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Gozoh Tsujimoto - One of the best experts on this subject based on the ideXlab platform.
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the oral lipid sensor gpr120 is not indispensable for the orosensory detection of dietary lipids in mice
Journal of Lipid Research, 2015Co-Authors: Deborah Ancel, Arnaud Bernard, Selvakumar Subramaniam, Patricia Passillydegrace, Naimakhtar Khan, Gozoh Tsujimoto, Toshihiro Hashimoto, Akira Hirasawa, Philippe BesnardAbstract:Implication of the long-chain fatty acid (LCFA) receptor GPR120, also termed free fatty acid receptor 4, in the taste-guided preference for lipids is a matter of debate. To further unravel the role of GPR120 in the “taste of fat”, the present study was conducted on GPR120-null mice and their wild-type littermates. Using a combination of morphological [i.e., immunohistochemical staining of circumvallate papillae (CVP)], behavioral (i.e., two-bottle preference tests, licking tests and conditioned taste aversion) and functional studies [i.e., calcium imaging in freshly isolated taste bud cells (TBCs)], we show that absence of GPR120 in the oral cavity was not associated with changes in i) gross anatomy of CVP, ii) LCFA-mediated increases in intracellular calcium levels ([Ca2+]i), iii) preference for oily and LCFA solutions and iv) conditioned avoidance of LCFA solutions. In contrast, the rise in [Ca2+]i triggered by grifolic acid, a specific GPR120 agonist, was dramatically curtailed when the GPR120 gene was lacking. Taken together, these data demonstrate that activation of lingual GPR120 and preference for fat are not connected, suggesting that GPR120 expressed in TBCs is not absolutely required for oral fat detection in mice
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structure activity relationships of gpr120 agonists based on a docking simulation
Molecular Pharmacology, 2010Co-Authors: Akira Hirasawa, Takayoshi Suzuki, Naoki Miyata, Takeo Awaji, Masaji Ishiguro, Tetsuya Adachi, Takafumi Hara, Ikuo Kimura, Gozoh TsujimotoAbstract:GPR120 is a G protein-coupled receptor expressed preferentially in the intestinal tract and adipose tissue, that has been implicated in mediating free fatty acid-stimulated glucagon-like peptide-1 (GLP-1) secretion. To develop GPR120-specific agonists, a series of compounds (denoted as NCG compounds) derived from a peroxisome proliferator-activated receptor γ agonist were synthesized, and their structure-activity relationships as GPR120 agonists were explored. To examine the agonistic activities of these newly synthesized NCG compounds, and of compounds already shown to have GPR120 agonistic activity (grifolic acid and MEDICA16), we conducted docking simulation in a GPR120 homology model that was developed on the basis of a photoactivated model derived from the crystal structure of bovine rhodopsin. We calculated the hydrogen bonding energies between the compounds and the GPR120 model. These energies correlated well with the GPR120 agonistic activity of the compounds ( R2 = 0.73). NCG21, the NCG compound with the lowest calculated hydrogen bonding energy, showed the most potent extracellular signal-regulated kinase (ERK) activation in a cloned GPR120 system. Furthermore, NCG21 potently activated ERK, intracellular calcium responses and GLP-1 secretion in murine enteroendocrine STC-1 cells that express GPR120 endogenously. Moreover, administration of NCG21 into the mouse colon caused an increase in plasma GLP-1 levels. Taken together, our present study showed that a docking simulation using a GPR120 homology model might be useful to predict the agonistic activity of compounds.
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structure activity relationships of gpr120 agonists based on a docking simulation
Molecular Pharmacology, 2010Co-Authors: Akira Hirasawa, Takayoshi Suzuki, Naoki Miyata, Takeo Awaji, Masaji Ishiguro, Tetsuya Adachi, Takafumi Hara, Ikuo Kimura, Gozoh TsujimotoAbstract:GPR120 is a G protein-coupled receptor expressed preferentially in the intestinal tract and adipose tissue, that has been implicated in mediating free fatty acid-stimulated glucagon-like peptide-1 (GLP-1) secretion. To develop GPR120-specific agonists, a series of compounds (denoted as NCG compounds) derived from a peroxisome proliferator-activated receptor γ agonist were synthesized, and their structure-activity relationships as GPR120 agonists were explored. To examine the agonistic activities of these newly synthesized NCG compounds, and of compounds already shown to have GPR120 agonistic activity (grifolic acid and MEDICA16), we conducted docking simulation in a GPR120 homology model that was developed on the basis of a photoactivated model derived from the crystal structure of bovine rhodopsin. We calculated the hydrogen bonding energies between the compounds and the GPR120 model. These energies correlated well with the GPR120 agonistic activity of the compounds ( R2 = 0.73). NCG21, the NCG compound with the lowest calculated hydrogen bonding energy, showed the most potent extracellular signal-regulated kinase (ERK) activation in a cloned GPR120 system. Furthermore, NCG21 potently activated ERK, intracellular calcium responses and GLP-1 secretion in murine enteroendocrine STC-1 cells that express GPR120 endogenously. Moreover, administration of NCG21 into the mouse colon caused an increase in plasma GLP-1 levels. Taken together, our present study showed that a docking simulation using a GPR120 homology model might be useful to predict the agonistic activity of compounds.
