Biology:GPR55

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Short description: Protein-coding gene in the species Homo sapiens


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

G protein-coupled receptor 55 also known as GPR55 is a G protein-coupled receptor that in humans is encoded by the GPR55 gene.[1]

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

History

GPR55 was identified and cloned for the first time in 1999.[4] Later it was identified by an in silico screen as a putative cannabinoid receptor because of a similar amino acid sequence in the binding region.[5] Research groups from Glaxo Smith Kline and Astra Zeneca characterized the receptor extensively because it was hoped to be responsible for the blood pressure lowering properties of cannabinoids. GPR55 is indeed activated by endogenous and exogenous cannabinoids such as plant and synthetic cannabinoids but GPR-55 knockout mice generated by a research group from Glaxo Smith Kline showed no altered blood pressure regulation after administration of the cannabidiol-derivative abnormal cannabidiol.[6]

Signal cascade

GPR55 is coupled to the G-protein G13 and activation of the receptor leads to stimulation of rhoA, cdc42 and rac1.[7]

Pharmacology

GPR55 is activated by the plant cannabinoids Δ9-THC[8] and the endocannabinoids anandamide, 2-AG and noladin ether in the low nanomolar range. Exocannabinoids such as the synthetic cannabinoid CP-55940 are also able to activate the receptor[8] while the structurally unrelated cannabinoid mimic WIN 55,212-2 fails to activate the receptor.[6] Recent research suggests that lysophosphatidylinositol and its 2-arachidonoyl derivative, 2-arachidonoyl lysophosphatidylinositol (2-ALPI), may be the endogenous ligands for GPR55[9][10][11] and the receptor appears likely to be a possible target for treatment of inflammation and pain as with the other cannabinoid receptors.[12][13]

This profile as a distinct non-CB1/CB2 receptor which responds to a variety of both endogenous and exogenous cannabinoid ligands has led some groups to suggest GPR55 should be categorised as the CB3 receptor, and this re-classification may follow in time.[14][15][16][17] However this is complicated by the fact that another possible CB3 receptor has been discovered in the hippocampus, although its gene has not yet been cloned,[18] suggesting that there may be at least four cannabinoid receptors which will eventually be characterised. Evidence accumulated during the last few years suggests that GPR55 plays a relevant role in cancer and opens the possibility of considering this orphan receptor as a new therapeutic target and potential biomarker in oncology.[19]

Ligands

Agonists

Ligands found to bind to GPR55 as agonists include:

Antagonists

Physiological function

The physiological role of GPR55 is unclear. Mice with a target deletion of the GPR55 gene show no specific phenotype.[6] GPR55 is widely expressed in the brain, especially in the cerebellum. It is expressed in the jejunum and ileum but apparently not more generally in the periphery.[8] Osteoblasts and osteoclasts express GPR55 and this has been shown to regulate bone cell function.[23]

