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, 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.
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.
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.
^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. PMID9931487.
^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. PMID16318877.
^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. PMID17765871.
^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. PMID18757503.
^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. PMID18845565.
^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. PMID18502582.
^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. PMID16517404.
^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. PMID20166924.
^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. PMID21233197.
^ abHeynen-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]. PMID22091480.
^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. PMID23679955.
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. PMID9931487.