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novel selective ligands for free fatty acid receptors gpr120 and gpr40
Naunyn-schmiedebergs Archives of Pharmacology, 2009Co-Authors: Takafumi Hara, Taka-aki Koshimizu, Keiko Sadakane, Chisato Itsubo, Toshihiro Hashimoto, Yoshinori Asakawa, Tetsuya Adachi, Akira Hirasawa, Gozoh TsujimotoAbstract:GPR120 and GPR40 are G-protein-coupled receptors whose endogenous ligands are medium- and long-chain free fatty acids, and they are thought to play an important physiological role in insulin release. Despite recent progress in understanding their roles, much still remains unclear about their pharmacology, and few specific ligands for GPR120 and GPR40 besides medium- to long-chain fatty acids have been reported so far. To identify new selective ligands for these receptors, more than 80 natural compounds were screened, together with a reference compound MEDICA16, which is known to activate GPR40, by monitoring the extracellular regulated kinase (ERK) and [Ca2+]i responses in inducible and stable expression cell lines for GPR40 and GPR120, respectively. MEDICA16 selectively activated [Ca2+]i response in GPR40-expressing cells but not in GPR120-expressing cells. Among the natural compounds tested, grifolin derivatives, grifolic acid and grifolic acid methyl ether, promoted ERK and [Ca2+]i responses in GPR120-expressing cells, but not in GPR40-expressing cells, and inhibited the α-linolenic acid (LA)-induced ERK and [Ca2+]i responses in GPR120-expressing cells. Interestingly, in accordance with the pharmacological profiles of these compounds, similar profiles of glucagon-like peptide-1 secretion were seen for mouse enteroendocrine cell line, STC-1 cells, which express GPR120 endogenously. Taken together, these studies identified a selective GPR40 agonist and several GPR120 partial agonists. These compounds would be useful probes to further investigate the physiological and pharmacological functions of GPR40 and GPR120.
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novel selective ligands for free fatty acid receptors gpr120 and gpr40
Naunyn-schmiedebergs Archives of Pharmacology, 2009Co-Authors: Takafumi Hara, Taka-aki Koshimizu, Keiko Sadakane, Chisato Itsubo, Toshihiro Hashimoto, Yoshinori Asakawa, Tetsuya Adachi, Akira Hirasawa, Gozoh TsujimotoAbstract:GPR120 and GPR40 are G-protein-coupled receptors whose endogenous ligands are medium- and long-chain free fatty acids, and they are thought to play an important physiological role in insulin release. Despite recent progress in understanding their roles, much still remains unclear about their pharmacology, and few specific ligands for GPR120 and GPR40 besides medium- to long-chain fatty acids have been reported so far. To identify new selective ligands for these receptors, more than 80 natural compounds were screened, together with a reference compound MEDICA16, which is known to activate GPR40, by monitoring the extracellular regulated kinase (ERK) and [Ca2+]i responses in inducible and stable expression cell lines for GPR40 and GPR120, respectively. MEDICA16 selectively activated [Ca2+]i response in GPR40-expressing cells but not in GPR120-expressing cells. Among the natural compounds tested, grifolin derivatives, grifolic acid and grifolic acid methyl ether, promoted ERK and [Ca2+]i responses in GPR120-expressing cells, but not in GPR40-expressing cells, and inhibited the α-linolenic acid (LA)-induced ERK and [Ca2+]i responses in GPR120-expressing cells. Interestingly, in accordance with the pharmacological profiles of these compounds, similar profiles of glucagon-like peptide-1 secretion were seen for mouse enteroendocrine cell line, STC-1 cells, which express GPR120 endogenously. Taken together, these studies identified a selective GPR40 agonist and several GPR120 partial agonists. These compounds would be useful probes to further investigate the physiological and pharmacological functions of GPR40 and GPR120.
Akira Hirasawa - One of the best experts on this subject based on the ideXlab platform.
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colocalization of gpr120 and anterior pituitary hormone producing cells in female japanese black cattle
Journal of Reproduction and Development, 2020Co-Authors: Sho Nakamura, Kohei Noda, Masafumi Miwa, Shuichi Matsuyama, Teruki Hagiwara, Shiori Minabe, Akira Hirasawa, Ryutaro MoriyamaAbstract:: Negative energy balance in domestic animals suppresses their reproductive function. These animals commonly use long-chain fatty acids (LCFAs) from adipocytes as an energy source under states of malnutrition. The G-protein coupled receptor, GPR120, is a specific receptor for LCFAs, but its role in reproductive function remains unknown in domestic animals. The purpose of this study was to examine whether GPR120 is involved in the reproductive system of cattle. GPR120 mRNA expression was evaluated in brain, pituitary, and ovarian tissue samples by RT-PCR. GPR120 gene expression was detected with high intensity only in the anterior pituitary sample, and GPR120-immunoreactive cells were found in the anterior pituitary gland. Double immunohistochemistry of GPR120 in the anterior pituitary hormone-producing cells, such as gonadotropes, thyrotropes, lactotropes, somatotropes, and corticotropes, was performed to clarify the distribution of GPR120 in the anterior pituitary gland of ovariectomized heifers. Luteinizing hormone β subunit (LHβ)- and follicle-stimulating hormone β subunit (FSHβ)-immunoreactive cells demonstrated GPR120 immunoreactivity at 80.7% and 85.9%, respectively. Thyrotropes, lactotropes, somatotropes, and corticotropes coexpressed GPR120 at 21.1%, 5.4%, 13.6%, and 14.5%, respectively. In conclusion, the present study suggests that GPR120 in the anterior pituitary gland might mediate LCFA signaling to regulate gonadotrope functions, such as hormone secretion or production, in cattle.
