GPR55 was identified and cloned for the first time in 1999.[8] Later it was identified by anin silico screen as a putative cannabinoid receptor because of a similar amino acid sequence in the binding region.[9] Research groups fromGlaxo Smith Kline andAstra 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 syntheticcannabinoids but GPR-55knockout mice generated by a research group fromGlaxo Smith Kline showed no altered blood pressure regulation after administration of thecannabidiol-derivativeabnormal cannabidiol.[10]
GPR55 is acted on by the phytocannabinoids Δ9-THC and CBD,[12] as well as theendocannabinoidsanandamide,2-AG andnoladin ether in the low nanomolar range. Exocannabinoids such as the synthetic cannabinoidCP-55940 are also able to activate the receptor[12] while the structurally unrelated cannabinoid mimicWIN 55,212-2 fails to activate the receptor.[10] Recent research suggests thatlysophosphatidylinositol and its 2-arachidonoyl derivative,2-arachidonoyl lysophosphatidylinositol (2-ALPI), may be the endogenous ligands for GPR55[13][14][15] and the receptor appears likely to be a possible target for treatment of inflammation and pain as with the other cannabinoid receptors.[16][17]
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.[18][19][20][21] However this is complicated by the fact that another possible CB3 receptor has been discovered[which?] in thehippocampus, although its gene has not yet been cloned,[22] 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.[23]
The physiological role of GPR55 is unclear. Mice with a target deletion of the GPR55 gene show no specificphenotype.[10] GPR55 is widely expressed in the brain, especially in thecerebellum. It is expressed in thejejunum andileum but apparently not more generally in the periphery.[12]Osteoblasts andosteoclasts express GPR55 and this has been shown to regulate bone cell function.[29]
^Sawzdargo M, Nguyen T, Lee DK, Lynch KR, Cheng R, Heng HH, et al. (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):193–198.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):928–934.Bibcode:2007BBRC..362..928O.doi:10.1016/j.bbrc.2007.08.078.PMID17765871.
^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, et al. (Sep 2008). "The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic pain".Pain.139 (1):225–236.doi:10.1016/j.pain.2008.04.006.PMID18502582.S2CID207307343.
^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):1411–1429.doi:10.2174/092986710790980069.PMID20166924.
^Andradas C (2013). "The Role of GPR55 in Cancer".Endocannabinoids Actions at Atypical, Non-cannabinoid Receptors. The Receptors. Vol. 24. Springer Verlag. pp. 115–133.doi:10.1007/978-1-4614-4669-9_5.ISBN978-1-4614-4668-2.
^Brown AJ, Daniels DA, Kassim M, Brown S, Haslam CP, Terrell VR, et al. (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):236–246.doi:10.1124/jpet.110.172650.PMID21233197.S2CID22317158.
^abHeynen-Genel S, Dahl R, Shi S, Milan L, Hariharan S, Bravo Y, et al. (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, et al. (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.
