Abstract
The search for cannabinoid receptors other than CB1R and CB2R has been ongoing for over a decade. A number of orphan receptors have been proposed as potential cannabinoid receptors primarily based on phylogenic arguments and reactivity towards known endocannabinoids and phytocannabinoids. Seven putative cannabinoid receptors are described and discussed, and evidence for and against their inclusion in this category are presented.
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References
Anavi-Goffer S, Baillie G, Irving AJ, Gertsch J, Greig IR, Pertwee RG, Ross RA (2012) Modulation of L-α-lysophosphatidylinositol/GPR55 mitogen-activated protein kinase (MAPK) signaling by cannabinoids. J Biol Chem 287(1):91–104. https://doi.org/10.1074/jbc.M111.296020
Baggelaar MP, Maccarrone M, van der Stelt M (2018) 2-Arachidonoylglycerol: a signaling lipid with manifold actions in the brain. Prog Lipid Res 71:1–17. https://doi.org/10.1016/j.plipres.2018.05.002
Balenga NA, Aflaki E, Kargl J, Platzer W, Schröder R, Blättermann S, Kostenis E, Brown AJ, Heinemann A, Waldhoer M (2011) GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils. Cell Res 21(10):1452–1469. https://doi.org/10.1038/cr.2011.60
Becker AM, Callahan DJ, Richner JM, Choi J, DiPersio JF, Diamond MS, Bhattacharya D (2015) GPR18 controls reconstitution of mouse small intestine intraepithelial lymphocytes following bone marrow transplantation. PLoS ONE 10(7):e0133854. https://doi.org/10.1371/journal.pone.0133854
Bédard A, Tremblay P, Chernomoretz A, Vallières L (2007) Identification of genes preferentially expressed by microglia and upregulated during cuprizone-induced inflammation. Glia 55(8):777–789. https://doi.org/10.1002/glia.20477
Benoit ME, Hernandez MX, Dinh ML, Benavente F, Vasquez O, Tenner AJ (2013) C1q-induced LRP1B and GPR6 proteins expressed early in Alzheimer disease mouse models, are essential for the C1q-mediated protection against amyloid-β neurotoxicity. J Biol Chem 288(1):654–665. https://doi.org/10.1074/jbc.M112.400168
Berglund BA, Boring DL, Howlett AC (1999) Investigation of structural analogs of prostaglandin amides for binding to and activation of CB1 and CB2 cannabinoid receptors in rat brain and human tonsils. Adv Exp Med Biol 469:527–533. https://doi.org/10.1007/978-1-4615-4793-8_77
Biringer RG (2020) The enzymology of the human prostanoid pathway. Mol Biol Rep 47(6):4569–4586. https://doi.org/10.1007/s11033-020-05526-z
Blom N, Gammeltoft S, Brunak S (1999) Sequence and structure-based prediction of eukaryotic protein phosphorylation sites. J Mol Biol 294(5):1351–1362. https://doi.org/10.1006/jmbi.1999.3310
Blom N, Sicheritz-Pontén T, Gupta R, Gammeltoft S, Brunak S (2004) Prediction of post-translational glycosylation and phosphorylation of proteins from the amino acid sequence. Proteomics 4(6):1633–1649. https://doi.org/10.1002/pmic.200300771
Böttcher G, Sjölund K, Ekblad E, Håkanson R, Schwartz TW, Sundler F (1984) Coexistence of peptide YY and glicentin immunoreactivity in endocrine cells of the gut. Regul Pept 8(4):261–266. https://doi.org/10.1016/0167-0115(84)90034-x
Brown AJ, Daniels DA, Kassim M, Brown S, Haslam CP, Terrell VR, Brown J, Nichols PL, Staton PC, Wise A, Dowell SJ (2011) Pharmacology of GPR55 in yeast and identification of GSK494581A as a mixed-activity glycine transporter subtype 1 inhibitor and GPR55 agonist. J Pharmacol Exp Ther 337(1):236–246. https://doi.org/10.1124/jpet.110.172650
Brown KJ, Laun AS, Song ZH (2017) Cannabidiol, a novel inverse agonist for GPR12. Biochem Biophys Res Commun 493(1):451–454. https://doi.org/10.1016/j.bbrc.2017.09.001
