title: Regulating the effects of GPR21, a novel target for type 2 diabetes.
abstract: Type 2 diabetes is a chronic metabolic disorder primarily caused by insulin resistance to which obesity is a major contributor. Expression levels of an orphan G protein-coupled receptor (GPCR), GPR21, demonstrated a trend towards a significant increase in the epididymal fat pads of wild type high fat high sugar (HFHS)-fed mice. To gain further insight into the potential role this novel target may play in the development of obesity-associated type 2 diabetes, the signalling capabilities of the receptor were investigated. Overexpression studies in HEK293T cells revealed GPR21 to be a constitutively active receptor, which couples to Gαq type G proteins leading to the activation of mitogen activated protein kinases (MAPKs). Overexpression of GPR21 in vitro also markedly attenuated insulin signalling. Interestingly, the effect of GPR21 on the MAPKs and insulin signalling was reduced in the presence of serum, inferring the possibility of a native inhibitory ligand. Homology modelling and ligand docking studies led to the identification of a novel compound that inhibited GPR21 activity. Its effects offer potential as an anti-diabetic pharmacological strategy as it was found to counteract the influence of GPR21 on the insulin signalling pathway.
authors.affiliation: Department of Biology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland.
authors.forename: Siobhán
authors.initials: S
authors.lastname: Leonard
authors.affiliation: Department of Biology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland.
authors.forename: Gemma K
authors.initials: GK
authors.lastname: Kinsella
authors.affiliation: Department of Drug Science and Technology, University of Turin, Turin, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Benetti
authors.affiliation: Department of Biology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland.
authors.forename: John B C
authors.initials: JBC
authors.lastname: Findlay
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D004963:Estrenes / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007333:Insulin Resistance; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013395:Sucrose / Q000009:adverse effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D004963:Estrenes; C489012:GPR21 protein, human; C571154:GPR21 protein, mouse; D011760:Pyrrolidinones; D043562:Receptors, G-Protein-Coupled; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D013395:Sucrose; D011493:Protein Kinase C; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C112631:G protein alpha 16; D043802:GTP-Binding Protein alpha Subunits, Gq-G11