drugs can be designed that display different affinities for a given receptor depending on the receptor partners contained within the Heteromer. It can therefore be predicted that customized drugs targeting a specific receptor Heteromer in the CNS might imporove safety and efficacy for their therapeutic targets. Finally, it will be important to identify receptor Heteromers that are involved in the pathogenesis of diseases, such as the recently discovered dopamine D1-D3 receptor Heteromer, which might play a key role in L-DOPA-induced dyskinesia in Parkinsons disease.
Rafael Franco - One of the best experts on this subject based on the ideXlab platform.
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Adenosine A2A and A3 Receptors Are Able to Interact with Each Other. A Further Piece in the Puzzle of Adenosine Receptor-Mediated Signaling.
International Journal of Molecular Sciences, 2020Co-Authors: Alejandro Lillo, Eva Martínez-pinilla, Gemma Navarro, Irene Reyes-resina, Rafael FrancoAbstract:The aim of this paper was to check the possible interaction of two of the four purinergic P1 receptors, the A2A and the A3. Discovery of the A2A-A3 receptor complex was achieved by means of immunocytochemistry and of bioluminescence resonance energy transfer. The functional properties and Heteromer print identification were addressed by combining binding and signaling assays. The physiological role of the novel Heteromer is to provide a differential signaling depending on the pre-coupling to signal transduction components and/or on the concentration of the endogenous agonist. The main feature was that the Heteromeric context led to a marked decrease of the signaling originating at A3 receptors. Interestingly from a therapeutic point of view, A2A receptor antagonists overrode the blockade, thus allowing A3 receptor-mediated signaling. The A2A-A3 receptor Heteromer print was detected in primary cortical neurons. These and previous results suggest that all four adenosine receptors may interact with each other. Therefore, each adenosine receptor could form Heteromers with distinct properties, expanding the signaling outputs derived from the binding of adenosine to its cognate receptors.
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Dopamine D2 and angiotensin II type 1 receptors form functional Heteromers in rat striatum.
Biochemical pharmacology, 2015Co-Authors: Eva Martínez-pinilla, Estefania Moreno, Gemma Navarro, Jose L Lanciego, Ana I. Rodriguez-perez, David Aguinaga, Jose L. Labandeira-garcia, Rafael FrancoAbstract:Identification of G protein-coupled receptors and their specific function in a given neuron becomes essential to better understand the variety of signal transduction mechanisms associated with neurotransmission. We hypothesized that angiotensin II type 1 (AT1) and dopamine D2 receptors form Heteromers in the central nervous system, specifically in striatum. Using bioluminescence resonance energy transfer, a direct interaction was demonstrated in cells transfected with the cDNA for the human version of the receptors. Heteromerization did not affect cAMP signaling via D2 receptors but attenuated the coupling of AT1 receptors to Gq. A common feature of Heteromers, namely cross-antagonism, i.e. the blockade of the signaling of one receptor by the blockade of the partner receptor, was tested in co-transfected cells. Candesartan, the selective AT1 receptor antagonist, was able to block D2-receptor mediated effects on cAMP levels, MAP kinase activation and β-arrestin recruitment. This effect of candesartan, which constitutes a property for the dopamine-angiotensin receptor Heteromer, was similarly occurring in primary cultures of neurons and rat striatal slices. The expression of Heteromers in striatum was confirmed by robust labeling using in situ proximity ligation assays. The results indicate that AT1 receptors are expressed in striatum and form Heteromers with dopamine D2 receptors that enable drugs selective for the AT1 receptor to alter the functional response of D2 receptors.
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Challenges in the Development of Heteromer-GPCR-Based Drugs
Progress in Molecular Biology and Translational Science, 2013Co-Authors: Rafael Franco, Eva Martínez-pinilla, Ana Ricobaraza, Peter J MccormickAbstract:G-protein-coupled receptors are targets of a variety of diseases. Drug screening has been classically performed assuming the occurrence of monomeric receptors. As more and more receptor Heteromers are identified, the challenge is now to develop screening assays to select Heteromer-specific drugs. These drugs may, for instance, be able to interact preferentially with prerather than with postsynaptic receptors. Heteromer-based drug discovery opens new perspectives in both Academic pursuits and for the Pharmaceutical industry.