Burstein SH, McQuain CA, Ross AH, Salmonsen RA, Zurier RE (2011) Resolution of inflammation by N-arachidonoylglycine. J Cell Biochem 112(11):3227–3233. https://doi.org/10.1002/jcb.23245
Callaerts-Vegh Z, Leo S, Vermaercke B, Meert T, D’Hooge R (2012) LPA5 receptor plays a role in pain sensitivity, emotional exploration and reversal learning. Genes Brain Behav 11(8):1009–1019. https://doi.org/10.1111/j.1601-183X.2012.00840.x
Capaldi S, Suku E, Antolini M, Di Giacobbe M, Giorgetti A, Buffelli M (2018) Allosteric sodium binding cavity in GPR3: a novel player in modulation of Aβ production. Sci Rep 8(1):11102. https://doi.org/10.1038/s41598-018-29475-7
Carey LM, Gutierrez T, Deng L, Lee WH, Mackie K, Hohmann AG (2017) Inflammatory and neuropathic nociception is preserved in GPR55 knockout mice. Sci Rep 7(1):944. https://doi.org/10.1038/s41598-017-01062-2
Caterina MJ, Rosen TA, Tominaga M, Brake AJ, Julius D (1999) A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398(6726):436–441. https://doi.org/10.1038/18906
Chen JK, Chen J, Imig JD, Wei S, Hachey DL, Guthi JS, Falck JR, Capdevila JH, Harris RC (2008) Identification of novel endogenous cytochrome p450 arachidonate metabolites with high affinity for cannabinoid receptors. J Biol Chem 283(36):24514–24524. https://doi.org/10.1074/jbc.M709873200
Chiang N, Dalli J, Colas RA, Serhan CN (2015) Identification of resolvin D2 receptor mediating resolution of infections and organ protection. J Exp Med 212(8):1203–1217. https://doi.org/10.1084/jem.20150225
Chiang N, de la Rosa X, Libreros S, Serhan CN (2017) Novel resolvin D2 receptor axis in infectious inflammation. J Immunol 198(2):842–851. https://doi.org/10.4049/jimmunol.1601650
Chu ZL, Jones RM, He H, Carroll C, Gutierrez V, Lucman A, Moloney M, Gao H, Mondala H, Bagnol D, Unett D, Liang Y, Demarest K, Semple G, Behan DP, Leonard J (2007) A role for beta-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release. Endocrinology 148(6):2601–2609. https://doi.org/10.1210/en.2006-1608
Chu ZL, Carroll C, Alfonso J, Gutierrez V, He H, Lucman A, Pedraza M, Mondala H, Gao H, Bagnol D, Chen R, Jones RM, Behan DP, Leonard J (2008) A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like Peptide-1 and glucose-dependent insulinotropic Peptide release. Endocrinology 149(5):2038–2047. https://doi.org/10.1210/en.2007-0966
Chu ZL, Carroll C, Chen R, Alfonso J, Gutierrez V, He H, Lucman A, Xing C, Sebring K, Zhou J, Wagner B, Unett D, Jones RM, Behan DP, Leonard J (2010) N-oleoyldopamine enhances glucose homeostasis through the activation of GPR119. Mol Endocrinol 24(1):161–170. https://doi.org/10.1210/me.2009-0239
Chuderland D, Seger R (2008) Calcium regulates ERK signaling by modulating its protein-protein interactions. Commun Integr Biol 1(1):4–5. https://doi.org/10.4161/cib.1.1.6107
Compton DR, Rice KC, De Costa BR, Razdan RK, Melvin LS, Johnson MR, Martin BR (1993) Cannabinoid structure-activity relationships: correlation of receptor binding and in vivo activities. J Pharmacol Exp Ther 265(1):218–226
Console-Bram L, Brailoiu E, Brailoiu GC, Sharir H, Abood ME (2014) Activation of GPR18 by cannabinoid compounds: a tale of biased agonism. Br J Pharmacol 171(16):3908–3917. https://doi.org/10.1111/bph.12746
Cox HM, Tough IR, Woolston AM, Zhang L, Nguyen AD, Sainsbury A, Herzog H (2010) Peptide YY is critical for acylethanolamine receptor Gpr119-induced activation of gastrointestinal mucosal responses. Cell Metab 11(6):532–542. https://doi.org/10.1016/j.cmet.2010.04.014
Davenport AP, Alexander SP, Sharman JL, Pawson AJ, Benson HE, Monaghan AE, Liew WC, Mpamhanga CP, Bonner TI, Neubig RR, Pin JP, Spedding M, Harmar AJ (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol Rev 65(3):967–986. https://doi.org/10.1124/pr.112.007179
