GPR55

G protein-coupled receptor 55
Identifiers
Symbols	GPR55 ; LPIR1
External IDs	OMIM: 604107 MGI: 2685064 HomoloGene: 36184 IUPHAR: 109 ChEMBL: 1075322 GeneCards: GPR55 Gene
Gene ontology Molecular function • G-protein coupled receptor activity • cannabinoid receptor activity Cellular component • plasma membrane • integral component of plasma membrane Biological process • G-protein coupled receptor signaling pathway • activation of phospholipase C activity • positive regulation of Rho protein signal transduction • cannabinoid signaling pathway • bone resorption • negative regulation of osteoclast differentiation • positive regulation of ERK1 and ERK2 cascade Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	9290	227326
Ensembl	ENSG00000135898	ENSMUSG00000049608
UniProt	Q9Y2T6	Q3UJF0
RefSeq (mRNA)	NM_005683	NM_001033290
RefSeq (protein)	NP_005674	NP_001028462
Location (UCSC)	Chr 2: 230.91 – 230.96 Mb	Chr 1: 85.94 – 85.96 Mb
PubMed search

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, 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 and cannabidiol,^[8] and the endocannabinoids anandamide, 2-AG, noladin ether in the low nanomolar range. The synthetic cannabinoid CP-55940 is 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:

• 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 ^[20]
• GSK-522,373
• O-1602
• Δ⁹-Tetrahydrocannabinol^[8]
• 2-Arachidonoylglycerol (2-AG)^[8]
• Noladin ether
• Oleoylethanolamide
• Palmitoylethanolamide
• ML-184, ML-185 and ML-186 ^[21]

Antagonists

• CID-16020046 - inverse agonist at GPR55
• O-1918
• ML-191, ML-192 and ML-193^[21]
• PSB-SB-487 and PSB-SB-1203 ^[22]
• Cannabidiol ^[8]

