GPR119

Pharmacology

GPR119 is expressed predominantly in the pancreas and gastrointestinal tract in rodents and humans, as well as in the brain in rodents. Activation of the receptor has been shown to cause a reduction in food intake and body weight gain in rats. GPR119 has also been shown to regulate incretin and insulin hormone secretion. As a result, new drugs acting on the receptor have been suggested as novel treatments for obesity and diabetes.

Ligands

A number of endogenous, synthetic and plant derived ligands for this receptor have been identified:

• 2-Oleoylglycerol (2OG)
• Anandamide
• AR-231,453
• MBX-2982
• Oleoylethanolamide (OEA) (Endogenous Ligand)
• PSN-375,963
• PSN-632,408

Human microbiota and GPR119 activation

Commensal bacteria are found to have important roles in human health, as bacterial metabolites are likely to be key components of host interactions by which they affect mammalian physiology. N-acyl amide synthase genes are found enriched in gastrointestinal bacteria and the lipids, that they encode, interact with GPCRs, which regulate gastrointestinal tract physiology, where cell-based models have demonstrated, that commensal GPR119 agonists regulate metabolic hormones and glucose homeostasis as efficiently as human ligands, and the clearest overlap in structure and function between bacterial and human GPCR-active ligands, is found for the endocannabinoid receptor GPR119.

The experiment have isolated both the palmitoyl and oleoyl analogs of N-acyl serinol, and found the latter only differs from 2-OG: C21H40O4 by the presence of an amide instead of an ester, and from OEA: C20H39NO2 by the presence of an additional ethanol substituent, where the N-oleoyl serinol (C21H41NO3; 18:1,n-9), is a similarly potent GPR119 agonist compared to the endogenous ligand OEA (EC50 12 μM vs. 7 μM), but elicits almost a 2-fold greater maximum activation, do suggest that chemical mimicry of eukaryotic signalling molecules may be common among commensal bacteria, that communicate through interactions between these two fundamental systems—which form the gut microbiota-endocannabinoidome axis.

Evolution

[[Sequence homology|Paralogues]]

Source:

• GPR6
• MC5R
• MC3R
• MC4R
• CNR1
• GPR12
• S1PR1
• MC1R
• S1PR3
• S1PR5
• GPR3
• S1PR2
• CNR2
• LPAR3
• LPAR1
• LPAR2
• MC2R
• S1PR4

References

References

1. "Entrez Gene: GPR119 G protein-coupled receptor 119".
2. (November 2007). "Novel cannabinoid receptors". British Journal of Pharmacology.
3. (April 2010). "Cannabinoids and the gut: new developments and emerging concepts". Pharmacology & Therapeutics.
4. (March 2010). "N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor". BMC Neuroscience.
5. (March 2006). "Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents". Cell Metabolism.
6. (December 2008). "Endogenous and synthetic agonists of GPR119 differ in signalling pathways and their effects on insulin secretion in MIN6c4 insulinoma cells". British Journal of Pharmacology.
7. (December 2008). "Fatty acid binding receptors and their physiological role in type 2 diabetes". Archiv der Pharmazie.
8. (May 2009). "GPR119 is required for physiological regulation of glucagon-like peptide-1 secretion but not for metabolic homeostasis". The Journal of Endocrinology.
9. (March 2008). "GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity". British Journal of Pharmacology.
10. (July 2009). "GPR119 agonists: a promising new approach for the treatment of type 2 diabetes and related metabolic disorders". Current Opinion in Drug Discovery & Development.
11. (September 2009). "Receptors for acylethanolamides-GPR55 and GPR119". Prostaglandins & Other Lipid Mediators.
12. (April 2010). "2,5-Disubstituted pyridines as potent GPR119 agonists". Bioorganic & Medicinal Chemistry Letters.
13. (September 2011). "2-Oleoyl glycerol is a GPR119 agonist and signals GLP-1 release in humans". The Journal of Clinical Endocrinology and Metabolism.
14. (September 2008). "Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119". Journal of Medicinal Chemistry.
15. (October 2009). "GPR119 agonists for the treatment of type 2 diabetes". Expert Opinion on Therapeutic Patents.
16. Lacroix, Sébastien. (2019-12-17). "Rapid and Concomitant Gut Microbiota and Endocannabinoidome Response to Diet-Induced Obesity in Mice". mSystems.
17. Cohen, Louis J.. (2017-09-07). "Commensal bacteria produce GPCR ligands that mimic human signaling molecules". Nature.
18. PubChem. "n-Oleoyl serinol".
19. "GeneCards®: The Human Gene Database".