Deliu E, Sperow M, Console-Bram L, Carter RL, Tilley DG, Kalamarides DJ, Kirby LG, Brailoiu GC, Brailoiu E, Benamar K, Abood ME (2015) The lysophosphatidylinositol receptor GPR55 modulates pain perception in the periaqueductal gray. Mol Pharmacol 88(2):265–272. https://doi.org/10.1124/mol.115.099333
DiLuigi A, Weitzman VN, Pace MC, Siano LJ, Maier D, Mehlmann LM (2008) Meiotic arrest in human oocytes is maintained by a Gs signaling pathway. Biol Reprod 78(4):667–672. https://doi.org/10.1095/biolreprod.107.066019
Edgemond WS, Hillard CJ, Falck JR, Kearn CS, Campbell WB (1998) Human platelets and polymorphonuclear leukocytes synthesize oxygenated derivatives of arachidonylethanolamide (anandamide): their affinities for cannabinoid receptors and pathways of inactivation. Mol Pharmacol 54(1):180–188. https://doi.org/10.1124/mol.54.1.180
Felder CC, Joyce KE, Briley EM, Mansouri J, Mackie K, Blond O, Lai Y, Ma AL, Mitchell RL (1995) Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol 48(3):443–450
Feltenmark S, Gautam N, Brunnström A, Griffiths W, Backman L, Edenius C, Lindbom L, Björkholm M, Claesson HE (2008) Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells. Proc Natl Acad Sci USA 105(2):680–685. https://doi.org/10.1073/pnas.0710127105
Ferré S, Baler R, Bouvier M, Caron MG, Devi LA, Durroux T, Fuxe K, George SR, Javitch JA, Lohse MJ, Mackie K, Milligan G, Pfleger KD, Pin JP, Volkow ND, Waldhoer M, Woods AS, Franco R (2009) Building a new conceptual framework for receptor heteromers. Nat Chem Biol 5(3):131–134. https://doi.org/10.1038/nchembio0309-131
Finlay DB, Joseph WR, Grimsey NL (2016) Glass M (2016) GPR18 undergoes a high degree of constitutive trafficking but is unresponsive to N-Arachidonoyl Glycine. PeerJ 4:e1835. https://doi.org/10.7717/peerj.1835
Fu Z, Gilbert ER, Liu D (2013) Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev 9(1):25–53
Fuchs A, Rempel V, Müller CE (2013) The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists. PLoS ONE 8(10):e77739. https://doi.org/10.1371/journal.pone.0077739
García-Gutiérrez MS, Navarrete F, Navarro G, Reyes-Resina I, Franco R, Lanciego JL, Giner S, Manzanares J (2018) Alterations in gene and protein expression of cannabinoid CB2 and GPR55 receptors in the dorsolateral prefrontal cortex of suicide victims. Neurotherapeutics 15(3):796–806. https://doi.org/10.1007/s13311-018-0610-y
González S, Moreno-Delgado D, Moreno E, Pérez-Capote K, Franco R, Mallol J, Cortés A, Casadó V, Lluís C, Ortiz J, Ferré S, Canela E, McCormick PJ (2012) Circadian-related heteromerization of adrenergic and dopamine D4 receptors modulates melatonin synthesis and release in the pineal gland. PLoS Biol 10(6):e1001347. https://doi.org/10.1371/journal.pbio.1001347
Grill M, Högenauer C, Blesl A, Haybaeck J, Golob-Schwarzl N, Ferreirós N, Thomas D, Gurke R, Trötzmüller M, Köfeler HC, Gallé B, Schicho R (2019) Members of the endocannabinoid system are distinctly regulated in inflammatory bowel disease and colorectal cancer. Sci Rep 9(1):2358. https://doi.org/10.1038/s41598-019-38865-4
Hansen KB, Rosenkilde MM, Knop FK, Wellner N, Diep TA, Rehfeld JF, Andersen UB, Holst JJ, Hansen HS (2011) 2-Oleoyl glycerol is a GPR119 agonist and signals GLP-1 release in humans. J Clin Endocrinol Metab 96(9):E1409-1417. https://doi.org/10.1210/jc.2011-0647
Hassing HA, Fares S, Larsen O, Pad H, Hauge M, Jones RM, Schwartz TW, Hansen HS, Rosenkilde MM (2016) Biased signaling of lipids and allosteric actions of synthetic molecules for GPR119. Biochem Pharmacol 119:66–75. https://doi.org/10.1016/j.bcp.2016.08.018
Henstridge CM, Balenga NA, Ford LA, Ross RA, Waldhoer M, Irving AJ (2009) The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation. FASEB J 23(1):183–193. https://doi.org/10.1096/fj.08-108670