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".
2. Brown AJ (Nov 2007). "Novel cannabinoid receptors". British Journal of Pharmacology 152 (5): 567–75. doi:10.1038/sj.bjp.0707481. PMC 2190013. PMID 17906678.
3. McHugh D, Hu SS, Rimmerman N, Juknat A, Vogel Z, Walker JM, Bradshaw HB (March 2010). "N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor". BMC Neuroscience 11: 44. doi:10.1186/1471-2202-11-44. PMC 2865488. PMID 20346144.
4. Sawzdargo M, Nguyen T, Lee DK, Lynch KR, Cheng R, Heng HH, George SR, O'Dowd BF (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 64 (2): 193–8. doi:10.1016/S0169-328X(98)00277-0. PMID 9931487.
5. Baker D, Pryce G, Davies WL, Hiley CR (Jan 2006). "In silico patent searching reveals a new cannabinoid receptor". Trends in Pharmacological Sciences 27 (1): 1–4. doi:10.1016/j.tips.2005.11.003. PMID 16318877.
6. Johns DG, Behm DJ, Walker DJ, Ao Z, Shapland EM, Daniels DA, Riddick M, Dowell S, Staton PC, Green P, Shabon U, Bao W, Aiyar N, Yue TL, Brown AJ, Morrison AD, Douglas SA (Nov 2007). "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. doi:10.1038/sj.bjp.0707419. PMC 2190033. PMID 17704827.
7. Lauckner JE, Jensen JB, Chen HY, Lu HC, Hille B, Mackie K (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 105 (7): 2699–704. doi:10.1073/pnas.0711278105. PMC 2268199. PMID 18263732.
8. Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ (Dec 2007). "The orphan receptor GPR55 is a novel cannabinoid receptor". British Journal of Pharmacology 152 (7): 1092–101. doi:10.1038/sj.bjp.0707460. PMC 2095107. PMID 17876302.
9. Oka S, Nakajima K, Yamashita A, Kishimoto S, Sugiura T (Nov 2007). "Identification of GPR55 as a lysophosphatidylinositol receptor". Biochemical and Biophysical Research Communications 362 (4): 928–34. doi:10.1016/j.bbrc.2007.08.078. PMID 17765871.
10. Henstridge CM, Balenga NA, Ford LA, Ross RA, Waldhoer M, Irving AJ (Jan 2009). "The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation". FASEB Journal 23 (1): 183–93. doi:10.1096/fj.08-108670. PMID 18757503.
11. Oka S, Toshida T, Maruyama K, Nakajima K, Yamashita A, Sugiura T (Jan 2009). "2-Arachidonoyl-sn-glycero-3-phosphoinositol: a possible natural ligand for GPR55". Journal of Biochemistry 145 (1): 13–20. doi:10.1093/jb/mvn136. PMID 18845565.
12. Staton PC, Hatcher JP, Walker DJ, Morrison AD, Shapland EM, Hughes JP, Chong E, Mander PK, Green PJ, Billinton A, Fulleylove M, Lancaster HC, Smith JC, Bailey LT, Wise A, Brown AJ, Richardson JC, Chessell IP (Sep 2008). "The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic pain". Pain 139 (1): 225–36. doi:10.1016/j.pain.2008.04.006. PMID 18502582.
13. Kress M, Kuner R (Jun 2009). "Mode of action of cannabinoids on nociceptive nerve endings". Experimental Brain Research 196 (1): 79–88. doi:10.1007/s00221-009-1762-0. PMID 19306092.
14. Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner LS, Griffin G, Jackson HC, Procter MJ, Rasamison CM, Tang-Christensen M, Widdowson PS, Williams GM, Reynet C (Mar 2006). "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. doi:10.1016/j.cmet.2006.02.004. PMID 16517404.
15. Ross RA (Mar 2009). "The enigmatic pharmacology of GPR55". Trends in Pharmacological Sciences 30 (3): 156–63. doi:10.1016/j.tips.2008.12.004. PMID 19233486.
16. Kapur A, Zhao P, Sharir H, Bai Y, Caron MG, Barak LS, Abood ME (Oct 2009). "Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands". The Journal of Biological Chemistry 284 (43): 29817–27. doi:10.1074/jbc.M109.050187. PMC 2785612. PMID 19723626.
17. Moriconi A, Cerbara I, Maccarrone M, Topai A (February 2010). "GPR55: Current knowledge and future perspectives of a purported "Type-3" cannabinoid receptor". Current Medicinal Chemistry 17 (14): 1411–29. doi:10.2174/092986710790980069. PMID 20166924.
18. de Fonseca FR, Schneider M (Jun 2008). "The endogenous cannabinoid system and drug addiction: 20 years after the discovery of the CB1 receptor" (PDF). Addiction Biology 13 (2): 143–6. doi:10.1111/j.1369-1600.2008.00116.x. PMID 18482429.
19. Andradas, Clara (2013). Endocannabinoids Actions at Atypical, Non-cannabinoid Receptors. Springer Verlag. pp. 115–133. ISBN 978-1-4614-4668-2.
20. Brown AJ, Daniels DA, Kassim M, Brown S, Haslam CP, Terrell VR, Brown J, Nichols PL, Staton PC, Wise A, Dowell SJ (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 337 (1): 236–46. doi:10.1124/jpet.110.172650. PMID 21233197.
21. Heynen-Genel S, Dahl R, Shi S, Milan L, Hariharan S, Bravo Y, Sergienko E, Hedrick M, Dad S, Stonich D, Su Y, Vicchiarelli M, Mangravita-Novo A, Smith LH, Chung TD, Sharir H, Barak LS, Abood ME (2010). "Screening for Selective Ligands for GPR55 - Agonists". Probe Reports from the NIH Molecular Libraries Program [Internet]. PMID 22091480.
22. Rempel V, Volz N, Gläser F, Nieger M, Bräse S, Müller CE (Jun 2013). "Antagonists for the orphan G-protein-coupled receptor GPR55 based on a coumarin scaffold". Journal of Medicinal Chemistry 56 (11): 4798–810. doi:10.1021/jm4005175. PMID 23679955.
23. Whyte LS, Ryberg E, Sims NA, Ridge SA, Mackie K, Greasley PJ, Ross RA, Rogers MJ (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 106 (38): 16511–6. doi:10.1073/pnas.0902743106. PMC 2737440. PMID 19805329.

Further reading

• Sawzdargo M, Nguyen T, Lee DK, Lynch KR, Cheng R, Heng HH, George SR, O'Dowd BF (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 64 (2): 193–8. doi:10.1016/S0169-328X(98)00277-0. PMID 9931487.