Regulating the effects of GPR21, a novel target for type 2 diabetes

Siobhán Leonard; Gemma K. Kinsella; Elisa Benetti; John B. C. Findlay

doi:10.1038/srep27002

journal article Open Access May 31, 2016

Regulating the effects of GPR21, a novel target for type 2 diabetes

Siobhán Leonard Gemma K. Kinsella

Elisa Benetti John B. C. Findlay

Scientific Reports Vol. 6 No. 1 · Springer Science and Business Media LLC

View at Publisher Save 10.1038/srep27002

Abstract

AbstractType 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.

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Details

Published: May 31, 2016
Vol/Issue: 6(1)
License: View

Authors

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Turin, Italy

J

John B. C. Findlay

School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, U.K., and National Centre of Genetic Resources and BiotechnologyCenargen/Embrapa, SAIN-Parque Rural, 70789-970 Brasilia, DF, Brazil

Cite This Article

Siobhán Leonard, Gemma K. Kinsella, Elisa Benetti, et al. (2016). Regulating the effects of GPR21, a novel target for type 2 diabetes. Scientific Reports, 6(1). https://doi.org/10.1038/srep27002

Regulating the effects of GPR21, a novel target for type 2 diabetes

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