Henstridge CM, Balenga NA, Schröder R, Kargl JK, Platzer W, Martini L, Arthur S, Penman J, Whistler JL, Kostenis E, Waldhoer M, Irving AJ (2010) GPR55 ligands promote receptor coupling to multiple signalling pathways. Br J Pharmacol 160(3):604–614. https://doi.org/10.1111/j.1476-5381.2009.00625.x
Hinckley M, Vaccari S, Horner K, Chen R, Conti M (2005) The G-protein-coupled receptors GPR3 and GPR12 are involved in cAMP signaling and maintenance of meiotic arrest in rodent oocytes. Dev Biol 287(2):249–261. https://doi.org/10.1016/j.ydbio.2005.08.019
Hu J, Oda SK, Shotts K, Donovan EE, Strauch P, Pujanauski LM, Victorino F, Al-Shami A, Fujiwara Y, Tigyi G, Oravecz T, Pelanda R, Torres RM (2014) Lysophosphatidic acid receptor 5 inhibits B cell antigen receptor signaling and antibody response. J Immunol 193(1):85–95. https://doi.org/10.4049/jimmunol.1300429
Huang Y, Skwarek-Maruszewska A, Horré K, Vandewyer E, Wolfs L, Snellinx A, Saito T, Radaelli E, Corthout N, Colombelli J, Lo AC, Van Aerschot L, Callaerts-Vegh Z, Trabzuni D, Bossers K, Verhaagen J, Ryten M, Munck S, D’Hooge R, Swaab DF, Hardy J, Saido TC, De Strooper B, Thathiah A (2015) Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer’s disease mouse models. Sci Transl Med 7(309):309164. https://doi.org/10.1126/scitranslmed.aab3492
Ignatov A, Lintzel J, Hermans-Borgmeyer I, Kreienkamp HJ, Joost P, Thomsen S, Methner A, Schaller HC (2003a) Role of the G-protein-coupled receptor GPR12 as high-affinity receptor for sphingosylphosphorylcholine and its expression and function in brain development. J Neurosci 23(3):907–914. https://doi.org/10.1523/JNEUROSCI.23-03-00907.2003
Ignatov A, Lintzel J, Kreienkamp HJ, Schaller HC (2003b) Sphingosine-1-phosphate is a high-affinity ligand for the G protein-coupled receptor GPR6 from mouse and induces intracellular Ca2+ release by activating the sphingosine-kinase pathway. Biochem Biophys Res Commun 311(2):329–336. https://doi.org/10.1016/j.bbrc.2003.10.006
Isawi IH, Morales P, Sotudeh N, Hurst DP, Lynch DL, Reggio PH (2020) GPR6 structural insights: homology model construction and docking studies. Molecules 25(3):725. https://doi.org/10.3390/molecules25030725
Járai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, Zimmer AM, Bonner TI, Buckley NE, Mezey E, Razdan RK, Zimmer A, Kunos G (1999) Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci USA 96(24):14136–14141. https://doi.org/10.1073/pnas.96.24.14136
Joffre J, Yeh CC, Wong E, Thete M, Xu F, Zlatanova I, Lloyd E, Kobzik L, Legrand M, Hellman J (2020) Activation of CB1R promotes lipopolysaccharide-induced IL-10 secretion by monocytic myeloid-derived suppressive cells and reduces acute inflammation and organ injury. J Immunol 204(12):3339–3350. https://doi.org/10.4049/jimmunol.2000213
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):825–831. https://doi.org/10.1038/sj.bjp.0707419
Kapur A, Zhao P, Sharir H, Bai Y, Caron MG, Barak LS, Abood ME (2009) Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands. J Biol Chem 284(43):29817–29827. https://doi.org/10.1074/jbc.M109.050187
Kargl J, Balenga N, Parzmair GP, Brown AJ, Heinemann A, Waldhoer M (2012) The cannabinoid receptor CB1 modulates the signaling properties of the lysophosphatidylinositol receptor GPR55. J Biol Chem 287(53):44234–44248. https://doi.org/10.1074/jbc.M112.364109
Katritch V, Fenalti G, Abola EE, Roth BL, Cherezov V, Stevens RC (2014) Allosteric sodium in class A GPCR signaling. Trends Biochem Sci 39(5):233–244. https://doi.org/10.1016/j.tibs.2014.03.002