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prime time for g protein coupled receptor Heteromers as therapeutic targets for cns disorders the dopamine d1 d3 receptor Heteromer
Cns & Neurological Disorders-drug Targets, 2010Co-Authors: Sergi Ferre, Carme Lluis, Jose L Lanciego, Rafael FrancoAbstract:A number of G-protein-coupled receptors (GPCRs) are currently under consideration as potential therapeutic targets for drugs acting in the central nervous system (CNS). Attempts to discover new medications have operated under the assumption that GPCRs are monomers and that a specific drug activates one single receptor coupled to one single signal transduction mechanism. In the neuronal membrane, GPCRs are now known to be arranged into homo- and hetero-oligomers; drugs acting on a single receptor within a specific Heteromer context are thought to induce a particular downstream signaling. However, there is recent evidence showing that Heteromertailored drugs can be designed that display different affinities for a given receptor depending on the receptor partners contained within the Heteromer. It can therefore be predicted that customized drugs targeting a specific receptor Heteromer in the CNS might imporove safety and efficacy for their therapeutic targets. Finally, it will be important to identify receptor Heteromers that are involved in the pathogenesis of diseases, such as the recently discovered dopamine D1-D3 receptor Heteromer, which might play a key role in L-DOPA-induced dyskinesia in Parkinsons disease.
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prime time for g protein coupled receptor Heteromers as therapeutic targets for cns disorders the dopamine d d receptor Heteromer
Cns & Neurological Disorders-drug Targets, 2010Co-Authors: Sergi Ferre, Jose L Lanciego, Carmen Lluis, Rafael FrancoAbstract:A number of G-protein-coupled receptors (GPCRs) are currently under consideration as potential therapeutic targets for drugs acting in the central nervous system (CNS). Attempts to discover new medications have operated under the assumption that GPCRs are monomers and that a specific drug activates one single receptor coupled to one single signal transduction mechanism. In the neuronal membrane, GPCRs are now known to be arranged into homo- and hetero-oligomers; drugs acting on a single receptor within a specific Heteromer context are thought to induce a particular downstream signaling. However, there is recent evidence showing that Heteromer-tailored drugs can be designed that display different affinities for a given receptor depending on the receptor partners contained within the Heteromer. It can therefore be predicted that customized drugs targeting a specific receptor Heteromer in the CNS might improve safety and efficacy for their therapeutic targets. Finally, it will be important to identify receptor Heteromers that are involved in the pathogenesis of diseases, such as the recently discovered dopamine D₁-D₃ receptor Heteromer, which might play a key role in L-DOPA-induced dyskinesia in Parkinson's disease.
Estefania Moreno - One of the best experts on this subject based on the ideXlab platform.
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Altered Signaling in CB1R-5-HT2AR Heteromers in Olfactory Neuroepithelium Cells of Schizophrenia Patients is Modulated by Cannabis Use.
Schizophrenia bulletin, 2020Co-Authors: D. Guinart, Estefania Moreno, Enric I. Canela, L. Galindo, Aida Cuenca-royo, Marta Barrera-conde, E.j. Pérez, Cristina Fernández-avilés, Christoph U. Correll, Vicent CasadoAbstract:Schizophrenia (SCZ) has been associated with serotonergic and endocannabinoid systems dysregulation, but difficulty in obtaining in vivo neurological tissue has limited its exploration. We investigated CB1R-5-HT2AR Heteromer expression and functionality via intracellular pERK and cAMP quantification in olfactory neuroepithelium (ON) cells of SCZ patients non-cannabis users (SCZ/nc), and evaluated whether cannabis modulated these parameters in patients using cannabis (SCZ/c). Results were compared vs healthy controls non-cannabis users (HC/nc) and healthy controls cannabis users (HC/c). Further, antipsychotic effects on Heteromer signaling were tested in vitro in HC/nc and HC/c. Results indicated that Heteromer expression was enhanced in both SCZ groups vs HC/nc. Additionally, pooling all 4 groups together, Heteromer expression correlated with worse attentional performance and more neurological soft signs (NSS), indicating that these changes may be useful markers for neurocognitive impairment. Remarkably, the previously reported signaling properties of CB1R-5-HT2AR Heteromers in ON cells were absent, specifically in SCZ/nc treated with clozapine. These findings were mimicked in cells from HC/nc exposed to clozapine, suggesting a major role of this antipsychotic in altering the quaternary structure of the CB1R-5-HT2AR Heteromer in SCZ/nc patients. In contrast, cells from SCZ/c showed enhanced Heteromer functionality similar to HC/c. Our data highlight a molecular marker of the interaction between antipsychotic medication and cannabis use in SCZ with relevance for future studies evaluating its association with specific neuropsychiatric alterations.
