A5089054159- Receptor Mechanisms and Signaling
- Photochromic and Fluorescence Chemistry
- Neuroscience and Neuropharmacology Research
- Photoreceptor and optogenetics research
- Neuropeptides and Animal Physiology
- Neurobiology and Insect Physiology Research
- Retinal Development and Disorders
- Protein Structure and Dynamics
- Olfactory and Sensory Function Studies
- Chemical Synthesis and Analysis
- Machine Learning in Bioinformatics
- Pharmacological Receptor Mechanisms and Effects
- Photosynthetic Processes and Mechanisms
- Pain Mechanisms and Treatments
- Steroid Chemistry and Biochemistry
- Bioactive Compounds and Antitumor Agents
- Zebrafish Biomedical Research Applications
- Circadian rhythm and melatonin
- bioluminescence and chemiluminescence research
- Estrogen and related hormone effects
- Computational Drug Discovery Methods
- Enzyme Structure and Function
- Axon Guidance and Neuronal Signaling
- SARS-CoV-2 and COVID-19 Research
- Stress Responses and Cortisol
Institute of Advanced Chemistry of Catalonia
2020-2024
Consejo Superior de Investigaciones Científicas
2024
Centre National de la Recherche Scientifique
2012-2023
Université de Montpellier
2011-2023
Inserm
2012-2023
Institut de Génomique Fonctionnelle
2014-2023
Institute for Bioengineering of Catalonia
2019-2023
Universidade Federal de São Paulo
2023
Universitat de Vic - Universitat Central de Catalunya
2015-2022
Hospital Del Mar
2022
Allosteric modulators bear great potential to fine-tune neurotransmitter action. Promising targets are metabotropic glutamate (mGlu) receptors, which associated with numerous brain diseases. Orthosteric and allosteric ligands act in synergy control the activity of these multidomain dimeric GPCRs. Here, we analyzed effect such molecules on concerted conformational changes full-length mGlu2 at single-molecule level. We first established FRET sensors through genetic code expansion combined...
Metabotropic glutamate receptors (mGluRs) are mandatory dimers playing important roles in regulating CNS function. Although assumed to form exclusive homodimers, 16 possible heterodimeric mGluRs have been proposed but their existence native cells remains elusive. Here, we set up two assays specifically identify the pharmacological properties of rat mGlu heterodimers composed mGlu2 and 4 subunits. We used either a heterodimer-specific conformational LRET-based biosensor or system that...
Abstract Antibodies have enormous therapeutic and biotechnology potential. G protein-coupled receptors (GPCRs), the main targets in drug development, are of major interest antibody development programs. Metabotropic glutamate dimeric GPCRs that can control synaptic activity a multitude ways. Here we identify llama nanobodies specifically recognize mGlu2 receptors, among eight subtypes mGluR subunits. Among these nanobodies, DN10 13 positive allosteric modulators (PAM) on homodimeric mGlu2,...
Phenylazopyridines are photoisomerizable compounds with high potential to control biological functions light. We have obtained a series of phenylazopyridines light dependent activity as negative allosteric modulators (NAM) metabotropic glutamate receptor subtype 5 (mGlu5). Here we describe the factors needed achieve an operational molecular photoisomerization and its effective translation into in vitro vivo photoswitching, which includes zebrafish larva motility regulation antinociceptive...
Type 4 metabotropic glutamate (mGlu4) receptors are emerging targets for the treatment of various disorders. Accordingly, numerous mGlu4-positive allosteric modulators (PAMs) have been identified, some which also display agonist activity. To identify structural bases their action, we explored relationship between binding pockets mGlu4 PAMs with different chemical scaffolds and functional properties. By use innovative biosensors second-messenger assays, show that all enhance action on...
Light-operated drugs constitute a major target in drug discovery, since they may provide spatiotemporal resolution for the treatment of complex diseases (i.e. chronic pain). JF-NP-26 is an inactive photocaged derivative metabotropic glutamate type 5 (mGlu5) receptor negative allosteric modulator raseglurant. Violet light illumination induces photochemical reaction prompting active-drug’s release, which effectively controls mGlu5 activity both ectopic expressing systems and striatal primary...