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dha supplementation prevent the progression of nash via gpr120 signaling
European Journal of Pharmacology, 2018Co-Authors: Kazuo Nakamoto, Koki Shimada, Shinichi Harada, Yasuko Morimoto, Akira Hirasawa, Shogo TokuyamaAbstract:Abstract Nonalcoholic steatohepatitis (NASH) is one of the most common liver diseases involving chronic accumulation of fat and inflammation, often leading to advanced fibrosis, cirrhosis and carcinoma. However, the pathological mechanism for this is unknown. GPR120/FFAR4 has been recognized as a functional fatty acid receptor and an attractive therapeutic target for metabolic diseases. In this study, we investigated the involvement of GPR120/FFAR4 in the pathogenesis of NASH. Mice fed with a 0.1% methionine and choline deficient high-fat (CDAHF) diet showed a significant increase in plasma aspartate transaminase and alanine transaminase levels, fatty deposition, inflammatory cell infiltration, and mild fibrosis. Docosahexaenoic acid (DHA, GPR120/FFAR4 agonist) suppressed the inflammatory cytokines in the liver tissues and prevented fibrosis in the wild type (WT) mice fed CDAHF diet, but not GPR120/FFAR4 deficient (GPR120KO) mice. GPR120KO mice fed CDAHF diet showed increment of the number of crown like structures and the immunoreactivity for F4/80 positive cells, and increased TNF-α mRNA in the liver compared to WT mice fed CDAHF diet. GPR120 KO mice fed CDAHF diet showed more severe liver inflammation than that of WT mice fed CDAHF diet, but not fibrosis. Our findings suggest that DHA supplementation could be prevented the development of NASH via GPR120/FFAR4 signaling. Furthermore, decrease of GPR120/FFAR4 signaling could be facilitated an inflammatory response in the process of NASH progression.
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the oral lipid sensor gpr120 is not indispensable for the orosensory detection of dietary lipids in mice
Journal of Lipid Research, 2015Co-Authors: Deborah Ancel, Arnaud Bernard, Selvakumar Subramaniam, Patricia Passillydegrace, Naimakhtar Khan, Gozoh Tsujimoto, Toshihiro Hashimoto, Akira Hirasawa, Philippe BesnardAbstract:Implication of the long-chain fatty acid (LCFA) receptor GPR120, also termed free fatty acid receptor 4, in the taste-guided preference for lipids is a matter of debate. To further unravel the role of GPR120 in the “taste of fat”, the present study was conducted on GPR120-null mice and their wild-type littermates. Using a combination of morphological [i.e., immunohistochemical staining of circumvallate papillae (CVP)], behavioral (i.e., two-bottle preference tests, licking tests and conditioned taste aversion) and functional studies [i.e., calcium imaging in freshly isolated taste bud cells (TBCs)], we show that absence of GPR120 in the oral cavity was not associated with changes in i) gross anatomy of CVP, ii) LCFA-mediated increases in intracellular calcium levels ([Ca2+]i), iii) preference for oily and LCFA solutions and iv) conditioned avoidance of LCFA solutions. In contrast, the rise in [Ca2+]i triggered by grifolic acid, a specific GPR120 agonist, was dramatically curtailed when the GPR120 gene was lacking. Taken together, these data demonstrate that activation of lingual GPR120 and preference for fat are not connected, suggesting that GPR120 expressed in TBCs is not absolutely required for oral fat detection in mice
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dysfunction of lipid sensor gpr120 leads to obesity in both mouse and human
Nature, 2012Co-Authors: Atsuhiko Ichimura, Odile Poulaingodefroy, Amelie Bonnefond, Loic Yengo, Takafumi Hara, Akira Hirasawa, Ikuo KimuraAbstract:Mice deficient in the lipid sensor GPR120 develop obesity, glucose intolerance and fatty liver when fed a high-fat diet, and a loss-of-function variant in the GPR120 gene strongly contributes to increased obesity in human. The G-protein-coupled receptor GPR120 is a receptor for free fatty acids, and is involved in homeostasis mechanisms such as fat-cell generation and the regulation of appetite. Here it is shown that without GPR120, mice on a high-fat diet develop obesity, glucose intolerance and fatty liver. In humans, GPR120 expression in adipose tissue is shown to be significantly elevated in obesity. The authors also identify a mutation that inhibits GPR120 signalling activity and is associated with an increased risk for obesity in Europeans. Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes1,2,3,4. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases3,5,6,7,8,9,10,11,12,13. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference5,6,14,15,16. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.