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Targeting the receptor-based interactome of the dopamine D1 receptor: looking for Heteromer-selective drugs.
Expert opinion on drug discovery, 2019Co-Authors: Verònica Casadó-anguera, Vicent Casado, Antoni Cortes, Estefania MorenoAbstract:Introduction: G protein-coupled receptors (GPCRs) are a superfamily of membrane proteins highly expressed in the brain that are involved in almost all functions of the CNS. During the last twenty years, a large number of GPCRs have been reported to form homodimers, heterodimers and higher order oligomers. Areas covered: This review summarizes the functional and pharmacological characteristics of the dopamine D1 receptor (D1R) interactome constituted by Heteromers with GPCRs or non-GPCRs. The review also focuses on Heteromer-selective ligands reported for GPCRs, including those for the receptor-based interactome of D1R. Expert opinion: Since the D1R plays a key role in basal ganglia motor control, where all the mentioned D1R Heteromers are present, the study of allosteric interactions within the D1R interactome may be of high therapeutic interest for treating motor dysfunction. Moreover, several of these Heteromers have also been detected in the prefrontal cortex and hippocampus, where they are involved in learning, memory and attention dysfunction. We propose that drugs targeting specific D1R Heteromers in the CNS will be more effective and safer, resulting in a reduction of side effects compared with traditional drugs targeting monomeric receptors. Heteromer-selective ligands will have a big impact on drug development with many pharmacological and clinical implications.
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Biased G Protein-Independent Signaling of Dopamine D1-D3 Receptor Heteromers in the Nucleus Accumbens.
Molecular neurobiology, 2019Co-Authors: Xavier Guitart, Estefania Moreno, César Quiroz, Antoni Cortes, William Rea, Marta Sánchez-soto, Ning-sheng Cai, Vivek Kumar, Liam Bourque, Enric I. CanelaAbstract:Several studies found in vitro evidence for Heteromerization of dopamine D1 receptors (D1R) and D3 receptors (D3R), and it has been postulated that functional D1R-D3R Heteromers that are normally present in the ventral striatum mediate synergistic locomotor-activating effects of D1R and D3R agonists in rodents. Based also on results obtained in vitro, with mammalian transfected cells, it has been hypothesized that those behavioral effects depend on a D1R-D3R Heteromer-mediated G protein-independent signaling. Here, we demonstrate the presence on D1R-D3R Heteromers in the mouse ventral striatum by using a synthetic peptide that selectively destabilizes D1R-D3R Heteromers. Parallel locomotor activity and ex vivo experiments in reserpinized mice and in vitro experiments in D1R-D3R mammalian transfected cells were performed to dissect the signaling mechanisms of D1R-D3R Heteromers. Co-administration of D1R and D3R agonists in reserpinized mice produced synergistic locomotor activation and a selective synergistic AKT phosphorylation in the most ventromedial region of the striatum in the shell of the nucleus accumbens. Application of the destabilizing peptide in transfected cells and in the shell of the nucleus accumbens allowed demonstrating that both in vitro and in vivo co-activation of D3R induces a switch from G protein-dependent to G protein-independent D1R-mediated signaling determined by D1R-D3R Heteromerization. The results therefore demonstrate that a biased G protein-independent signaling of D1R-D3R Heteromers localized in the shell of the nucleus accumbens mediate the locomotor synergistic effects of D1R and D3R agonists in reserpinized mice.
