A5047477513- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Neuropeptides and Animal Physiology
- Protein Kinase Regulation and GTPase Signaling
- S100 Proteins and Annexins
- Diabetes Treatment and Management
- Pancreatic function and diabetes
- Viral Infectious Diseases and Gene Expression in Insects
- Chemical Synthesis and Analysis
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Phosphodiesterase function and regulation
- CRISPR and Genetic Engineering
- Caveolin-1 and cellular processes
- Regulation of Appetite and Obesity
- Pharmacological Receptor Mechanisms and Effects
- Molecular Sensors and Ion Detection
- Molecular Biology Techniques and Applications
- Nicotinic Acetylcholine Receptors Study
- Heat shock proteins research
- Semiconductor materials and interfaces
- Retinal Development and Disorders
- Biochemical Analysis and Sensing Techniques
- Molecular Junctions and Nanostructures
- Computational Drug Discovery Methods
- Monoclonal and Polyclonal Antibodies Research
University of Copenhagen
2012-2025
Institut de Génomique Fonctionnelle
2017-2023
Université de Montpellier
2017-2023
Centre National de la Recherche Scientifique
2017-2023
Inserm
2017-2023
Monash University
2020-2021
Novo Nordisk (Denmark)
2020-2021
Cardiff University
2020
The University of Sydney
2020
Medical University of Vienna
2020
The glucagon‐like peptide‐1 receptor (GLP‐1R) plays an important role in regulating insulin secretion and reducing body weight, making it a prominent target the treatment of type 2 diabetes obesity. Extensive research on GLP‐1R signaling has provided insights into connection between function physiological outcomes, such as correlation Gs secretion, yet exact mechanisms remain unclear. Here, we explore internalization pathway GLP‐1R, which is crucial for controlling release maintaining...
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,...
Binding and signaling kinetics have previously proven important in validation of biased agonism at GPCRs. Here we provide a comprehensive kinetic pharmacological comparison clinically relevant μ-opioid receptor agonists, including the novel agonist oliceridine (TRV130) which is clinical trial for pain management. We demonstrate that bias profile observed selected agonists not time-dependent with dramatic differences their binding properties can display same degree bias. analyses...
Abstract Most G protein-coupled receptors (GPCRs) recruit β-arrestins and internalize upon agonist stimulation. For the μ-opioid receptor (μ-OR), this process has been linked to development of opioid tolerance. GPCR kinases (GRKs), particularly GRK2 GRK3, have shown be important for μ-OR recruitment β-arrestin internalization. However, contribution GRK3 internalization, remain determined in their complete absence. Using CRISPR/Cas9-mediated genome editing we established HEK293 cells with...
Nanowire-based field-effect transistors (FETs) can be used as ultra-sensitive and label-free biosensors for detecting protein–protein interactions. A way to increase the performance of such sensors is dilute sensing buffer drastically. However, we show here that this have an important effect on function proteins. Moreover, it demonstrated dilution significantly affects pH stability buffer, which consequently impacts charge protein thus response signal-to-noise ratio in experiments. Three...
G protein-coupled receptors (GPCRs) are key players in cell communication and encoded by the largest family our genome. As such, GPCRs represent main targets drug development programs. Sequence analysis revealed several classes of GPCRs: class A rhodopsin-like majority, B includes secretin-like adhesion GPCRs, F frizzled receptors, C for neurotransmitters, glutamate GABA, those sweet umami taste calcium receptors. Class far more complex than other being mandatory dimers, with each subunit...
Abstract G protein coupled receptors (GPCRs) play essential roles in intercellular communication. Although reported two decades ago, the assembly of GPCRs into dimer and larger oligomers their native environment is still a matter intense debate. Here, using number brightness analysis fluorescently labeled cultured hippocampal neurons, we confirm that metabotropic glutamate receptor type 2 (mGlu ) homodimer at expression levels physiological range, while heterodimeric GABA B form complexes....
Formyl peptide receptor 2 (FPR2) is a G protein-coupled pattern recognition sensing both mitochondrial- and bacterial-derived formylated peptides, including the PSMα toxins secreted by community-associated methicillin-resistant Staphylococcus aureus strains. Similar to many other FPR2 agonistic nanomolar concentrations of PSMα2 PSMα3 activate neutrophils increase cytosolic concentration Ca2+ release NADPH oxidase-derived reactive oxygen species. In addition, peptides induce homologous...
