Papers by Maricel Gómez-soler
International Journal of Molecular Sciences, 2019
Background: Several biophysical techniques have been successfully implemented to detect G protein... more Background: Several biophysical techniques have been successfully implemented to detect G protein-coupled receptors (GPCRs) heteromerization. Although these approaches have made it possible to ascertain the presence of GPCR heteromers in animal models of disease, no success has been accomplished in pathological human post-mortem brains. The AlphaScreen technology has been consistently used to quantify small analyte accumulation or depletion, bimolecular interactions, and post-translational modifications. The high signal-to-background, dynamic range and sensitivity exhibited by this technology support that it may be suitable to detect GPCR heteromers even under non-optimal conditions. Methods: Here, we describe the development of a new AlphaScreen assay to detect GPCR oligomers in human post-mortem brain. Results: Adenosine A2A-dopamine D2 receptor (A2AR/D2R) heteromer formation was monitored in caudate from healthy and Parkinson’s disease (PD) subjects. The approach was first valida...
Frontiers in Neuroscience, 2018
Parkinson's disease (PD) is a neurodegenerative disorder of unknown etiology. The main treatment ... more Parkinson's disease (PD) is a neurodegenerative disorder of unknown etiology. The main treatment of PD consists of medication with dopamine-based drugs, which palliate the symptoms but may produce adverse effects after chronic administration. Accordingly, there is a need to develop novel neuroprotective therapies. Several studies suggest that omega-3 polyunsaturated fatty acids (n-3 PUFA) might provide protection against brain damage. Here, we studied several experimental models of PD, using striatal neuronal cultures, striatal slices, and mice, to assess the neuroprotective effects of docosahexaenoic acid (DHA), the main n-3 PUFA in the brain, administered in its triglyceride form (TG-DHA). Hence, we determined the beneficial effects of TG-DHA on neural viability following 6-hydroxydopamine (6-OHDA)-induced neurotoxicity, a wellestablished PD model. We also implemented a novel mouse behavioral test, the beam walking test, to finely assess mouse motor skills following dopaminergic denervation. This test showed potential as a useful behavioral tool to assess novel PD treatments. Our results indicated that TG-DHA-mediated neuroprotection was independent of the net incorporation of PUFA into the striatum, thus suggesting a tight control of brain lipid homeostasis both in normal and pathological conditions.
Molecular Neurobiology, 2017
Dopamine D 2 receptor (D 2 R) activation triggers both G protein-and β-arrestin-dependent signali... more Dopamine D 2 receptor (D 2 R) activation triggers both G protein-and β-arrestin-dependent signaling. Biased D 2 R ligands activating β-arrestin pathway have been proposed as potential antipsychotics. The ability of D 2 R to heteromerize with adenosine A 2A receptor (A 2A R) has been associated to D 2 R agonist-induced β-arrestin recruitment. Accordingly, here we aimed to demonstrate the A 2A R dependence of D 2 R/β-arrestin signaling. By combining bioluminescence resonance energy transfer (BRET) between β-arrestin-2 tagged with yellow fluorescent protein and bimolecular luminescence complementation (BiLC) of D 2 R/A 2A R homomers and heteromers, we demonstrated that the D 2 R agonists quinpirole and UNC9994 could promote β-arrestin-2 recruitment only when A 2A R/D 2 R heteromers were expressed. Subsequently, the role of A 2A R in the antipsychotic-like activity of UNC9994 was assessed in wild-type and A 2A R −/− mice administered with phencyclidine (PCP) or amphetamine (AMPH). Interestingly, while UNC9994 reduced hyperlocomotion in wild-type animals treated either with PCP or AMPH, in A 2A R −/− mice, it failed to reduce PCP-induced hyperlocomotion or produced only a moderate reduction of AMPH-mediated hyperlocomotion. Overall, the results presented here reinforce the notion that D 2 R/A 2A R heteromerization facilitates D 2 R βarrestin recruitment, and furthermore, reveal a pivotal role for A 2A R in the antipsychotic-like activity of the β-arrestin-biased D 2 R ligand, UNC9994.
Scientific Reports, 2016
Membrane levels of docosahexaenoic acid (DHA), an essential omega-3 polyunsaturated fatty acid (ω... more Membrane levels of docosahexaenoic acid (DHA), an essential omega-3 polyunsaturated fatty acid (ω-3 PUFA), are decreased in common neuropsychiatric disorders. DHA modulates key cell membrane properties like fluidity, thereby affecting the behaviour of transmembrane proteins like G protein-coupled receptors (GPCRs). These receptors, which have special relevance for major neuropsychiatric disorders have recently been shown to form dimers or higher order oligomers and evidence suggests that DHA levels affect GPCR function by modulating oligomerisation. In this study, we assessed the effect of membrane DHA content on the formation of a class of protein complexes with particular relevance for brain disease: adenosine A2A and dopamine D2 receptor oligomers. Using extensive multiscale computer modelling, we find a marked propensity of DHA for interaction with both A2A and D2 receptors, which leads to an increased rate of receptor oligomerisation. Bioluminescence resonance energy transfer (...