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cannabis users show enhanced expression of cb1 5ht2a receptor Heteromers in olfactory neuroepithelium cells
Molecular Neurobiology, 2018Co-Authors: L. Galindo, Estefania Moreno, D. Guinart, Eugenia Menoyo, Fernando Lopezarmenta, Aida Cuencaroyo, Merce Izquierdoserra, Laura Xicota, Cristina Fernandez, Jose M FernandezfernandezAbstract:Cannabinoid CB1 receptors (CB1R) and serotonergic 2A receptors (5HT2AR) form Heteromers in the brain of mice where they mediate the cognitive deficits produced by delta-9-tetrahydrocannabinol. However, it is still unknown whether the expression of this heterodimer is modulated by chronic cannabis use in humans. In this study, we investigated the expression levels and functionality of CB1R-5HT2AR Heteromers in human olfactory neuroepithelium (ON) cells of cannabis users and control subjects, and determined their molecular characteristics through adenylate cyclase and the ERK 1/2 pathway signaling studies. We also assessed whether Heteromer expression levels correlated with cannabis consumption and cognitive performance in neuropsychological tests. ON cells from controls and cannabis users expressed neuronal markers such as βIII-tubulin and nestin, displayed similar expression levels of genes related to cellular self-renewal, stem cell differentiation, and generation of neural crest cells, and showed comparable Na+ currents in patch clamp recordings. Interestingly, CB1R-5HT2AR Heteromer expression was significantly increased in cannabis users and positively correlated with the amount of cannabis consumed, and negatively with age of onset of cannabis use. In addition, a negative correlation was found between Heteromer expression levels and attention and working memory performance in cannabis users and control subjects. Our findings suggest that cannabis consumption regulates the formation of CB1R-5HT2AR Heteromers, and may have a key role in cognitive processing. These heterodimers could be potential new targets to develop treatment alternatives for cognitive impairments.
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functional μ opioid galanin receptor Heteromers in the ventral tegmental area
The Journal of Neuroscience, 2017Co-Authors: Estefania Moreno, César Quiroz, Josefa Mallol, Carme Lluis, Antoni Cortes, Vicent Casado, Enric I. Canela, Sergi FerreAbstract: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. SIGNIFICANCE STATEMENT The μ-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel in vitro experiments in mammalian transfected cells and in situ and in vivo experiments in rat VTA, we demonstrate that a significant population of these MORs form functional Heteromers with the galanin receptor subtype Gal1 (Gal1R), which modulate the activity of the VTA dopaminergic neurons. The MOR-Gal1R Heteromer can explain previous results showing antagonistic galanin–opioid interactions and offers a new therapeutic target for the treatment of opioid use disorder.
Carme Lluis - One of the best experts on this subject based on the ideXlab platform.
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functional μ opioid galanin receptor Heteromers in the ventral tegmental area
The Journal of Neuroscience, 2017Co-Authors: Estefania Moreno, César Quiroz, Josefa Mallol, Carme Lluis, Antoni Cortes, Vicent Casado, Enric I. Canela, Sergi FerreAbstract: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. SIGNIFICANCE STATEMENT The μ-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel in vitro experiments in mammalian transfected cells and in situ and in vivo experiments in rat VTA, we demonstrate that a significant population of these MORs form functional Heteromers with the galanin receptor subtype Gal1 (Gal1R), which modulate the activity of the VTA dopaminergic neurons. The MOR-Gal1R Heteromer can explain previous results showing antagonistic galanin–opioid interactions and offers a new therapeutic target for the treatment of opioid use disorder.
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allosteric mechanisms within the adenosine a2a dopamine d2 receptor heterotetramer
Neuropharmacology, 2016Co-Authors: Sergi Ferre, Estefania Moreno, Carme Lluis, Gemma Navarro, Jordi Bonaventura, Antonio Cortes, Vicent Casado, Dardo Tomasi, Nora D VolkowAbstract:Abstract The structure constituted by a G protein coupled receptor (GPCR) homodimer and a G protein provides a main functional unit and oligomeric entities can be viewed as multiples of dimers. For GPCR Heteromers, experimental evidence supports a tetrameric structure, comprised of two different homodimers, each able to signal with its preferred G protein. GPCR homomers and Heteromers can act as the conduit of allosteric interactions between orthosteric ligands. The well-known agonist/agonist allosteric interaction in the adenosine A2A receptor (A2AR)–dopamine D2 receptor (D2R) Heteromer, by which A2AR agonists decrease the affinity of D2R agonists, gave the first rationale for the use of A2AR antagonists in Parkinson's disease. We review new pharmacological findings that can be explained in the frame of a tetrameric structure of the A2AR–D2R Heteromer: first, ligand-independent allosteric modulations by the D2R that result in changes of the binding properties of A2AR ligands; second, differential modulation of the intrinsic efficacy of D2R ligands for G protein-dependent and independent signaling; third, the canonical antagonistic Gs–Gi interaction within the frame of the Heteromer; and fourth, the ability of A2AR antagonists, including caffeine, to also exert the same allosteric modulations of D2R ligands than A2AR agonists, while A2AR agonists and antagonists counteract each other's effects. These findings can have important clinical implications when evaluating the use of A2AR antagonists. They also call for the need of monitoring caffeine intake when evaluating the effect of D2R ligands, when used as therapeutic agents in neuropsychiatric disorders or as probes in imaging studies. This article is part of the Special Issue entitled ‘Purines in Neurodegeneration and Neuroregeneration’.