FPR2, a member of the family G protein-coupled receptors (GPCRs), mediates neutrophil migration, response that has been linked to β-arrestin recruitment. β-Arrestin regulates GPCR endocytosis and can also elicit non-canonical receptor signaling. To determine poorly understood role in FPR2 NADPH-oxidase activation neutrophils, Barbadin was used as research tool this study. shown bind clathrin adaptor protein (AP2) thereby prevent β-arrestin/AP2 interaction β-arrestin-mediated endocytosis. In...
Biased ligands that selectively confer activity in one pathway over another are pharmacologically important because biased signaling may reduce on-target side effects and improve drug efficacy. Here, we describe an N-terminal modification the incretin hormone glucagon-like peptide (GLP-1) alters capabilities of GLP-1 receptor (GLP-1R) by making it G protein internalization but was originally designed to DPP-4 resistance thereby prolong half-life GLP-1. Despite similar binding affinity, cAMP...
GPCR desensitization and down-regulation are considered key molecular events underlying the development of tolerance in vivo. Among many regulatory proteins that involved these complex processes, GASP-1 have been shown to participate sorting several receptors toward degradation pathway. This protein belongs recently identified GPCR-associated (GASPs) family comprises ten members for which structural functional details poorly documented. We present here a detailed structure–function...
In order to avoid a prolonged pro-inflammatory neutrophil response, signaling downstream of an agonist-activated G protein-coupled receptor (GPCR) has be rapidly terminated. Among the family GPCR kinases (GRKs) that regulate phosphorylation and termination, GRK2, which is highly expressed by immune cells, plays important role. The medium chain fatty acid GPR84 as well formyl peptide 2 (FPR2), receptors in neutrophils, play key role regulating inflammation. this study, we investigated effects...
The corticotropin-releasing hormone receptor type 1 (CRHR1) plays an important role in orchestrating neuroendocrine, behavioral, and autonomic responses to stress. To identify molecules capable of directly modulating CRHR1 signaling, we performed a yeast-two-hybrid screen using the C-terminal intracellular tail as bait. We identified several members membrane-associated guanylate kinase (MAGUK) family: postsynaptic density protein 95 (PSD95), synapse-associated 97 (SAP97), SAP102 membrane...
Kainate receptors belong to the family of glutamate ion channels, which are responsible for majority rapid excitatory synaptic transmission in central nervous system. The therapeutic potential kainate is still poorly understood, also due lack potent and subunit-selective pharmacological tools. In search selective ligands GluK3 receptor subtype, a series quinoxaline-2,3-dione analogues was synthesized pharmacologically characterized at selected recombinant ionotropic receptors. Among them,...
G protein-coupled receptors (GPCRs) are seven transmembrane that respond to external stimuli and undergo conformational changes activate proteins modulate cellular processes leading biological outcomes. To prevent overstimulation prolonged exposure stimuli, GPCRs regulated by internalization. While the canonical GPCR internalization mechanism in mammalian cells is arrestin-dependent, clathrin-mediated endocytosis, more diverse mechanisms have been described over years. However, there a lack...
Negative allosteric modulation of the metabotropic glutamate 5 (mGlu<sub>5</sub>) receptor has emerged as a potential strategy for treatment neurologic disorders. Despite success in preclinical studies, many mGlu<sub>5</sub> negative modulators (NAMs) that have reached clinical trials failed due to lack efficacy. In this study, we provide detailed vitro pharmacological characterization nine clinically and preclinically tested NAMs. We evaluated inhibition l-glutamate–induced signaling with...
G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins in human genome. Their signaling is regulated by scaffold containing PDZ domains, but although these interactions are important for GPCR function, they still poorly understood. We here present a quantitative characterization kinetics and affinity between GPCRs one best characterized proteins, postsynaptic density protein 95 (PSD-95), using fluorescence polarization (FP) surface plasmon resonance (SPR). By...
Positive allosteric modulation of metabotropic glutamate subtype 5 (mGlu<sub>5</sub>) receptor has emerged as a potential new therapeutic strategy for the treatment schizophrenia and cognitive impairments. However, positive modulator (PAM) agonist activity been associated with adverse side effects, neurotoxicity also observed pure PAMs. The structural pharmacological basis versus mGlu<sub>5</sub> PAM in vivo effects remains unknown. Thus, gaining insights into signaling fingerprints, well...
Abstract Formyl peptide receptor 2 (FPR2), a member of the family G protein-coupled receptors (GPCRs), mediates neutrophil migration, response that has been linked to β-arrestin recruitment. β-Arrestin regulates GPCR endocytosis and can also elicit non-canonical signaling. To determine poorly understood role in FPR2 NADPH-oxidase activation neutrophils, Barbadin was used as research tool this study. shown bind clathrin adaptor protein (AP2) thereby prevent β- arrestin/AP2 interaction...