GPR55

History

GPR55 was identified and cloned for the first time in 1999. 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. 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.

Signal cascade

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

Pharmacology

GPR55 is acted on by the phytocannabinoids Δ9-THC and CBD, as well as 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 while the structurally unrelated cannabinoid mimic WIN 55,212-2 fails to activate the receptor. Recent research suggests that lysophosphatidylinositol and its 2-arachidonoyl derivative, 2-arachidonoyl lysophosphatidylinositol (2-ALPI), may be the endogenous ligands for GPR55 and the receptor appears likely to be a possible target for treatment of inflammation and pain as with the other cannabinoid receptors.

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. 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, 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.

Ligands

;Agonists Ligands found to bind to GPR55 as agonists include:

• Lysophosphatidylinositol
• 2-Arachidonoyl lysophosphatidylinositol
• Abnormal cannabidiol (Abn-CBD)
• AM-251 (also CB1 antagonist)
• CP 55,940
• GSK-319,197
• GSK-494,581 - also glycine transporter 1 inhibitor
• GSK-522,373
• O-1602
• Δ9-Tetrahydrocannabinol
• Tetrahydrocannabivarin (THCV)
• 2-Arachidonoylglycerol (2-AG)
• Noladin ether
• Oleoylethanolamide
• Palmitoylethanolamide
• PACAP
• ML-184, ML-185 and ML-186

;Antagonists

• CID-16020046 - inverse agonist at GPR55
• O-1918
• ML-191, ML-192 and ML-193
• PSB-SB-487 and PSB-SB-1203
• Cannabidiol
• KLS-13019

Physiological function

The physiological role of GPR55 is unclear. Mice with a target deletion of the GPR55 gene show no specific phenotype. 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. Osteoblasts and osteoclasts express GPR55 and this has been shown to regulate bone cell function.

References

References

1. "Entrez Gene: GPR55 G protein-coupled receptor 55".
2. (Nov 2007). "Novel cannabinoid receptors". British Journal of Pharmacology.
3. (March 2010). "N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor". BMC Neuroscience.
4. (Feb 1999). "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.
5. (Jan 2006). "In silico patent searching reveals a new cannabinoid receptor". Trends in Pharmacological Sciences.
6. (Nov 2007). "The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects". British Journal of Pharmacology.
7. (Feb 2008). "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.
8. (Dec 2007). "The orphan receptor GPR55 is a novel cannabinoid receptor". British Journal of Pharmacology.
9. (Nov 2007). "Identification of GPR55 as a lysophosphatidylinositol receptor". Biochemical and Biophysical Research Communications.
10. (Jan 2009). "The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation". FASEB Journal.
11. (Jan 2009). "2-Arachidonoyl-sn-glycero-3-phosphoinositol: a possible natural ligand for GPR55". Journal of Biochemistry.
12. (Sep 2008). "The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic pain". Pain.
13. (Jun 2009). "Mode of action of cannabinoids on nociceptive nerve endings". Experimental Brain Research.
14. (Mar 2006). "Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents". Cell Metabolism.
15. (Mar 2009). "The enigmatic pharmacology of GPR55". Trends in Pharmacological Sciences.
16. (Oct 2009). "Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands". The Journal of Biological Chemistry.
17. (February 2010). "GPR55: Current knowledge and future perspectives of a purported "Type-3" cannabinoid receptor". Current Medicinal Chemistry.
18. (Jun 2008). "The endogenous cannabinoid system and drug addiction: 20 years after the discovery of the CB1 receptor". Addiction Biology.
19. (2013). "Endocannabinoids Actions at Atypical, Non-cannabinoid Receptors.". Springer Verlag.
20. (Apr 2011). "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.
21. (2021). "Gene Expression Data Mining Reveals the Involvement of GPR55 and Its Endogenous Ligands in Immune Response, Cancer, and Differentiation". International Journal of Molecular Sciences.
22. (2010). "Screening for Selective Ligands for GPR55 - Agonists". Probe Reports From the NIH Molecular Libraries Program [internet].
23. (Jun 2013). "Antagonists for the orphan G-protein-coupled receptor GPR55 based on a coumarin scaffold". Journal of Medicinal Chemistry.
24. (2025). "Effect of Fatty Acyl Composition for Lysophosphatidylinositol on Neuroinflammatory Responses in Primary Neuronal Cultures". Journal of Molecular Neuroscience.
25. (Sep 2009). "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.