Research

 Although most odorant receptors (ORs) are extensively expressed in nasal olfactory sensory neurons, ectopic expression of ORs in non-chemosensory tissues has been recently reported. More recently, we and other researchers demonstrated ectopic expression of ORs in a variety of tissues including the pancreas, brain, bladder, heart, skin, kidney, muscle, testis, liver, and gut. The function of ORs is revealed one by one, and the importance of its physiological function is emerging. In general, ORs bind to a number of odorants with a wide range of binding affinities. Furthermore, odorants generally possess one or more functional groups that can activate multiple ORs. However, our knowledge of the molecular pharmacology of ectopic ORs remains limited due to the lack of selective and specific agonists. We recently designed and synthesized novel synthetic agonists of ectopic ORs. Molecular docking and site-directed mutagenesis studies suggest that a combination of hydrophilic and hydrophobic interactions is central to the selective and specific binding of synthetic agonists to ORs (Park et al., 2017). We will apply these technologies to ectopic ORs to have in vivo functions as potential Drug Targets.How to cite:Click Park BB, Lee N, Kim Y, Jae Y, Choi S, Kang N, Hong YR, Ok K, Cho J, Jeon YH, Lee EH, Byun Y, Koo JH. Analogues of Dehydroacetic Acid as Selective and Potent Agonists of an Ectopic Odorant Receptor through a Combination of Hydrophilic and Hydrophobic Interactions. ChemMedChem. 2017 Apr 6;12(7):477-482. doi: 10.1002/cmdc.201600612.

 Cumulative evidence indicates that diet and metabolic products, including bacteria- and host-origin metabolites, regulate host pathology and physiology by regulating metabolism, immune responses, and inflammation. One important mechanism by which microbiota affects the host is signaling through G protein-binding receptors (GPCRs), called metabolic sensing GPCRs. In the gut, immune and non-immune cells express GPCRs as well as odorant GPCRs and their activations may provide anti-inflammatory signals through the regulation of both immune system functions and epithelial integrity. Members of the GPCR family serve as a link between Microbiota, brain, immune system and intestinal epithelium. Conversely, GPCR signal disorders are associated with some diseases, including cancer, diabetes, obesity, and cardiovascular disease. How to cite:Click Kang N, Koo JH. Olfactory receptors in non-chemosensory tissues.BMB Rep. 2012 Nov;45(11):612-22. doi: 10.5483/bmbrep.2012.45.11.232.

 Astrocytes are the most abundant cell type in the brain and they are involved in Brain Energy Metabolism through astrocyte-neuron metabolic cooperation. Medium-chain fatty acids (MCFAs) are mostly generated from dietary triglycerides and can penetrate the blood-brain barrier. Astrocytes in the brain use MCFAs as an alternative energy source. Stimulation with MCFAs increases glycolytic activity and consequently induces release of lactate by astrocytes into the extracellular space. However, little is known about the molecular mechanism by which astrocytes sense free FAs and increase lactate release and by which GPCRs recognize free FAs in astrocytes. We demonstrate a novel molecular mechanism by which astrocytes recognize free MCFAs (Lee et al. 2018). Our findings suggest that astrocytes play crucial roles in lipid sensing in the brain and modulate metabolism in nearby neurons by releasing lactate and/or GABA. We propose that the modulation of lactate and GABA production mediated by GPCRs and MAO-B is a new approach to control energy metabolism in astrocytes.How to cite: Click Lee N, Sa M, Hong YR, Lee CJ, Koo JH. Fatty Acid Increases cAMP-dependent Lactate and MAO-B-dependent GABA Production in Mouse Astrocytes by Activating a Gαs Protein-coupled Receptor. Exp Neurobiol. 2018 Oct;27(5):365-376. doi: 10.5607/en.2018.27.5.365.

 Many ORs are expressed by tumor cells and tissues, suggesting that they may be associated with cancer progression or may be cancer biomarkers. We suggest the clinical relevance and significance of the levels of OR expression and Brain-Immune Crosstalk in cancers (Valdevoo et al. 2021; Cho and Koo 2021; Chung et al. 2022). We analyzed the levels of OR expression based on RNA-sequencing data reported in the Cancer Genome Atlas, and analyzed the associations between patient survival and levels of OR expression by visualizing OR expression patterns using t-distributed stochastic neighbor embedding (t-SNE). These analyses of the relationships between patient survival and expression patterns obtained from an open mRNA database in cancer patients suggest that ORs may be cancer biomarkers and therapeutic targets.How to cite:Click Vadevoo SMP, Gunassekaran GR, Lee C, Lee N, Lee J, Chae S, Park JY, Koo J, Lee B. The macrophage odorant receptor Olfr78 mediates the lactate-induced M2 phenotype of tumor-associated macrophages. Proc Natl Acad Sci U S A. 2021 Sep 14;118(37):e2102434118. doi: 10.1073/pnas.2102434118. Cho HJ, Koo JH. Odorant G protein-coupled receptors as potential therapeutic targets for adult diffuse gliomas: a systematic analysis and review. BMB Rep. 2021 Dec;54(12):601-607. doi: 10.5483/BMBRep.2021.54.12.165. Chung C, Cho HJ, Lee C, Koo JH. Odorant receptors in cancer. BMB Rep. 2022 Feb;55(2):72-80. doi: 10.5483/BMBRep.2022.55.2.010.

 Microglia, the principal neuroimmune sentinel in the brain, continuously sense changes in their environment and respond to invading pathogens, toxins, and cellular debris, thereby affecting neuroinflammation. Microbial pathogens produce small metabolites that influence neuroinflammation, but the molecular mechanisms that determine whether pathogen derived small metabolites affect microglial activation of neuroinflammation remain to be elucidated. We found that Microglia express high levels of two mouse odorant receptors (ORs), Olfr110 and Olfr111, which recognize a pathogenic metabolite (Lee et al. 2020). Greater knowledge of these interactions could provide fundamental insight into the interface between the brain and immune system during brain infection and inflammation. This interaction induces microglial activation, suggesting a unique pathogen-derived metabolite-mediated Brain-Immune Axis associated with neuroinflammation. Conventional pattern recognition receptors involved in microglial activation are receptors for pathogen-derived macromolecules, including cell wall components, peptidoglycan, lipoteichoic acid, and flagellin. Our findings provide an alternative strategy for pathogen recognition by the brain that involves small metabolite–OR interactions.How to cite:Click Lee N, Jae Y, Kim M, Cho T, Lee C, Hong YR, Hyeon DY, Ahn S, Kwon H, Kim K, Jung JH, Chae S, Shin JO, Bok J, Byun Y, Hwang D, Koo JH. A pathogen-derived metabolite induces microglial activation via odorant receptors. FEBS J. 2020 Jan 30. doi: 10.1111/febs.15234.