Biology subjects

Marie, M.

Publications and source records attributed to Marie, M..

3 recordsLinked to original sources

bioRxiv2026

Allosteric Gating Mechanism Regulates Odorant Selectivity and Antagonism in Odorant Receptors

Odorant receptors (ORs) belong to class A G protein coupled receptors that detect diverse small molecules, yet the steps that link odorant association to receptor mediated selectivity remains incompletely defined. Here we combined 1.26 milliseconds of all-atom odorant association Molecular Dynamics simulations with Markov state modeling and cell-based cAMP measurements to examine two human ORs receptors that recognize chemically distinct odorants. In the class I receptor OR51E2, propionate associates via two extracellular pathways gated for selectivity by residues in the extracellular loop 2 and 3. The longer alkyl chain heptanoate occupies this gate and reduces propionate association and signaling which is consistent with the observed antagonist behavior of heptanoate. Pocket-expanding mutations at F155 and L158 allosterically regulate ECL2-ECL3 gate by permitting longer-chain fatty acids to adopt fully inserted poses that support gate closure, while also attenuating propionate responses. In the class II receptor OR1A1, hydrophobic odorants partition into the membrane and reach the orthosteric site mostly through multiple transmembrane paths. A mutational scan of gating residues and analysis of intermediate-state occupancies suggest that an orthosteric substitution at G108 can allosterically bias odorant association path choice. Together, these results support a model in which odorant association paths and gate residence, together with allosteric coupling between the orthosteric site and entry gates, contribute to odorant specificity and antagonism in odorant receptors.

biophysics↗

bioRxiv2019

Pharmacological inhibition of GPR4 remediates intestinal inflammation in a mouse colitis model

Inflammatory bowel disease (IBD) is characterized by chronic, recurring inflammation of the digestive tract. Current therapeutic approaches are limited and include biologics and steroids such as anti-TNF monoclonal antibodies and corticosteroids, respectively. Significant adverse drug effects can occur for chronic usage and include increased risk of infection in some patients. GPR4, a pH-sensing G protein-coupled receptor, has recently emerged as a potential therapeutic target for intestinal inflammation. We have assessed the effects of a GPR4 antagonist, 2-(4-((2-Ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)phenyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (GPR4 antagonist 13, also known as NE 52-QQ57) in the dextran sulfate sodium (DSS)-induced acute colitis mouse model. The GPR4 antagonist 13 inhibited intestinal inflammation. The clinical parameters such as body weight loss and fecal score were reduced in the GPR4 antagonist 13 treatment group compared to vehicle control. Macroscopic disease indicators such as colon shortening, splenic expansion, and mesenteric lymph node enlargement were all reduced in severity in the GPR4 antagonist 13 treated mice. Histopathological features of active colitis were alleviated in GPR4 antagonist 13 treatment groups compared to vehicle control. Finally, inflammatory gene expression in the colon tissues and vascular adhesion molecule expression in the intestinal endothelia were attenuated by GPR4 antagonist 13. Our results indicate that GPR4 antagonist 13 provides a protective effect in the DSS-induced acute colitis mouse model, and inhibition of GPR4 can be explored as a novel anti-inflammatory approach.

pharmacology and toxicology↗

bioRxiv2018

TDAG8 (GPR65) Inhibits Intestinal Inflammation in the DSS-Induced Experimental Colitis Mouse Model

T cell death-associated gene 8 (TDAG8, also known as GPR65) is a proton-sensing G protein-coupled receptor (GPCR) predominantly expressed in immune cells. Genome-wide association studies identify TDAG8 as a susceptibility candidate gene linked to several human inflammatory diseases including inflammatory bowel disease (IBD), asthma, spondyloarthritis, and multiple sclerosis. In this study, our results demonstrate that mice deficient of TDAG8 exhibited more severe inflammatory phenotypes than wild-type mice in a chronic dextran sulfate sodium (DSS)-induced colitis mouse model. Several disease parameters, such as diarrhea, colon shortening, fibrosis, histopathological score, and mesenteric lymph node enlargement were aggravated in TDAG8-null mice in comparison to wild-type mice treated with DSS. Increased leukocyte infiltration and myofibroblast expansion were observed in colonic tissues of DSS-treated TDAG8-null mice. These changes may represent a cellular basis of the observed exacerbation of intestinal inflammation and fibrosis in these mice. In line with high expression of TDAG8 in infiltrated leukocytes, real-time RT-PCR revealed that TDAG8 mRNA expression was increased in inflamed intestinal tissue samples of IBD patients when compared to normal intestinal tissues. Altogether, our data demonstrate that TDAG8 suppresses intestinal inflammation and fibrosis in the chronic DSS-induced colitis mouse model, suggesting potentiation of TDAG8 with agonists may have anti-inflammatory therapeutic effects in IBD.

pathology↗