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Allosteric Mechanisms in the Adenosine A2A-Dopamine D2 Receptor Heteromer
Current Topics in Neurotoxicity, 2015Co-Authors: Sergi Ferre, Estefania Moreno, Carme Lluis, Gemma Navarro, Jordi Bonaventura, Nora D Volkow, Vicent CasadoAbstract:The pentameric structure constituted by one G protein coupled receptor (GPCR) homodimer and one heterotrimeric G protein provides a main functional unit and oligomeric entities can be viewed as multiples of dimers. For GPCR Heteromers, experimental evidence supports a tetrameric structure, comprised of two different homodimers, each able to signal with their preferred G protein. GPCR homomers and Heteromers can act as the conduit of allosteric interactions of orthosteric ligands. One ligand binding to one of the receptor units (protomer) modulates the properties of the same or another orthosteric ligand binding to another protomer. The agonist/agonist interaction in the adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) Heteromer, by which A2AR agonists decrease the affinity of D2R agonists, constitutes a well-known example and gave the first rationale for the use of A2AR antagonists in Parkinson’s disease. We review most recent studies that extend those findings to, first, ligand-independent allosteric modulations of the D2R protomer that result in changes of the binding properties of A2AR ligands in the A2AR-D2R Heteromer; second, the differential modulation of the intrinsic efficacy of D2R ligands for G protein-dependent and independent signaling; and third, the existence of the canonical antagonistic Gs-Gi interaction within the frame of the A2AR-D2R Heteromer. These studies support the heterotetrameric structure of GPCR Heteromers.
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allosteric interactions between agonists and antagonists within the adenosine a2a receptor dopamine d2 receptor heterotetramer
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Estefania Moreno, Karima Azdad, Josefa Mallol, Gemma Navarro, Jordi Bonaventura, Marc Brugarolas, Veronica Casadoanguera, Enric I. Canela, Carme LluisAbstract: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.
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l dopa disrupts adenosine a2a cannabinoid cb1 dopamine d2 receptor Heteromer cross talk in the striatum of hemiparkinsonian rats biochemical and behavioral studies
Experimental Neurology, 2014Co-Authors: Annalisa Pinna, Josefa Mallol, Carme Lluis, Jordi Bonaventura, Daniel Farre, Marta Sanchez, Nicola Simola, Giulia Costa, Younis Baqi, Christa E. MüllerAbstract:Long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA), still the most effective treatment in Parkinson's disease (PD), is associated with severe motor complications such as dyskinesia. Experimental and clinical data have indicated that adenosine A2A receptor antagonists can provide symptomatic improvement by potentiating L-DOPA efficacy and minimizing its side effects. It is known that the G-protein-coupled adenosine A2A, cannabinoid CB1 and dopamine D2 receptors may interact and form functional A2A-CB1-D2 receptor Heteromers in co-transfected cells as well as in rat striatum. These data suggest that treatment with a combination of drugs or a single compound selectively acting on A2A-CB1-D2 Heteromers may represent an alternative therapeutic treatment of PD. We investigated the expression of A2A-CB1-D2 receptor Heteromers in the striatum of both naive and hemiparkinsonian rats (HPD-rats) bearing a unilateral 6-hydroxydopamine (6-OHDA) lesion, and assessed how receptor Heteromer expression and biochemical properties were affected by L-DOPA treatment. Radioligand binding data showed that A2A-CB1-D2 receptor Heteromers are present in the striatum of both naive and HPD-rats. However, behavioral results indicated that the combined administration of A2A (MSX-3 or SCH58261) and CB1 (rimonabant) receptor antagonists, in the presence of L-DOPA does not produce a response different from administration of the A2A receptor antagonist alone. These behavioral results prompted identification of Heteromers in L-DOPA-treated animals. Interestingly, the radioligand binding results in samples from lesioned animals suggest that the Heteromer is lost following acute or chronic treatment with L-DOPA.