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o53 l alteration du recepteur des acides gras insatures de type omega 3 gpr120 entraine une obesite chez l homme et la souris
Diabetes & Metabolism, 2012Co-Authors: Amelie Bonnefond, Atsuhiko Ichimura, Odile Poulaingodefroy, Audrey Leloire, Helene Choquet, David Meyre, Loic Yengo, Akira Hirasawa, François Pattou, Isabelle WolowczukAbstract:Introduction GPR120 est un recepteur couple aux proteines G qui fixe les acides gras libres insatures a longue chaine (particulierement les omega-3). GPR120 jouerait un role important dans l’equilibre de divers mecanismes physiologiques comme l’adipogenese, la regulation de l’appetit ou encore l’appetence alimentaire. Le but de cette etude est d’analyser le role de GPR120 dans le metabolisme energetique de la Souris et de l’Homme. Materiels et methodes Nous avons genere une Souris deficiente pour Gpr120 (KO) et avons etudie son metabolisme (poids-taille, depenses energetiques, masse grasse, glycemie-insulinemie, voies de signalisation impliquees dans l’insulino-resistance, la lipogenese et l’adipogenese), sous differentes conditions (regime standard ou hyperlipidique, tests de tolerance au glucose et a l’insuline). Chez l’Homme, nous avons compare l’expression de GPR120 dans le tissu adipeux omental et sous-cutane, de 14 sujets obeses versus 14 temoins. GPR120 a ete sequence chez 312 individus presentant une obesite severe. Les mutations non-synonymes identifiees ont ete genotypees chez 6 942 individus obeses et 7 654 temoins, et leurs effets sur la fonction de GPR120 ont ete etudies dans des lignees cellulaires. Resultats Sous regime hyperlipidique, la Souris KO developpe une obesite, une intolerance au glucose et une steatose hepatique, avec une diminution de la differenciation et de la lipogenese des adipocytes, et une augmentation de la lipogenese hepatique. L’insulino-resistance de la Souris KO est liee a une diminution du signal insulinique et a une augmentation de l’inflammation du tissu adipeux. Chez l’Homme, nous avons montre que l’expression de GPR120 dans le tissu adipeux etait plus elevee chez les individus obeses (P = 4.0×10 −4 ). Le sequencage de GPR120 a revele une mutation non-synonyme (p. R270H) qui inhibe les voies de signalisation de GPR120 et augmente fortement le risque d’obesite (OR = 1.62; P = 8.0×10 −6 ). Conclusion Notre etude demontre que le senseur lipidique GPR120 joue un role fondamental dans le controle de la balance energetique chez l’Homme et la Souris.
Kelly R Monk - One of the best experts on this subject based on the ideXlab platform.
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GPR126 adgrg6 contributes to the terminal schwann cell response at the neuromuscular junction following peripheral nerve injury
Glia, 2020Co-Authors: Albina Jablonkashariff, Kelly R Monk, Katherine Campbell, Alison K SnyderwarwickAbstract:GPR126/Adgrg6 is an adhesion G protein-coupled receptor essential for Schwann cell (SC) myelination with important contributions to repair after nerve crush injury. Despite critical functions in myelinating SCs, the role of GPR126 within nonmyelinating terminal Schwann cells (tSCs) at the neuromuscular junction (NMJ), is not known. tSCs have important functions in synaptic maintenance and reinnervation, and after injury tSCs extend cytoplasmic processes to guide regenerating axons to the denervated NMJ. In this study, we show that GPR126 is expressed in tSCs, and that absence of GPR126 in SCs (SC-specific GPR126 knockout, cGPR126) results in a NMJ maintenance defect in the hindlimbs of aged mice, but not in young adult mice. After nerve transection and repair, cGPR126 mice display delayed NMJ reinnervation, altered tSC morphology with decreased S100β expression, and reduced tSC cytoplasmic process extensions. The immune response promoting reinnervation at the NMJ following nerve injury is also altered with decreased macrophage infiltration, Tnfα, and anomalous cytokine expression compared to NMJs of control mice. In addition, Vegfa expression is decreased in muscle, suggesting that cGPR126 non-cell autonomously modulates angiogenesis after nerve injury. In sum, cGPR126 mice demonstrated delayed NMJ reinnervation and decreased muscle mass following nerve transection and repair compared to control littermates. The integral function of GPR126 in tSCs at the NMJ provides the framework for new therapeutic targets for neuromuscular disease.
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structural basis for adhesion g protein coupled receptor GPR126 function
Nature Communications, 2020Co-Authors: Katherine Leon, Kelly R Monk, Rebecca L Cunningham, Joshua A Riback, Ezra Feldman, Tobin R Sosnick, Minglei Zhao, Demet AracAbstract:Many drugs target the extracellular regions (ECRs) of cell-surface receptors. The large and alternatively-spliced ECRs of adhesion G protein-coupled receptors (aGPCRs) have key functions in diverse biological processes including neurodevelopment, embryogenesis, and tumorigenesis. However, their structures and mechanisms of action remain unclear, hampering drug development. The aGPCR GPR126/Adgrg6 regulates Schwann cell myelination, ear canal formation, and heart development; and GPR126 mutations cause myelination defects in human. Here, we determine the structure of the complete zebrafish GPR126 ECR and reveal five domains including a previously unknown domain. Strikingly, the GPR126 ECR adopts a closed conformation that is stabilized by an alternatively spliced linker and a conserved calcium-binding site. Alternative splicing regulates ECR conformation and receptor signaling, while mutagenesis of the calcium-binding site abolishes GPR126 function in vivo. These results demonstrate that GPR126 ECR utilizes a multi-faceted dynamic approach to regulate receptor function and provide relevant insights for ECR-targeted drug design.
