GPR142 Membrane Protein Introduction

Introduction of GPR142

GPR142 belongs to “Class A” of GPCR family, which comprises a large amount of important cell surface mediators of signal transduction and physiological process and be related to multiple ailments. So GPCRs have become a class of druggable targets that have been extensively studied for therapeutic intervention. There are three transcript variants of GPR142. Besides, the amino acid residues Arg224, Asn235, Arg301, Lys314, and Asp397 show strong hydrogen bond interactions with potential agonists of GPR142.

Function of GPR142 Membrane Protein

The abundance of GPR142 in pancreatic β-cells reveals a potential function in the treatment of type II diabetes. As the native agonists, amino acids L-Tryptophan (L-Trp) and L-Phenylalanine (L-Phe) can selectively activate GPR142 via G_q and G_i signaling pathway in HEK293 cells. While in native cellular system, such as primary pancreatic islets, the insulin secretagogue activity of GPR142 agonists is performed by G_q pathway. The stimulation of GPR142 can initiate intracellular signal transduction to enhance the secretion of glucose-dependent insulin and the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), then improve glucose disposal. Synthetic agonists, such as potent aminopyrazole-phenylalanine, also have the capacity to stimulate GPR142, thus regulate insulin secretion to maintain glucostasis. Meanwhile, GPR142 is a pivotal modulator to control the release of insulin and GIP in refeeding experiments. So GPR142 agonists have been prompted as potential therapies for type II diabetes treatment.

Fig.1 The seven transmembrane domains of GPR142. (Kaushik, 2018)

Application of GPR142 Membrane Protein in Literature

1. Kaushik A.C., et al. Structure Based Virtual Screening Studies to Identify Novel Potential Compounds for GPR142 and Their Relative Dynamic Analysis for Study of Type 2 Diabetes. Frontiers in chemistry. 2018, 6: 23. PubMed ID: 29492402
   
   

   The authors use virtual screening to identify potential agonists of GPR142 from 1171519 compounds and validate them by induced fit docking, pharmacophore modeling, and system biology approaches. They predicted the 3D structure and active site of GPR142. The analysis shows that compound 2 may be a novel GPR142 agonist, exhibiting an increase in insulin production via G_q mediated signaling pathway. It has the potential therapeutic function for type II diabetes.

2. Lin H.V., et al. GPR142 controls tryptophan-induced insulin and incretin hormone secretion to improve glucose metabolism. PloS one. 2016, 11(6): e0157298. PubMed ID: 27322810
   
   

   This article demonstrates that GPR142 signaling can be activated by L-Phenylalanine, in addition to L-Tryptophan. But other natural amino acids have no such capacity. Furthermore, activated by tryptophan and a synthetic GPR142 agonist, GPR142-dependent increase of insulin and incretin hormones can improve glucose disposal in mice. In contrast, phenylalanine improves glucose disposal independently of GPR142.

3. Guo L., et al. Discovery and optimization of a novel triazole series of GPR142 agonists for the treatment of type 2 diabetes. ACS medicinal chemistry letters. 2016, 7(12): 1107-1111. PubMed ID: 22884988
   
   

   The authors discover a class of triazole GPR142 agonists with the help of high throughput screen. Compound 20e is the most effective agonist to serve as the therapy for type 2 diabetes. Moreover, they described the optimization strategies to improve 20e potency, efficacy, metabolic stability, and solubility.

4. Kaushik A.C. and Sahi S. Insights into unbound-bound states of GPR142 receptor in a membrane-aqueous system using molecular dynamics simulations. Journal of Biomolecular Structure and Dynamics. 2018, 36(7): 1788-1805. PubMed ID: 28571491
   
   

   This article reports the 3D-structure of GPR142 through threading and Ab initio methods. Using MD simulation analyses, the authors evaluate the conserved functional regions, including active site. Residues Lys314 (TM1) and Asp397 (TM3) may be the active site in the intracellular region of GPR142.

5. Wang J., et al. GPR142 agonists stimulate glucose-dependent insulin secretion via G_q-dependent signaling. PloS one. 2016, 11(4): e0154452. PubMed ID: 27104960
   
   

   This article demonstrates that both native and synthetic GPR142 agonists can activate G_q as well as G_i signaling pathway in HEK293 cells. However, in the primary pancreatic islets, a native cellular system, the insulin secretagogue activity of GPR142 agonists performed by G_q pathway.

GPR142 Preparation Options

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