GPR55

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G protein-coupled receptor 55
Identifiers
Symbols GPR55 ; LPIR1
External IDs OMIM604107 MGI2685064 HomoloGene36184 IUPHAR: GPR55 ChEMBL: 1075322 GeneCards: GPR55 Gene
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 [1] [2]

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[edit]

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[edit]

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

Pharmacology[edit]

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 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[edit]

Agonists

Ligands found to bind to GPR55 as agonists include:

Antagonists

Physiological function[edit]

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.[24]

References[edit]

  1. ^ "Entrez Gene: GPR55 G protein-coupled receptor 55". 
  2. ^ Brown AJ. (2007). "Novel cannabinoid receptors". Br J Pharmacol. 152 (5): 567–575. doi:10.1038/sj.bjp.0707481. PMC 2190013. PMID 17906678. 
  3. ^ McHugh D, Hu SS, Rimmerman N, Juknat A, Vogil 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 (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 Res. Mol. Brain Res. 64 (2): 193–8. doi:10.1016/S0169-328X(98)00277-0. PMID 9931487. 
  5. ^ Baker D, Pryce G, Davies WL, Hiley CR (2006). "In silico patent searching reveals a new cannabinoid receptor". Trends Pharmacol. Sci. 27 (1): 1–4. doi:10.1016/j.tips.2005.11.003. PMID 16318877. 
  6. ^ a b c 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 (2007). "The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects". Br. J. Pharmacol. 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 (2008). "GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current". Proc. Natl. Acad. Sci. U.S.A. 105 (7): 2699–704. doi:10.1073/pnas.0711278105. PMC 2268199. PMID 18263732. 
  8. ^ a b c Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ (2007). "The orphan receptor GPR55 is a novel cannabinoid receptor". Br. J. Pharmacol. 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 (November 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 (January 2009). "The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation". The FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology 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 (January 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 (September 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 (March 2009). "Mode of action of cannabinoids on nociceptive nerve endings". Experimental Brain Research. Experimentelle Hirnforschung. Experimentation Cerebrale 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 (March 2006). "Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents". Cell Metab. 3 (3): 167–75. doi:10.1016/j.cmet.2006.02.004. PMID 16517404. 
  15. ^ Ross RA (March 2009). "The enigmatic pharmacology of GPR55". Trends Pharmacol. Sci. 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 (October 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 (June 2008). "The endogenous cannabinoid system and drug addiction: 20 years after the discovery of the CB1 receptor". Addict Biol 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, A. J.; Daniels, D. A.; Kassim, M.; Brown, S.; Haslam, C. P.; Terrell, V. R.; Brown, J.; Nichols, P. L.; Staton, P. C.; Wise, A.; Dowell, S. J. (2011). "Pharmacology of GPR55 in Yeast and Identification of GSK494581A as a Mixed-Activity Glycine Transporter Subtype 1 Inhibitor and GPR55 Agonist". Journal of Pharmacology and Experimental Therapeutics 337 (1): 236–246. doi:10.1124/jpet.110.172650. PMID 21233197.  edit
  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, L. H.; Chung, T. D. Y.; Sharir, H.; Barak, L. S.; Abood, M. E. (2010). "Screening for Selective Ligands for GPR55 - Agonists". PMID 22091480.  edit
  22. ^ Heynen-Genel, S.; Dahl, R.; Shi, S.; Milan, L.; Hariharan, S.; Sergienko, E.; Hedrick, M.; Dad, S.; Stonich, D.; Su, Y.; Vicchiarelli, M.; Mangravita-Novo, A.; Smith, L. H.; Chung, T. D. Y.; Sharir, H.; Caron, M. G.; Barak, L. S.; Abood, M. E. (2010). "Screening for Selective Ligands for GPR55 - Antagonists". PMID 22091481.  edit
  23. ^ Rempel, V.; Volz, N.; Gläser, F.; Nieger, M.; Bräse, S.; Müller, C. E. (2013). "Antagonists for the orphan G protein-coupled receptor GPR55 based on a coumarin scaffold". Journal of Medicinal Chemistry 56 (11): 130516144836005. doi:10.1021/jm4005175. PMID 23679955.  edit
  24. ^ Whyte LS, Ryberg E, Sims NA, Ridge SA, Mackie K, Greasley PJ, Ross RA, Rogers MJ (September 2009). "The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo". Proc. Natl. Acad. Sci. U.S.A. 106 (38): 16511–6. doi:10.1073/pnas.0902743106. PMC 2737440. PMID 19805329. 

Further reading[edit]

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