Biophysical Journal, 2014
ACS Chemical Biology, 2014
This is an open access article published under an ACS AuthorChoice License, which permits copying... more This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
Trends in Biochemical Sciences, 2005
The existence of intramembrane receptor-receptor interactions for heptaspanning membrane receptor... more The existence of intramembrane receptor-receptor interactions for heptaspanning membrane receptors is now fully accepted, but a model considering dimers as the basic unit that binds to two ligand molecules is lacking. Here, we propose a two-state-dimer model in which the ligand-induced conformational changes from one component of the dimer are communicated to the other. Our model predicts cooperativity in binding, which is relevant because the other current models fail to address this phenomenon satisfactorily. Our twostate-dimer model also predicts the variety of responses elicited by full or partial agonists, neutral antagonists and inverse agonists. This model can aid our understanding of the operation of heptaspanning receptors and receptor channels, and, potentially, be important for improving the treatment of cardiovascular, neurological and neuropsychyatric diseases.
Frontiers in Physiology, 2012
Current Medicinal Chemistry-Central Nervous System Agents, 2003
The FEBS Journal, 2011
Dopamine D4 receptors (D4Rs) are G protein‐coupled receptors that play a role in attention and co... more Dopamine D4 receptors (D4Rs) are G protein‐coupled receptors that play a role in attention and cognition. In the present study, we investigated the dimerization properties of this receptor. Western blot analysis of the human D4.2R, D4.4R and D4.7R revealed the presence of higher molecular weight immunoreactive bands, which might indicate the formation of receptor dimers and multimers. Homo‐ and heterodimerization of the receptors was confirmed by co‐immunoprecipitation and bioluminescence resonance energy transfer studies. Although dimerization of a large number of G protein‐coupled receptors has been described, the functional importance often remains to be elucidated. Folding efficiency is rate‐limiting for D4R biogenesis and quality control in the endoplasmic reticulum plays an important role for D4R maturation. Co‐immunoprecipitation and immunofluorescence microscopy studies using wild‐type and a nonfunctional D4.4R folding mutant show that oligomerization occurs in the endoplasm...
Neuropharmacology, 2011
G protein coupled receptors (GPCRs) mediate a multitude of responses serving hormonal, neurotrans... more G protein coupled receptors (GPCRs) mediate a multitude of responses serving hormonal, neurotransmitter, and sensory functions. These receptors are important drug targets; in fact, about 27 % of prescribed drugs are GPCR ligands. The dopamine D 2 receptor is prominently expressed within the CNS as two distinct isoforms; D 2L (long isoform) and D 2S (short isoform). The former is mainly expressed postsynaptically, whereas the latter functions primarily as an inhibitory auto-and heteroreceptor. The D 2 receptor is of considerable pharmacological interest, as it constitutes the main target for most antiparkinsonian and antipsychotic drugs in clinical use. While many ion channels have long been known to be voltage sensitive, this property has not been attributed to GPCRs until quite recently. As a notable example, the muscarinic M 2 receptor was shown to display depolarization-induced decreases in agonist binding and functional potency. M 2 receptor voltage sensitivity has been implicated in the autoreceptor function of this GPCR, by permitting rapid control of neurotransmitter release kinetics by membrane voltage.
Journal of Receptors and Signal Transduction, 2010
Based on indications of direct physical interactions between neuropeptide and monoamine receptors... more Based on indications of direct physical interactions between neuropeptide and monoamine receptors in the early 1980s, the term receptor-receptor interactions was introduced and later on the term receptor heteromerization in the early 1990s. Allosteric mechanisms allow an integrative activity to emerge either intramolecularly in G protein-coupled receptor (GPCR) monomers or intermolecularly via receptor-receptor interactions in GPCR homodimers, heterodimers, and receptor mosaics. Stable heteromers of Class A receptors may be formed that involve strong high energy arginine-phosphate electrostatic interactions. These receptor-receptor interactions markedly increase the repertoire of GPCR recognition, signaling and trafficking in which the minimal signaling unit in the GPCR homomers appears to be one receptor and one G protein. GPCR homomers and GPCR assemblies are not isolated but also directly interact with other proteins to form horizontal molecular networks at the plasma membrane.