Kohno M, Hasegawa H, Inoue A, Muraoka M, Miyazaki T, Oka K, Yasukawa M (2006) Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18. Biochem Biophys Res Commun 347(3):827–832. https://doi.org/10.1016/j.bbrc.2006.06.175
Kotarsky K, Boketoft A, Bristulf J, Nilsson NE, Norberg A, Hansson S, Owman C, Sillard R, Leeb-Lundberg LM, Olde B (2006) Lysophosphatidic acid binds to and activates GPR92, a G protein-coupled receptor highly expressed in gastrointestinal lymphocytes. J Pharmacol Exp Ther 318(2):619–628. https://doi.org/10.1124/jpet.105.098848
Kozak KR, Crews BC, Morrow JD, Wang LH, Ma YH, Weinander R, Jakobsson PJ, Marnett LJ (2002) Metabolism of the endocannabinoids, 2-arachidonylglycerol and anandamide, into prostaglandin, thromboxane, and prostacyclin glycerol esters and ethanolamides. J Biol Chem 277(47):44877–44885. https://doi.org/10.1074/jbc.M206788200
Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Hoover J, Jang W, Katz K, Ovetsky M, Riley G, Sethi A, Tully R, Villamarin-Salomon R, Rubinstein W, Maglott DR (2016) ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res 44(D1):D862-868. https://doi.org/10.1093/nar/gkv1222
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 USA 105(7):2699–2704. https://doi.org/10.1073/pnas.0711278105
Lauffer L, Iakoubov R, Brubaker PL (2008) GPR119: “double-dipping” for better glycemic control. Endocrinology 149(5):2035–2037. https://doi.org/10.1210/en.2008-0182
Lauffer LM, Iakoubov R, Brubaker PL (2009) GPR119 is essential for oleoylethanolamide-induced glucagon-like peptide-1 secretion from the intestinal enteroendocrine L-cell. Diabetes 58(5):1058–1066. https://doi.org/10.2337/db08-1237
Laun AS (2018) A study of GPR3, GPR6, of GPR12 as novel molecular targets for cannabidiol. Electronic Theses and Dissertations. Paper 2945. https://doi.org/10.18297/etd/2945
Laun AS, Song ZH (2017) GPR3 and GPR6, novel molecular targets for cannabidiol. Biochem Biophys Res Commun 490(1):17–21. https://doi.org/10.1016/j.bbrc.2017.05.165
Laun AS, Shrader SH, Song ZH (2018) Novel inverse agonists for the orphan G protein-coupled receptor 6. Heliyon 4(11):e00933. https://doi.org/10.1016/j.heliyon.2018.e00933
Laun AS, Shrader SH, Brown KJ, Song ZH (2019) GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol. Acta Pharmacol Sin 40(3):300–308. https://doi.org/10.1038/s41401-018-0031-9
Lee CW, Rivera R, Gardell S, Dubin AE, Chun J (2006) GPR92 as a new G12/13- and Gq-coupled lysophosphatidic acid receptor that increases cAMP, LPA5. J Biol Chem 281(33):23589–23597. https://doi.org/10.1074/jbc.M603670200
Ligresti A, De Petrocellis L, Di Marzo V (2016) From phytocannabinoids to cannabinoid receptors and endocannabinoids: pleiotropic physiological and pathological roles through complex pharmacology. Physiol Rev 96(4):1593–1659. https://doi.org/10.1152/physrev.00002.2016
Lin ZJ, Lu XM, Zhu TJ, Fang YC, Gu QQ, Zhu W (2008) GPR12 selections of the metabolites from an endophytic Streptomyces sp. associated with Cistanches deserticola. Arch Pharm Res 31(9):1108–1114. https://doi.org/10.1007/s12272-001-1276-4
Lin ME, Rivera RR, Chun J (2012) Targeted deletion of LPA5 identifies novel roles for lysophosphatidic acid signaling in development of neuropathic pain. J Biol Chem 287(21):17608–17617. https://doi.org/10.1074/jbc.m111.330183
Lopategi A, Flores-Costa R, Rius B, López-Vicario C, Alcaraz-Quiles J, Titos E, Clària J (2019) Frontline science: specialized proresolving lipid mediators inhibit the priming and activation of the macrophage NLRP3 inflammasome. J Leukoc Biol 105(1):25–36. https://doi.org/10.1002/JLB.3HI0517-206RR
Lowther KM, Uliasz TF, Götz KR, Nikolaev VO, Mehlmann LM (2013) Regulation of constitutive GPR3 signaling and surface localization by GRK2 and β-arrestin-2 overexpression in HEK293 cells. PLoS ONE 8(6):e65365. https://doi.org/10.1371/journal.pone.0065365