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in vivo identification of small molecules mediating GPR126 adgrg6 signaling during schwann cell development
Annals of the New York Academy of Sciences, 2019Co-Authors: Ethan C Bradley, Kelly R Monk, Torsten Schoneberg, Rebecca L Cunningham, Caroline Wilde, Rory K Morgan, Emma A Klug, Sophia M Letcher, Ines LiebscherAbstract:GPR126/Adgrg6, an adhesion family G protein-coupled receptor (aGPCR), is required for the development of myelinating Schwann cells in the peripheral nervous system. Myelin supports and insulates vertebrate axons to permit rapid signal propagation throughout the nervous system. In mammals and zebrafish, mutations in GPR126 arrest Schwann cells at early developmental stages. We exploited the optical and pharmacological tractability of larval zebrafish to uncover drugs that mediate myelination by activating GPR126 or functioning in parallel. Using a fluorescent marker of mature myelinating glia (Tg[mbp:EGFP-CAAX]), we screened hypomorphic GPR126 mutant larvae for restoration of myelin basic protein (mbp) expression along peripheral nerves following small molecule treatment. Our screens identified five compounds sufficient to promote mbp expression in GPR126 hypomorphs. Using an allelic series of GPR126 mutants, we parsed the ability of small molecules to restore mbp, suggesting differences in drug efficacy dependent on Schwann cell developmental state. Finally, we identify apomorphine hydrochloride as a direct small molecule activator of GPR126 using combined in vivo/in vitro assays and show that aporphine class compounds promote Schwann cell development in vivo. Our results demonstrate the utility of in vivo screening for aGPCR modulators and identify small molecules that interact with the GPR126-mediated myelination program.
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structural basis for adhesion g protein coupled receptor GPR126 function
bioRxiv, 2019Co-Authors: Katherine Leon, Kelly R Monk, Rebecca L Cunningham, Joshua A Riback, Ezra Feldman, Tobin R Sosnick, Minglei Zhao, Demet AracAbstract:Abstract Many drugs target the extracellular regions (ECRs) of cell-surface receptors. The large and alternatively-spliced ECRs of adhesion G protein-coupled receptors (aGPCRs) have key functions in diverse biological processes including neurodevelopment, embryogenesis, and tumorigenesis. However, their structures and mechanisms of action remain unclear, hampering drug development. The aGPCR GPR126/Adgrg6 regulates Schwann cell myelination, ear canal formation, and heart development; and GPR126 mutations cause myelination defects in human. Here, we determine the structure of the complete zebrafish GPR126 ECR and reveal five domains including a previously-unknown domain. Strikingly, the GPR126 ECR adopts a closed conformation that is stabilized by an alternatively spliced linker and a conserved calcium-binding site. Alternative splicing regulates ECR conformation and receptor signaling, while mutagenesis of the newly-characterized calcium-binding site abolishes GPR126 function in vivo. These results demonstrate that GPR126 ECR utilizes a multi-faceted dynamic approach to regulate receptor function and provide novel insights into ECR-targeted drug design.
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GPR126 adgrg6 has schwann cell autonomous and nonautonomous functions in peripheral nerve injury and repair
The Journal of Neuroscience, 2016Co-Authors: Amit Mogha, Breanne L Harty, Dan Carlin, Jessica Joseph, Nicholas E Sanchez, Ueli Suter, X S Piao, Valeria Cavalli, Kelly R MonkAbstract:Schwann cells (SCs) are essential for proper peripheral nerve development and repair, although the mechanisms regulating these processes are incompletely understood. We previously showed that the adhesion G protein-coupled receptor GPR126/Adgrg6 is essential for SC development and myelination. Interestingly, the expression of GPR126 is maintained in adult SCs, suggestive of a function in the mature nerve. We therefore investigated the role of GPR126 in nerve repair by studying an inducible SC-specific GPR126 knock-out mouse model. Here, we show that remyelination is severely delayed after nerve-crush injury. Moreover, we also observe noncell-autonomous defects in macrophage recruitment and axon regeneration in injured nerves following loss of GPR126 in SCs. This work demonstrates that GPR126 has critical SC-autonomous and SC-nonautonomous functions in remyelination and peripheral nerve repair. SIGNIFICANCE STATEMENT Lack of robust remyelination represents one of the major barriers to recovery of neurological functions in disease or following injury in many disorders of the nervous system. Here we show that the adhesion class G protein-coupled receptor (GPCR) GPR126/Adgrg6 is required for remyelination, macrophage recruitment, and axon regeneration following nerve injury. At least 30% of all approved drugs target GPCRs; thus, GPR126 represents an attractive potential target to stimulate repair in myelin disease or following nerve injury.
Felix B Engel - One of the best experts on this subject based on the ideXlab platform.
