Biology:GPR119

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Short description: Protein-coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

G protein-coupled receptor 119 also known as GPR119 is a G protein-coupled receptor that in humans is encoded by the GPR119 gene.[1]

GPR119, along with GPR55 and GPR18, have been implicated as novel cannabinoid receptors.[2][3][4]

Pharmacology

GPR119 is expressed predominantly in the pancreas and gastrointestinal tract in rodents and humans, as well as in the brain in rodents.[5] Activation of the receptor has been shown to cause a reduction in food intake and body weight gain in rats.[5] GPR119 has also been shown to regulate incretin and insulin hormone secretion.[6][7][8] As a result, new drugs acting on the receptor have been suggested as novel treatments for obesity and diabetes.[5][7][9]

Ligands

A number of endogenous, synthetic and plant derived ligands for this receptor have been identified:[10][11][12]

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.[16] 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.[17]

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),[18] 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,[17] that communicate through interactions between these two fundamental systems—which form the gut microbiota-endocannabinoidome axis.[16]

Evolution

Paralogues

Source:[19]

References

  1. ↑ "Entrez Gene: GPR119 G protein-coupled receptor 119". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=139760. 
  2. ↑ 2.0 2.1 2.2 "Novel cannabinoid receptors". British Journal of Pharmacology 152 (5): 567–575. November 2007. doi:10.1038/sj.bjp.0707481. PMID 17906678. 
  3. ↑ "Cannabinoids and the gut: new developments and emerging concepts". Pharmacology & Therapeutics 126 (1): 21–38. April 2010. doi:10.1016/j.pharmthera.2009.12.005. PMID 20117132. 
  4. ↑ "N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor". BMC Neuroscience 11: 44. March 2010. doi:10.1186/1471-2202-11-44. PMID 20346144. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents". Cell Metabolism 3 (3): 167–175. March 2006. doi:10.1016/j.cmet.2006.02.004. PMID 16517404. 
  6. ↑ 6.0 6.1 6.2 "Endogenous and synthetic agonists of GPR119 differ in signalling pathways and their effects on insulin secretion in MIN6c4 insulinoma cells". British Journal of Pharmacology 155 (7): 1056–1065. December 2008. doi:10.1038/bjp.2008.337. PMID 18724386. 
  7. ↑ 7.0 7.1 "Fatty acid binding receptors and their physiological role in type 2 diabetes". Archiv der Pharmazie 341 (12): 753–761. December 2008. doi:10.1002/ardp.200800096. PMID 19009545. 
  8. ↑ "GPR119 is required for physiological regulation of glucagon-like peptide-1 secretion but not for metabolic homeostasis". The Journal of Endocrinology 201 (2): 219–230. May 2009. doi:10.1677/JOE-08-0453. PMID 19282326. 
  9. ↑ 9.0 9.1 9.2 "GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity". British Journal of Pharmacology 153 (Suppl 1): S76–S81. March 2008. doi:10.1038/sj.bjp.0707529. PMID 18037923. 
  10. ↑ "GPR119 agonists: a promising new approach for the treatment of type 2 diabetes and related metabolic disorders". Current Opinion in Drug Discovery & Development 12 (4): 519–532. July 2009. PMID 19562648. 
  11. ↑ "Receptors for acylethanolamides-GPR55 and GPR119". Prostaglandins & Other Lipid Mediators 89 (3–4): 105–111. September 2009. doi:10.1016/j.prostaglandins.2009.07.001. PMID 19615459. 
  12. ↑ "2,5-Disubstituted pyridines as potent GPR119 agonists". Bioorganic & Medicinal Chemistry Letters 20 (8): 2577–2581. April 2010. doi:10.1016/j.bmcl.2010.02.083. PMID 20227877. 
  13. ↑ "2-Oleoyl glycerol is a GPR119 agonist and signals GLP-1 release in humans". The Journal of Clinical Endocrinology and Metabolism 96 (9): E1409–E1417. September 2011. doi:10.1210/jc.2011-0647. PMID 21778222. 
  14. ↑ "Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119". Journal of Medicinal Chemistry 51 (17): 5172–5175. September 2008. doi:10.1021/jm8006867. PMID 18698756. 
  15. ↑ "GPR119 agonists for the treatment of type 2 diabetes". Expert Opinion on Therapeutic Patents 19 (10): 1339–1359. October 2009. doi:10.1517/13543770903153878. PMID 19780700. 
  16. ↑ 16.0 16.1 Lacroix, Sébastien (2019-12-17). "Rapid and Concomitant Gut Microbiota and Endocannabinoidome Response to Diet-Induced Obesity in Mice". mSystems 4 (6): e00407-19. doi:10.1128/mSystems.00407-19. PMID 31848310. 
  17. ↑ 17.0 17.1 Cohen, Louis J. (2017-09-07). "Commensal bacteria produce GPCR ligands that mimic human signaling molecules". Nature 549 (7670): 48–53. doi:10.1038/nature23874. PMID 28854168. 
  18. ↑ PubChem. "n-Oleoyl serinol" (in en). https://pubchem.ncbi.nlm.nih.gov/compound/44183838. 
  19. ↑ "GeneCards®: The Human Gene Database". https://www.genecards.org/cgi-bin/carddisp.pl?gene=GPR119&keywords=gpr119#paralogs. 

Further reading



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