Lu X, Zhang N, Meng B, Dong S, Hu Y (2012) Involvement of GPR12 in the regulation of cell proliferation and survival. Mol Cell Biochem 366(1–2):101–110. https://doi.org/10.1007/s11010-012-1287-x
Lu VB, Puhl HL 3rd, Ikeda SR (2013) N-Arachidonyl glycine does not activate G protein-coupled receptor 18 signaling via canonical pathways. Mol Pharmacol 83(1):267–282. https://doi.org/10.1124/mol.112.081182
Lundequist A, Boyce JA (2011) LPA5 is abundantly expressed by human mast cells and important for lysophosphatidic acid induced MIP-1β release. PLoS ONE 6(3):e18192. https://doi.org/10.1371/journal.pone.0018192
Mackie K, Stella N (2006) Cannabinoid receptors and endocannabinoids: evidence for new players. AAPS J 8(2):E298–E306. https://doi.org/10.1007/BF02854900
MacLennan SJ, Reynen PH, Kwan J, Bonhaus DW (1998) Evidence for inverse agonism of SR141716A at human recombinant cannabinoid CB1 and CB2 receptors. Br J Pharmacol 124(4):619–622. https://doi.org/10.1038/sj.bjp.0701915
Mangini M, Iaccino E, Mosca MG, Mimmi S, D’Angelo R, Quinto I, Scala G, Mariggiò S (2017) Peptide-guided targeting of GPR55 for anti-cancer therapy. Oncotarget 8(3):5179–5195. https://doi.org/10.18632/oncotarget.14121
Martínez-Pinilla E, Reyes-Resina I, Oñatibia-Astibia A, Zamarbide M, Ricobaraza A, Navarro G, Moreno E, Dopeso-Reyes IG, Sierra S, Rico AJ, Roda E, Lanciego JL, Franco R (2014) CB1 and GPR55 receptors are co-expressed and form heteromers in rat and monkey striatum. Exp Neurol 261:44–52. https://doi.org/10.1016/j.expneurol.2014.06.017
Martínez-Pinilla E, Rico AJ, Rivas-Santisteban R, Lillo J, Roda E, Navarro G, Lanciego JL, Franco R (2020) Expression of GPR55 and either cannabinoid CB1 or CB2 heteroreceptor complexes in the caudate, putamen, and accumbens nuclei of control, parkinsonian, and dyskinetic non-human primates. Brain Struct Funct 225(7):2153–2164. https://doi.org/10.1007/s00429-020-02116-4
McHugh D, Hu SS, Rimmerman N, Juknat A, Vogel Z, Walker JM, Bradshaw HB (2010) N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor. BMC Neurosci 11:44. https://doi.org/10.1186/1471-2202-11-44
McHugh D, Page J, Dunn E, Bradshaw HB (2012) Δ(9) -Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells. Br J Pharmacol 165(8):2414–2424. https://doi.org/10.1111/j.1476-5381.2011.01497.x
McHugh D, Roskowski D, Xie S, Bradshaw HB (2014) Δ(9)-THC and N-arachidonoyl glycine regulate BV-2 microglial morphology and cytokine release plasticity: implications for signaling at GPR18. Front Pharmacol 4:162. https://doi.org/10.3389/fphar.2013.00162
Meyer zu DM, Heringdorf D, Lass H, Kuchar I, Lipinski M, Alemany R, Rümenapp U, Jakobs KH (2001) Stimulation of intracellular sphingosine-1-phosphate production by G-protein-coupled sphingosine-1-phosphate receptors. Eur J Pharmacol 414(2–3):145–154. https://doi.org/10.1016/s0014-2999(01)00789-0
Miller S, Hu SS, Leishman E, Morgan D, Wager-Miller J, Mackie K, Bradshaw HB, Straiker A (2017) A GPR119 signaling system in the murine eye regulates intraocular pressure in a sex-dependent manner. Investig Ophthalmol vis Sci 58(7):2930–2938. https://doi.org/10.1167/iovs.16-21330
Miller S, Daily L, Leishman E, Bradshaw H, Straiker A (2018) Δ9-tetrahydrocannabinol and cannabidiol differentially regulate intraocular pressure. Investig Ophthalmol vis Sci 59(15):5904–5911. https://doi.org/10.1167/iovs.18-24838
Morales P, Reggio PH (2017) An update on non-CB1, non-CB2 cannabinoid related G-protein-coupled receptors. Cannabis Cannabinoid Res 2(1):265–273. https://doi.org/10.1089/can.2017.0036
Morales P, Hurst DP, Reggio PH (2017) Methods for the development of in silico GPCR models. Methods Enzymol 593:405–448. https://doi.org/10.1016/bs.mie.2017.05.005