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mir 27a b is a posttranscriptional regulator of GPR126 adgrg6
Annals of the New York Academy of Sciences, 2019Co-Authors: Gentian Musa, Swati Srivastava, Jana Petzold, Salvador Cazorlavazquez, Felix B EngelAbstract:GPR126 (Adgrg6), a member of the adhesion G protein-coupled receptor family, has been associated with a variety of human diseases. Yet, despite its clinical importance, the mechanisms regulating GPR126 expression are poorly understood. Here, we aimed at identifying upstream regulatory mechanisms of GPR126 expression utilizing the heart as model organ in which GPR126 regulates trabeculation. Here, we focused on possible regulation of GPR126 regulation by microRNAs, which have emerged as key players in regulating development, have a critical role in disease progression, and might serve as putative therapeutic targets. In silico analyses identified one conserved binding site in the 3' UTR of GPR126 for microRNA 27a and 27b (miR-27a/b). In addition, miR-27a/b and GPR126 expression were differentially expressed during rat heart development. A regulatory role of miR-27a/b in controlling GPR126 expression was substantiated by reduced GPR126 mRNA levels upon ectopic expression of miR-27a/b in HEK293T cells and miR-27b in zebrafish embryos. Regulation of GPR126 expression by direct binding of miR-27a/b to the 3' UTR of GPR126 was verified by luciferase reporter assays in HEK293T cells. Finally, the modulation of GPR126 expression in zebrafish by injection of either miR-27b or miR-27b inhibitor in single cell-stage embryos resulted in hypo- or hypertrabeculation, respectively. Collectively, the data indicate that GPR126 expression is regulated by miR-27a/b.
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GPR126 adgrg6 is expressed in cell types known to be exposed to mechanical stimuli
Annals of the New York Academy of Sciences, 2019Co-Authors: Gentian Musa, Felix B Engel, Salvador Cazorlavazquez, Machteld J Van Amerongen, Marc P Stemmler, Markus Eckstein, Arndt Hartmann, Thomas Braun, Thomas BrabletzAbstract:GPR126 (ADGRG6) is an adhesion G protein-coupled receptor that plays an important role in a variety of tissues/organs, such as heart, sciatic nerve, cartilage, and ear. Moreover, GPR126 (ADGRG6) mutations are associated with human diseases, like adolescent idiopathic scoliosis, lung disease, bladder cancer, and intellectual disability. Despite its clinical importance, it remains elusive how GPR126 is activated and mediates signal transduction and what cellular processes depend on GPR126 signaling. Here, we generated a lacZ reporter mouse line to determine endogenous GPR126 (Adgrg6) expression in a cell type-specific manner during embryonic development, at postnatal day 5 and in adult animals. Our results confirm GPR126 expression data previously obtained utilizing antibodies and in situ hybridization in embryonic heart and sciatic nerve. In addition, we provide data with cellular resolution for previously described RT-PCR-based data, including lung and bladder. Moreover, new GPR126-expressing tissues and cell types were identified, such as ureter and acinar secretory cells. Collectively, our data demonstrate that the newly generated lacZ reporter mouse is a suitable model to study GPR126 expression during development and adulthood, provide detailed insight into GPR126 expression at the cellular level, and reveal that all identified GPR126-expressing cells are known to be exposed to mechanical stimuli.
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international union of basic and clinical pharmacology xciv adhesion g protein coupled receptors
Pharmacological Reviews, 2015Co-Authors: Jorg Hamann, Gabriela Aust, Demet Arac, Felix B Engel, Caroline Formstone, Robert Fredriksson, Randy A Hall, Breanne L Harty, Christiane Kirchhoff, Barbara KnappAbstract:The Adhesion family forms a large branch of the pharmacologically important superfamily of G protein–coupled receptors (GPCRs). As Adhesion GPCRs increasingly receive attention from a wide spectrum of biomedical fields, the Adhesion GPCR Consortium, together with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification, proposes a unified nomenclature for Adhesion GPCRs. The new names have ADGR as common dominator followed by a letter and a number to denote each subfamily and subtype, respectively. The new names, with old and alternative names within parentheses, are: ADGRA1 (GPR123), ADGRA2 (GPR124), ADGRA3 (GPR125), ADGRB1 (BAI1), ADGRB2 (BAI2), ADGRB3 (BAI3), ADGRC1 (CELSR1), ADGRC2 (CELSR2), ADGRC3 (CELSR3), ADGRD1 (GPR133), ADGRD2 (GPR144), ADGRE1 (EMR1, F4/80), ADGRE2 (EMR2), ADGRE3 (EMR3), ADGRE4 (EMR4), ADGRE5 (CD97), ADGRF1 (GPR110), ADGRF2 (GPR111), ADGRF3 (GPR113), ADGRF4 (GPR115), ADGRF5 (GPR116, Ig-Hepta), ADGRG1 (GPR56), ADGRG2 (GPR64, HE6), ADGRG3 (GPR97), ADGRG4 (GPR112), ADGRG5 (GPR114), ADGRG6 (GPR126), ADGRG7 (GPR128), ADGRL1 (latrophilin-1, CIRL-1, CL1), ADGRL2 (latrophilin-2, CIRL-2, CL2), ADGRL3 (latrophilin-3, CIRL-3, CL3), ADGRL4 (ELTD1, ETL), and ADGRV1 (VLGR1, GPR98). This review covers all major biologic aspects of Adhesion GPCRs, including evolutionary origins, interaction partners, signaling, expression, physiologic functions, and therapeutic potential.
