A5007138163- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Hormonal Regulation and Hypertension
- Chemical Synthesis and Analysis
- Renin-Angiotensin System Studies
- Apelin-related biomedical research
- Monoclonal and Polyclonal Antibodies Research
- Computational Drug Discovery Methods
- Pharmacological Receptor Mechanisms and Effects
- Ubiquitin and proteasome pathways
- Diabetes Treatment and Management
- Cellular transport and secretion
- Cell Adhesion Molecules Research
- Neurobiology and Insect Physiology Research
- Pancreatic function and diabetes
- Cardiovascular Disease and Adiposity
- Synthesis and Catalytic Reactions
- Chronic Lymphocytic Leukemia Research
- Immunotherapy and Immune Responses
- Retinopathy of Prematurity Studies
- Nanoplatforms for cancer theranostics
- Free Radicals and Antioxidants
- Biochemical and Structural Characterization
- Anesthesia and Pain Management
Université de Sherbrooke
2012-2024
Centre Hospitalier Universitaire de Sherbrooke
2022
Crystal structures provide first atomic-level insights into δ-opioid receptor activation by two structurally diverse agonists.
G protein–coupled receptors engage both proteins and β-arrestins, their coupling can be biased by ligands mutations. Here, to resolve structural elements mechanisms underlying effector the angiotensin II (AngII) type 1 receptor (AT1R), we combined alanine scanning mutagenesis of entire sequence with pharmacological profiling Gα q β-arrestin engagement mutant molecular dynamics simulations. We showed that AT1R involved a large number residues spread across receptor, whereas fewer regions...
Abstract Latrophilin-3 (Lphn3; also known as ADGRL3) is a member of the adhesion G Protein Coupled Receptor subfamily, which participates in stabilization and maintenance neuronal networks by mediating intercellular through heterophilic interactions with transmembrane ligands. Polymorphisms modifying Lphn3 gene are associated attention-deficit/hyperactivity disorder (ADHD) children its persistence into adulthood. How these genetic alterations affect receptor function remains unknown. Here,...
The octapeptide angiotensin II (AngII) exerts a variety of cardiovascular effects through the activation AngII type 1 receptor (AT<sub>1</sub>), G protein–coupled receptor. AT<sub>1</sub> engages and activates several signaling pathways, including heterotrimeric proteins G<sub>q</sub> G<sub>12</sub>, as well extracellular signal–regulated kinases (ERK) 1/2 pathway. Additionally, following stimulation, <i>β</i>arrestin is recruited to receptor, leading desensitization. It increasingly...
The role of transmembrane domain six (TMD6) the angiotensin II type 1 receptor, which is predicted to undergo conformational changes after agonist binding, was investigated using substituted-cysteine accessibility method. Each residue in Lys240-Leu265 fragment mutated, one at a time, cysteine. resulting mutants were expressed COS-7 cells, subsequently treated with charged sulfhydryl-specific alkylating agent methanethiosulfonate-ethylammonium (MTSEA). This treatment led significant reduction...
Class A (rhodopsin-like) G protein-coupled receptors possess conserved residues and motifs that are important for their specific activity. In the present study, we examined role of residue Asp97<sup>2.50</sup> as well Glu147<sup>3.49</sup>, Arg148<sup>3.50</sup>, Tyr149<sup>3.51</sup> ERY motif on functionality urotensin II receptor (UT). Mutations D97<sup>2.50</sup>A, R148<sup>3.50</sup>A, R148<sup>3.50</sup>H abolished ability UT to activate phospholipase C, whereas mutations...
A stereospecific convergent synthesis of N-[(9-fluorenyl)methoxycarbonyl]-p-[3-(trifluoromethyl)-3H-diazirin-3-yl]-l-phenylalanine (Fmoc-12, Fmoc-Tdf) and its incorporation into the C-terminal position angiotensin II (AngII) peptide to form 125I[Sar1,Tdf8]AngII (125I-13) is presented. This amino acid photoprobe a highly reactive carbene-generating diazirine phenylalanine derivative that can be used for photoaffinity labeling. Using model receptors, we compared reactivity Met selectivity 12...
Leu-enkephalin and d-Ala2-Leu-enkephalin were modified at their N- C-termini with guanidyl tetrazole groups. The resulting molecules prepared in solution or by solid phase peptide synthesis. affinity of the different analogues mu (MOP) delta opioid receptors (DOP) was then assessed competitive binding stably transfected DOP MOP HEK293 cells. Inhibition cAMP production recruitment β-arrestin also investigated. Finally, lipophilicity (logD7.4) plasma stability each compound measured. Compared...