Moreno E, Andradas C, Medrano M, Caffarel MM, Pérez-Gómez E, Blasco-Benito S, Gómez-Cañas M, Pazos MR, Irving AJ, Lluís C, Canela EI, Fernández-Ruiz J, Guzmán M, McCormick PJ, Sánchez C (2014) Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling. J Biol Chem 289(32):21960–21972. https://doi.org/10.1074/jbc.M114.561761
Oda SK, Strauch P, Fujiwara Y, Al-Shami A, Oravecz T, Tigyi G, Pelanda R, Torres RM (2013) Lysophosphatidic acid inhibits CD8 T cell activation and control of tumor progression. Cancer Immunol Res 1(4):245–255. https://doi.org/10.1158/2326-6066.CIR-13-0043-T
Odori S, Hosoda K, Tomita T, Fujikura J, Kusakabe T, Kawaguchi Y, Doi R, Takaori K, Ebihara K, Sakai Y, Uemoto S, Nakao K (2013) GPR119 expression in normal human tissues and islet cell tumors: evidence for its islet-gastrointestinal distribution, expression in pancreatic beta and alpha cells, and involvement in islet function. Metabolism 62(1):70–78. https://doi.org/10.1016/j.metabol.2012.06.010
Oh DY, Yoon JM, Moon MJ, Hwang JI, Choe H, Lee JY, Kim JI, Kim S, Rhim H, O’Dell DK, Walker JM, Na HS, Lee MG, Kwon HB, Kim K, Seong JY (2008) Identification of farnesyl pyrophosphate and N-arachidonylglycine as endogenous ligands for GPR92. J Biol Chem 283(30):21054–21064. https://doi.org/10.1074/jbc.M708908200
Oka S, Nakajima K, Yamashita A, Kishimoto S, Sugiura T (2007) Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem Biophys Res Commun 362(4):928–934. https://doi.org/10.1016/j.bbrc.2007.08.078
Oka S, Toshida T, Maruyama K, Nakajima K, Yamashita A, Sugiura T (2009) 2-Arachidonoyl-sn-glycero-3-phosphoinositol: a possible natural ligand for GPR55. J Biochem 145(1):13–20. https://doi.org/10.1093/jb/mvn136
Padmanabhan S, Myers AG, Prasad BM (2009) Constitutively active GPR6 is located in the intracellular compartments. FEBS Lett 583(1):107–112. https://doi.org/10.1016/j.febslet.2008.11.033
Paugh SW, Cassidy MP, He H, Milstien S, Sim-Selley LJ, Spiegel S, Selley DE (2006) Sphingosine and its analog, the immunosuppressant 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol, interact with the CB1 cannabinoid receptor. Mol Pharmacol 70(1):41–50. https://doi.org/10.1124/mol.105.020552
Penumarti A, Abdel-Rahman AA (2014a) The novel endocannabinoid receptor GPR18 is expressed in the rostral ventrolateral medulla and exerts tonic restraining influence on blood pressure. J Pharmacol Exp Ther 349(1):29–38. https://doi.org/10.1124/jpet.113.209213
Penumarti A, Abdel-Rahman AA (2014b) Neuronal nitric oxide synthase-dependent elevation in adiponectin in the rostral ventrolateral medulla underlies g protein-coupled receptor 18-mediated hypotension in conscious rats. J Pharmacol Exp Ther 351(1):44–53. https://doi.org/10.1124/jpet.114.216036
Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev 62(4):588–631. https://doi.org/10.1124/pr.110.003004
Plastira I, Bernhart E, Goeritzer M, Reicher H, Kumble VB, Kogelnik N, Wintersperger A, Hammer A, Schlager S, Jandl K, Heinemann A, Kratky D, Malle E, Sattler W (2016) 1-Oleyl-lysophosphatidic acid (LPA) promotes polarization of BV-2 and primary murine microglia towards an M1-like phenotype. J Neuroinflamm 13(1):205. https://doi.org/10.1186/s12974-016-0701-9
Rajaraman G, Simcocks A, Hryciw DH, Hutchinson DS, McAinch AJ (2016) G protein coupled receptor 18: a potential role for endocannabinoid signaling in metabolic dysfunction. Mol Nutr Food Res 60(1):92–102. https://doi.org/10.1002/mnfr.201500449
Rapino C, Castellucci A, Lizzi AR, Sabatucci A, Angelucci CB, Tortolani D, Rossi G, D’Andrea G, Maccarrone M (2019) Modulation of endocannabinoid-binding receptors in human neuroblastoma cells by tunicamycin. Molecules 24(7):1432. https://doi.org/10.3390/molecules24071432