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the multiple signaling modalities of adhesion g protein coupled receptor GPR126 in development
Receptors and clinical investigation, 2014Co-Authors: Chinmoy Patra, Kelly R Monk, Felix B EngelAbstract:The G protein-coupled receptor (GPCR) superfamily is the largest known receptor family in the human genome. Although the family of adhesion GPCRs comprises the second largest sub-family, their function is poorly understood. Here, we review the current knowledge about the adhesion GPCR family member GPR126. GPR126 possesses a signal peptide, a 7TM domain homologous to secretin-like GPCRs, a GPS motif and an extended N-terminus containing a CUB (Complement, Uegf, Bmp1) domain, a PTX (Pentraxin) domain, a hormone binding domain and 27 putative N-glycosylation sites. Knockdown and knockout experiments in zebrafish and mice have demonstrated that GPR126 plays an essential role in neural, cardiac and ear development. In addition, genome-wide association studies have implicated variations at the GPR126 locus in obstructive pulmonary dysfunction, in scoliosis and as a determinant of trunk length and body height. GPR126 appears to exert its function depending on the organ system via G protein- and/or N-terminus-dependent signaling. Here, we review the current knowledge about GPR126, which, due to the variety of its functions and its multiple signaling modalities, provides a model adhesion GPCR to understand general functional concepts utilized by adhesion GPCRs.
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GPR126 functions in schwann cells to control differentiation and myelination via g protein activation
The Journal of Neuroscience, 2013Co-Authors: Amit Mogha, Felix B Engel, Andrew E Benesh, Chinmoy Patra, Torsten Schoneberg, Ines Liebscher, Kelly R MonkAbstract:The myelin sheath surrounding axons ensures that nerve impulses travel quickly and efficiently, allowing for the proper function of the vertebrate nervous system. We previously showed that the adhesion G-protein-coupled receptor (aGPCR) GPR126 is essential for peripheral nervous system myelination, although the molecular mechanisms by which GPR126 functions were incompletely understood. aGPCRs are a significantly understudied protein class, and it was unknown whether GPR126 couples to G-proteins. Here, we analyze DhhCre;GPR126fl/fl conditional mutants, and show that GPR126 functions in Schwann cells (SCs) for radial sorting of axons and myelination. Furthermore, we demonstrate that elevation of cAMP levels or protein kinase A activation suppresses myelin defects in GPR126 mouse mutants and that cAMP levels are reduced in conditional GPR126 mutant peripheral nerve. Finally, we show that GPR126 directly increases cAMP by coupling to heterotrimeric G-proteins. Together, these data support a model in which GPR126 functions in SCs for proper development and myelination and provide evidence that these functions are mediated via G-protein-signaling pathways.
Takafumi Hara - One of the best experts on this subject based on the ideXlab platform.
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dysfunction of lipid sensor gpr120 leads to obesity in both mouse and human
Nature, 2012Co-Authors: Atsuhiko Ichimura, Odile Poulaingodefroy, Amelie Bonnefond, Loic Yengo, Takafumi Hara, Akira Hirasawa, Ikuo KimuraAbstract:Mice deficient in the lipid sensor GPR120 develop obesity, glucose intolerance and fatty liver when fed a high-fat diet, and a loss-of-function variant in the GPR120 gene strongly contributes to increased obesity in human. The G-protein-coupled receptor GPR120 is a receptor for free fatty acids, and is involved in homeostasis mechanisms such as fat-cell generation and the regulation of appetite. Here it is shown that without GPR120, mice on a high-fat diet develop obesity, glucose intolerance and fatty liver. In humans, GPR120 expression in adipose tissue is shown to be significantly elevated in obesity. The authors also identify a mutation that inhibits GPR120 signalling activity and is associated with an increased risk for obesity in Europeans. Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes1,2,3,4. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases3,5,6,7,8,9,10,11,12,13. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference5,6,14,15,16. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.
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structure activity relationships of gpr120 agonists based on a docking simulation
Molecular Pharmacology, 2010Co-Authors: Akira Hirasawa, Takayoshi Suzuki, Naoki Miyata, Takeo Awaji, Masaji Ishiguro, Tetsuya Adachi, Takafumi Hara, Ikuo Kimura, Gozoh TsujimotoAbstract:GPR120 is a G protein-coupled receptor expressed preferentially in the intestinal tract and adipose tissue, that has been implicated in mediating free fatty acid-stimulated glucagon-like peptide-1 (GLP-1) secretion. To develop GPR120-specific agonists, a series of compounds (denoted as NCG compounds) derived from a peroxisome proliferator-activated receptor γ agonist were synthesized, and their structure-activity relationships as GPR120 agonists were explored. To examine the agonistic activities of these newly synthesized NCG compounds, and of compounds already shown to have GPR120 agonistic activity (grifolic acid and MEDICA16), we conducted docking simulation in a GPR120 homology model that was developed on the basis of a photoactivated model derived from the crystal structure of bovine rhodopsin. We calculated the hydrogen bonding energies between the compounds and the GPR120 model. These energies correlated well with the GPR120 agonistic activity of the compounds ( R2 = 0.73). NCG21, the NCG compound with the lowest calculated hydrogen bonding energy, showed the most potent extracellular signal-regulated kinase (ERK) activation in a cloned GPR120 system. Furthermore, NCG21 potently activated ERK, intracellular calcium responses and GLP-1 secretion in murine enteroendocrine STC-1 cells that express GPR120 endogenously. Moreover, administration of NCG21 into the mouse colon caused an increase in plasma GLP-1 levels. Taken together, our present study showed that a docking simulation using a GPR120 homology model might be useful to predict the agonistic activity of compounds.