Journal of Receptors and Signal Transduction, 2010
Although the G protein-coupled receptor (GPCR) oligomerization has been questioned during the las... more Although the G protein-coupled receptor (GPCR) oligomerization has been questioned during the last decade, under some premises the existence of a supramolecular organization of these receptors begins now to be widely accepted by the scientific community. Indeed, GPCR oligomers may enhance the diversity and performance by which extracellular signals are transferred to the G proteins in the process of receptor transduction, although the mechanism that underlie this phenomenon remains still unexplained. Recently, a trans-conformational switching model has been proposed as a mechanism allowing direct inhibition of receptor activation. Thus, heterotropic receptor-receptor allosteric regulations are behind the GPCR oligomeric function. Accordingly, we revise here how GPCR oligomerization impinge in several important receptor functions like biosynthesis, plasma membrane diffusion or velocity, pharmacology and signaling. Overall, the rationale of receptor oligomerization might lie in the cellular need of sensing complex extracellular signals and to translate into a simple computational mode.
Journal of Neurochemistry, 2012
In the CNS, an antagonistic interaction has been shown between adenosine A2A and dopamine D2 rece... more In the CNS, an antagonistic interaction has been shown between adenosine A2A and dopamine D2 receptors (A2ARs and D2Rs) that may be relevant both in normal and pathological conditions (i.e., Parkinson's disease). Thus, the molecular determinants mediating this receptor–receptor interaction have recently been explored, as the fine tuning of this target (namely the A2AR/D2R oligomer) could possibly improve the treatment of certain CNS diseases. Here, we used a fluorescence resonance energy transfer‐based approach to examine the allosteric modulation of the D2R within the A2AR/D2R oligomer and the dependence of this receptor–receptor interaction on two regions rich in positive charges on intracellular loop 3 of the D2R. Interestingly, we observed a negative allosteric effect of the D2R agonist quinpirole on A2AR ligand binding and activation. However, these allosteric effects were abolished upon mutation of specific arginine residues (217–222 and 267–269) on intracellular loop 3 of...
Journal of Molecular Biology, 2011
CNS & Neurological Disorders - Drug Targets, 2013
Cellular Physiology and Biochemistry, 2011
Acetylcholine challenge produces M 3 muscarinic acetylcholine receptor activation and accessory/ ... more Acetylcholine challenge produces M 3 muscarinic acetylcholine receptor activation and accessory/ scaffold proteins recruitment into a signalsome complex. The dynamics of such a complex is not well understood but a conserved NPxxY motif located within transmembrane 7 and juxtamembrane helix 8 of the receptor was found to modulate G protein activation. Here by means of receptor mutagenesis we unravel the role of the conserved M 3 muscarinic acetylcholine receptor NPxxY motif on ligand binding, signaling and multiprotein complex formation. Interestingly, while a N7.49D receptor mutant showed normal ligand binding properties a N7.49A mutant had reduced antagonist binding and increased affinity for carbachol. Also, besides this last mutant was able to physically couple to Gα q/11 after carbachol challenge it was neither capable to activate phospholipase C nor phospholipase D. On the other hand, we demonstrated that the Asn-7.49 is important for the interaction between M 3 R and ARF1 and also for the formation of the ARF/Rho/βγ signaling complex, a complex that might determine the rapid activation and desensitization of PLD. Overall, these results indicate that the NPxxY motif of the M 3 muscarinic acetylcholine receptor acts as key conformational switch for receptor signaling and multiprotein complex formation.
Brain Research, 2012
This article is focused on understanding the mechanisms for the interactions between the central ... more This article is focused on understanding the mechanisms for the interactions between the central catecholamine (CA) and oxytocin (OXY) neurons and their relevance for brain function especially social behaviour in the field of pair bonding. Such a topic is analysed under two perspectives namely the intercellular communication modes between CA and OXT neurons and the molecular integrative mechanisms at the plasma membrane level between their respective decoding systems. As a matter of fact, recent observations strongly indicate a major role of volume transmission and receptor-receptor interactions in the CA/OXT neuron interplay in the brain control of social behaviour and pair bonding. This article is part of a Special Issue entitled: Brain Integration.
Brain Research, 2012
The control of glutamatergic corticostriatal transmission is essential for the induction and expr... more The control of glutamatergic corticostriatal transmission is essential for the induction and expression of plasticity mechanisms in the striatum, a phenomenon thickly regulated by G protein-coupled receptors (GPCRs). Interestingly, in addition to dopamine receptors, adenosine and metabotropic glutamate receptors also play a key role in striatal functioning. The existence of a supramolecular organization (i.e. oligomer) containing dopamine, adenosine and metabotropic glutamate receptors in the striatal neurons is now being widely accepted by the scientific community. Indeed, these oligomers may enhance the diversity and performance by which extracellular striatal signals are transferred to the G-proteins in the process of receptor transduction, and also may allow unpredictable receptor-receptor allosteric regulations. Overall, here we want to review how formations of adenosine, dopamine and metabotropic glutamate receptors-containing oligomers impinge into striatal functioning in both normal and pathological conditions. This article is part of a Special Issue entitled: Brain Integration.
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Papers by Maricel Gómez-soler