GPCRs play critical roles in cell communication. Although can form heteromers, their role signaling remains elusive. Here we used rat metabotropic glutamate (mGlu) receptors as prototypical dimers to study the functional interaction between each subunit. mGluRs both constitutive homo- and heterodimers. Whereas mGlu2 mGlu4 couple G proteins, protein activation is mediated by heptahelical domain (HD) exclusively mGlu2-4 Such asymmetric transduction results from action of dimeric extracellular...
Abstract G protein-coupled receptors (GPCRs) can integrate extracellular signals via allosteric interactions within dimers and higher-order oligomers. However, the structural bases of these remain unclear. Here, we use GABA B receptor heterodimer as a model it forms large complexes in brain. It is subjected to genetic mutations mainly affecting transmembrane 6 (TM6) involved human diseases. By cross-linking, identify interfaces B1 -GABA B2 , well interactions. Our data are consistent with an...
The olfacto-genital syndrome (Kallmann syndrome) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. This is a genetically heterogeneous developmental disease with various modes of transmission, including oligogenic inheritance. Previous reports have involved defective cell signaling by semaphorin-3A in the pathogenesis. Here, we report that embryonic phenotype Plxna1-/- mutant mice lacking plexin-A1 (a major receptor class 3 semaphorins),...
G protein-coupled receptors (GPCRs) are among the most promising drug targets. They often form homo- and heterodimers with allosteric cross-talk between receptor entities, which contributes to fine-tuning of transmembrane signaling. Specifically controlling activity GPCR dimers ligands is a good approach clarify their physiological roles validate them as Here, we examined mode action positive modulators (PAMs) that bind at interface domains heterodimeric GABA B receptor. Our site-directed...
The insecticide carbaryl is commonly found in indirectly exposed freshwater ecosystems at low concentrations considered safe for fish communities. In this study, we showed that after only 24 h of exposure to environmental (0.066–660 ng/L), zebrafish larvae exhibit impairments essential behaviours. Interestingly, the observed behavioural effects induced by were acetylcholinesterase-independent. To elucidate molecular initiating event resulted effects, silico predictions followed vitro...
Metabotropic glutamate receptors (mGluRs) play key roles in the modulation of many synapses. Chloride (Cl-) is known to directly bind and regulate function different actors neuronal activity, several studies have pointed possible mGluRs by Cl-. Herein, we demonstrate that Cl- behaves as a positive allosteric modulator mGluRs. For example, whereas potency was 3.08 ± 0.33 μM on metabotropic (mGlu) 4 high-Cl- buffer, signaling activity almost abolished low Cl_ cell-based assays. 78.6 3.5 mM....
β2-Adrenoceptors (β2-AR) are prototypical G-protein-coupled receptors and important pharmacological targets with relevant roles in physiological processes diseases. Herein, we introduce Photoazolol-1–3, a series of photoswitchable azobenzene β2-AR antagonists that can be reversibly controlled light. These new photochromic ligands designed following the azologization strategy, p-acetamido substituting hydrophobic moiety present many antagonists. Using fluorescence resonance energy transfer...
Catecholamine-triggered β-adrenoceptor (β-AR) signaling is essential for the correct functioning of heart. Although both β1 - and β2 -AR subtypes are expressed in cardiomyocytes, drugs selectively targeting have proven this receptor as main target therapeutic effects beta blockers Here, we report a new strategy light-control activation by means photoswitchable with high level -/β2 selectivity. All reported molecules allow an efficient real-time optical control function vitro. Moreover, using...
Abstract Knowing the site of drug action is important to optimize effectiveness and address any side effects. We used light-sensitive drugs identify brain region-specific role mGlu5 metabotropic glutamate receptors in control pain. Optical activation systemic JF-NP-26, a caged, normally inactive, negative allosteric modulator (NAM) receptors, cingulate, prelimbic infralimbic cortices thalamus inhibited neuropathic pain hypersensitivity. Systemic treatment alloswitch-1, an intrinsically...
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