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structure activity relationships of gpr120 agonists based on a docking simulation
Molecular Pharmacology, 2010Co-Authors: Akira Hirasawa, Takayoshi Suzuki, Naoki Miyata, Takeo Awaji, Masaji Ishiguro, Tetsuya Adachi, Takafumi Hara, Ikuo Kimura, Gozoh TsujimotoAbstract:GPR120 is a G protein-coupled receptor expressed preferentially in the intestinal tract and adipose tissue, that has been implicated in mediating free fatty acid-stimulated glucagon-like peptide-1 (GLP-1) secretion. To develop GPR120-specific agonists, a series of compounds (denoted as NCG compounds) derived from a peroxisome proliferator-activated receptor γ agonist were synthesized, and their structure-activity relationships as GPR120 agonists were explored. To examine the agonistic activities of these newly synthesized NCG compounds, and of compounds already shown to have GPR120 agonistic activity (grifolic acid and MEDICA16), we conducted docking simulation in a GPR120 homology model that was developed on the basis of a photoactivated model derived from the crystal structure of bovine rhodopsin. We calculated the hydrogen bonding energies between the compounds and the GPR120 model. These energies correlated well with the GPR120 agonistic activity of the compounds ( R2 = 0.73). NCG21, the NCG compound with the lowest calculated hydrogen bonding energy, showed the most potent extracellular signal-regulated kinase (ERK) activation in a cloned GPR120 system. Furthermore, NCG21 potently activated ERK, intracellular calcium responses and GLP-1 secretion in murine enteroendocrine STC-1 cells that express GPR120 endogenously. Moreover, administration of NCG21 into the mouse colon caused an increase in plasma GLP-1 levels. Taken together, our present study showed that a docking simulation using a GPR120 homology model might be useful to predict the agonistic activity of compounds.
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novel selective ligands for free fatty acid receptors gpr120 and gpr40
Naunyn-schmiedebergs Archives of Pharmacology, 2009Co-Authors: Takafumi Hara, Taka-aki Koshimizu, Keiko Sadakane, Chisato Itsubo, Toshihiro Hashimoto, Yoshinori Asakawa, Tetsuya Adachi, Akira Hirasawa, Gozoh TsujimotoAbstract:GPR120 and GPR40 are G-protein-coupled receptors whose endogenous ligands are medium- and long-chain free fatty acids, and they are thought to play an important physiological role in insulin release. Despite recent progress in understanding their roles, much still remains unclear about their pharmacology, and few specific ligands for GPR120 and GPR40 besides medium- to long-chain fatty acids have been reported so far. To identify new selective ligands for these receptors, more than 80 natural compounds were screened, together with a reference compound MEDICA16, which is known to activate GPR40, by monitoring the extracellular regulated kinase (ERK) and [Ca2+]i responses in inducible and stable expression cell lines for GPR40 and GPR120, respectively. MEDICA16 selectively activated [Ca2+]i response in GPR40-expressing cells but not in GPR120-expressing cells. Among the natural compounds tested, grifolin derivatives, grifolic acid and grifolic acid methyl ether, promoted ERK and [Ca2+]i responses in GPR120-expressing cells, but not in GPR40-expressing cells, and inhibited the α-linolenic acid (LA)-induced ERK and [Ca2+]i responses in GPR120-expressing cells. Interestingly, in accordance with the pharmacological profiles of these compounds, similar profiles of glucagon-like peptide-1 secretion were seen for mouse enteroendocrine cell line, STC-1 cells, which express GPR120 endogenously. Taken together, these studies identified a selective GPR40 agonist and several GPR120 partial agonists. These compounds would be useful probes to further investigate the physiological and pharmacological functions of GPR40 and GPR120.
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novel selective ligands for free fatty acid receptors gpr120 and gpr40
Naunyn-schmiedebergs Archives of Pharmacology, 2009Co-Authors: Takafumi Hara, Taka-aki Koshimizu, Keiko Sadakane, Chisato Itsubo, Toshihiro Hashimoto, Yoshinori Asakawa, Tetsuya Adachi, Akira Hirasawa, Gozoh TsujimotoAbstract:GPR120 and GPR40 are G-protein-coupled receptors whose endogenous ligands are medium- and long-chain free fatty acids, and they are thought to play an important physiological role in insulin release. Despite recent progress in understanding their roles, much still remains unclear about their pharmacology, and few specific ligands for GPR120 and GPR40 besides medium- to long-chain fatty acids have been reported so far. To identify new selective ligands for these receptors, more than 80 natural compounds were screened, together with a reference compound MEDICA16, which is known to activate GPR40, by monitoring the extracellular regulated kinase (ERK) and [Ca2+]i responses in inducible and stable expression cell lines for GPR40 and GPR120, respectively. MEDICA16 selectively activated [Ca2+]i response in GPR40-expressing cells but not in GPR120-expressing cells. Among the natural compounds tested, grifolin derivatives, grifolic acid and grifolic acid methyl ether, promoted ERK and [Ca2+]i responses in GPR120-expressing cells, but not in GPR40-expressing cells, and inhibited the α-linolenic acid (LA)-induced ERK and [Ca2+]i responses in GPR120-expressing cells. Interestingly, in accordance with the pharmacological profiles of these compounds, similar profiles of glucagon-like peptide-1 secretion were seen for mouse enteroendocrine cell line, STC-1 cells, which express GPR120 endogenously. Taken together, these studies identified a selective GPR40 agonist and several GPR120 partial agonists. These compounds would be useful probes to further investigate the physiological and pharmacological functions of GPR40 and GPR120.