References

  1. ↑ "Entrez Gene: GPR55 G protein-coupled receptor 55". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9290. 
  2. ↑ "Novel cannabinoid receptors". British Journal of Pharmacology 152 (5): 567–75. Nov 2007. doi:10.1038/sj.bjp.0707481. PMID 17906678. 
  3. ↑ "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. 
  4. ↑ "Identification and cloning of three novel human G protein-coupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively expressed in human brain". Brain Research. Molecular Brain Research 64 (2): 193–8. Feb 1999. doi:10.1016/S0169-328X(98)00277-0. PMID 9931487. 
  5. ↑ "In silico patent searching reveals a new cannabinoid receptor". Trends in Pharmacological Sciences 27 (1): 1–4. Jan 2006. doi:10.1016/j.tips.2005.11.003. PMID 16318877. 
  6. ↑ 6.0 6.1 6.2 "The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects". British Journal of Pharmacology 152 (5): 825–31. Nov 2007. doi:10.1038/sj.bjp.0707419. PMID 17704827. 
  7. ↑ "GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current". Proceedings of the National Academy of Sciences of the United States of America 105 (7): 2699–704. Feb 2008. doi:10.1073/pnas.0711278105. PMID 18263732. Bibcode: 2008PNAS..105.2699L. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 "The orphan receptor GPR55 is a novel cannabinoid receptor". British Journal of Pharmacology 152 (7): 1092–101. Dec 2007. doi:10.1038/sj.bjp.0707460. PMID 17876302. 
  9. ↑ "Identification of GPR55 as a lysophosphatidylinositol receptor". Biochemical and Biophysical Research Communications 362 (4): 928–34. Nov 2007. doi:10.1016/j.bbrc.2007.08.078. PMID 17765871. 
  10. ↑ "The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation". FASEB Journal 23 (1): 183–93. Jan 2009. doi:10.1096/fj.08-108670. PMID 18757503. 
  11. ↑ "2-Arachidonoyl-sn-glycero-3-phosphoinositol: a possible natural ligand for GPR55". Journal of Biochemistry 145 (1): 13–20. Jan 2009. doi:10.1093/jb/mvn136. PMID 18845565. 
  12. ↑ "The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic pain". Pain 139 (1): 225–36. Sep 2008. doi:10.1016/j.pain.2008.04.006. PMID 18502582. 
  13. ↑ "Mode of action of cannabinoids on nociceptive nerve endings". Experimental Brain Research 196 (1): 79–88. Jun 2009. doi:10.1007/s00221-009-1762-0. PMID 19306092. 
  14. ↑ "Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents". Cell Metabolism 3 (3): 167–75. Mar 2006. doi:10.1016/j.cmet.2006.02.004. PMID 16517404. 
  15. ↑ "The enigmatic pharmacology of GPR55". Trends in Pharmacological Sciences 30 (3): 156–63. Mar 2009. doi:10.1016/j.tips.2008.12.004. PMID 19233486. 
  16. ↑ "Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands". The Journal of Biological Chemistry 284 (43): 29817–27. Oct 2009. doi:10.1074/jbc.M109.050187. PMID 19723626. 
  17. ↑ "GPR55: Current knowledge and future perspectives of a purported "Type-3" cannabinoid receptor". Current Medicinal Chemistry 17 (14): 1411–29. February 2010. doi:10.2174/092986710790980069. PMID 20166924. 
  18. ↑ "The endogenous cannabinoid system and drug addiction: 20 years after the discovery of the CB1 receptor". Addiction Biology 13 (2): 143–6. Jun 2008. doi:10.1111/j.1369-1600.2008.00116.x. PMID 18482429. http://www.zi-mannheim.de/fileadmin/user_upload/redakteure/psychopharma/De_Fonseca_2008.pdf. 
  19. ↑ Andradas, Clara (2013). "The Role of GPR55 in Cancer". Endocannabinoids Actions at Atypical, Non-cannabinoid Receptors.. Springer Verlag. pp. 115–133. doi:10.1007/978-1-4614-4669-9_5. ISBN 978-1-4614-4668-2. 
  20. ↑ "Pharmacology of GPR55 in yeast and identification of GSK494581A as a mixed-activity glycine transporter subtype 1 inhibitor and GPR55 agonist". The Journal of Pharmacology and Experimental Therapeutics 337 (1): 236–46. Apr 2011. doi:10.1124/jpet.110.172650. PMID 21233197. 
  21. ↑ 21.0 21.1 "Screening for Selective Ligands for GPR55 - Agonists". Probe Reports from the NIH Molecular Libraries Program [Internet]. 2010. PMID 22091480. 
  22. ↑ "Antagonists for the orphan G-protein-coupled receptor GPR55 based on a coumarin scaffold". Journal of Medicinal Chemistry 56 (11): 4798–810. Jun 2013. doi:10.1021/jm4005175. PMID 23679955. 
  23. ↑ "The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo". Proceedings of the National Academy of Sciences of the United States of America 106 (38): 16511–6. Sep 2009. doi:10.1073/pnas.0902743106. PMID 19805329. Bibcode: 2009PNAS..10616511W. 

Further reading

  • "Identification and cloning of three novel human G protein-coupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively expressed in human brain". Brain Research. Molecular Brain Research 64 (2): 193–8. Feb 1999. doi:10.1016/S0169-328X(98)00277-0. PMID 9931487. 



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