Linking an opioid to a nonopioid pharmacophore represents promising approach for reducing opioid-induced side effects during pain management. Herein, we describe the optimization of previously reported opioid-neurotensin hybrids (OPNT-hybrids),
The octapeptide hormone angiotensin II exerts a wide variety of cardiovascular effects through the activation Type 1 (AT1) receptor, which belongs to G protein-coupled receptor superfamily. Like other protein- coupled receptors, AT1 possesses seven transmembrane domains that provide structural support for formation ligand-binding pocket. role fifth domain (TMD5) was investigated using substituted cysteine accessibility method. All residues within Thr-190 Leu-217 region were mutated one at...
Abstract Collagen type IV (CnIV) and fibronectin (Fn) were used as ligands to study the distribution of α2β1 α4β1 integrins in low-density, detergent-resistant microdomains (DRM) Jurkat lymphocytes. CnIV-coated microspheres induced (optical trapping) redistribution GM1-associated fluorecence from cell periphery area contact. This was not observed cells treated with β-methyl cyclodextrin (MCD). Fn- or bovine serum albumin-coated did modify peripheral fluorescence. These observations confirmed...
The octapeptide hormone angiotensin II (AngII) exerts a wide variety of cardiovascular effects through the activation AT1 receptor, which belongs to G protein-coupled receptor superfamily. Like other receptors, possesses seven transmembrane domains that provide structural support for formation ligand-binding pocket. Here, we investigated role first and fourth (TMDs) in binding pocket human using substituted-cysteine accessibility method. Each residue within Phe-28(1.32)–Ile-53(1.57) fragment...
The mechanism by which GPCRs (G-protein-coupled receptors) undergo activation is believed to involve conformational changes following agonist binding. We have used photoaffinity labelling identify domains within that make contact with various photoreactive ligands in order better understand the mechanism. Here, a series of four {[Bpa1]U-II (Bpa p-benzoyl-L-phenylalanine), [Bpa2]U-II, [Bpa3]U-II and [Bpa4]U-II} three partial {[Bpa1Pen5D-Trp7Orn8]U-II (Pen penicillamine),...
The octapeptide hormone angiotensin II (AngII) exerts a wide variety of cardiovascular effects through the activation type-1 (AT1) receptor, which belongs to G protein-coupled receptor superfamily. Like other receptors, AT1 possesses seven transmembrane domains that provide structural support for formation ligand-binding pocket. In order identify those residues in second domain (TMD2) contribute binding pocket we used substituted cysteine accessibility method. All within Leu-70 Trp-94 region...
Abstract The renin-angiotensin system regulates blood pressure and fluid balance in the body primarily via angiotensin receptor 1 (AT1R). Renal AT1R was found to be responsible for Ang II-mediated hypertension. G protein-coupled kinase 2 (GRK2) modulates desensitization increased GRK2 protein expression is reported hypertensive patients. However, consequences of inhibition on kidney functions remain unknown. We employed shGRK2 knockdown mice (shGRK2 mice) test role development function that...
The octapeptide hormone angiotensin II (AngII) binds to and activates the human type 1 receptor (hAT(1)) of G protein-coupled class A family. Several activation mechanisms have been proposed for this family, but they not yet experimentally validated. We previously used methionine proximity assay show that 11 residues in transmembrane domain (TMD) III, VI, VII hAT(1) reside close C-terminal residue AngII. With exception a single change TMD same contacts are present on N111G-hAT(1),...
Significance Gα s protein is classically known as a signaling component of cell surface G protein-coupled receptor transduction pathways. However, has also been localized on endosomes, where it plays role in sorting to lysosomes. How regulates this trafficking step unclear. Although structure for years, we found motif that allows its interaction with ubiquitin, key signal cargo the lysosomal pathway. We show disrupting ubiquitin-interacting (UIM) impairs components endosomal machinery and...
Abstract Enkephalins are pentapeptidic endogenous ligands that regulate nociception by binding to mu (MOP) and delta (DOP) opioid receptors. To further explore the role of leucine residue Leu‐enkephalin, 12 peptidomimetic analogs were synthesized systematically replacing this with non‐natural amino acids. The tested for their ability bind DOP MOP. We also investigated potency these inhibit cAMP production recruit β‐arrestin 2 via both found replacement substituted acid derivatives alanine,...