Regulating the effects of GPR21, a novel target for type 2 diabetes
| Autor: | John B. C. Findlay, Elisa Benetti, Gemma K. Kinsella, Siobhán Leonard |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Sucrose medicine.medical_specialty MAP Kinase Kinase 4 G protein GPR21 type 2 diabetes G protein-coupled receptors Diet High-Fat p38 Mitogen-Activated Protein Kinases Article Receptors G-Protein-Coupled Mice 03 medical and health sciences Insulin resistance G protein-coupled receptors Insulin receptor substrate Internal medicine medicine Animals Humans Estrenes Protein Kinase C G protein-coupled receptor Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Multidisciplinary GPR21 biology Kinase Wild type medicine.disease Pyrrolidinones Cell biology Mice Inbred C57BL Insulin receptor HEK293 Cells 030104 developmental biology Endocrinology Diabetes Mellitus Type 2 Gene Expression Regulation biology.protein GTP-Binding Protein alpha Subunits Gq-G11 type 2 diabetes Insulin Resistance Signal transduction Signal Transduction |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep27002 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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