Recchiuti A, Serhan CN (2012) Pro-resolving lipid mediators (SPMs) and their actions in regulating miRNA in novel resolution circuits in inflammation. Front Immunol 3:298. https://doi.org/10.3389/fimmu.2012.00298
Reyes-Resina I, Navarro G, Aguinaga D, Canela EI, Schoeder CT, Załuski M, Kieć-Kononowicz K, Saura CA, Müller CE, Franco R (2018) Molecular and functional interaction between GPR18 and cannabinoid CB2 G-protein-coupled receptors Relevance in neurodegenerative diseases. Biochem Pharmacol 157:169–179. https://doi.org/10.1016/j.bcp.2018.06.001
Ruiz-Medina J, Ledent C, Valverde O (2011) GPR3 orphan receptor is involved in neuropathic pain after peripheral nerve injury and regulates morphine-induced antinociception. Neuropharmacology 61(1–2):43–50. https://doi.org/10.1016/j.neuropharm.2011.02.014
Ruz-Maldonado I, Liu B, Atanes P, Pingitore A, Huang GC, Choudhary P, Persaud SJ (2020) The cannabinoid ligands SR141716A and AM251 enhance human and mouse islet function via GPR55-independent signalling. Cell Mol Life Sci 77(22):4709–4723. https://doi.org/10.1007/s00018-019-03433-6
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):1092–1101. https://doi.org/10.1038/sj.bjp.0707460
Saliba SW, Jauch H, Gargouri B, Keil A, Hurrle T, Volz N, Mohr F, van der Stelt M, Bräse S, Fiebich BL (2018) Anti-neuroinflammatory effects of GPR55 antagonists in LPS-activated primary microglial cells. J Neuroinflamm 15:322. https://doi.org/10.1186/s12974-018-1362-7
Selley DE, Welch SP, Sim-Selley LJ (2013) Sphingosine lysolipids in the CNS: endogenous cannabinoid antagonists or a parallel pain modulatory system? Life Sci 93(5–6):187–193. https://doi.org/10.1016/j.lfs.2013.06.004
Sharir H, Console-Bram L, Mundy C, Popoff SN, Kapur A, Abood ME (2012) The endocannabinoids anandamide and virodhamine modulate the activity of the candidate cannabinoid receptor GPR55. J Neuroimmune Pharmacol 7(4):856–865. https://doi.org/10.1007/s11481-012-9351-6
Sheskin T, Hanus L, Slager J, Vogel Z, Mechoulam R (1997) Structural requirements for binding of anandamide-type compounds to the brain cannabinoid receptor. J Med Chem 40(5):659–667. https://doi.org/10.1021/jm960752x
Snider NT, Nast JA, Tesmer LA, Hollenberg PF (2009) A cytochrome P450-derived epoxygenated metabolite of anandamide is a potent cannabinoid receptor 2-selective agonist. Mol Pharmacol 75(4):965–972. https://doi.org/10.1124/mol.108.053439
Soderstrom K, Soliman E, Van Dross R (2017) Cannabinoids modulate neuronal activity and cancer by CB1 and CB2 receptor-independent mechanisms. Front Pharmacol 8:720. https://doi.org/10.3389/fphar.2017.00720
Soga T, Ohishi T, Matsui T, Saito T, Matsumoto M, Takasaki J, Matsumoto S, Kamohara M, Hiyama H, Yoshida S, Momose K, Ueda Y, Matsushime H, Kobori M, Furuichi K (2005) Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor. Biochem Biophys Res Commun 326(4):744–751. https://doi.org/10.1016/j.bbrc.2004.11.120
Southern C, Cook JM, Neetoo-Isseljee Z, Taylor DL, Kettleborough CA, Merritt A, Bassoni DL, Raab WJ, Quinn E, Wehrman TS, Davenport AP, Brown AJ, Green A, Wigglesworth MJ, Rees S (2013) Screening β-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors. J Biomol Screen 18(5):599–609. https://doi.org/10.1177/1087057113475480
Sridar C, Snider NT, Hollenberg PF (2011) Anandamide oxidation by wild-type and polymorphically expressed CYP2B6 and CYP2D6. Drug Metab Dispos 39(5):782–788. https://doi.org/10.1124/dmd.110.036707
Steentoft C, Vakhrushev SY, Joshi HJ, Kong Y, Vester-Christensen MB, Schjoldager KT, Lavrsen K, Dabelsteen S, Pedersen NB, Marcos-Silva L, Gupta R, Bennett EP, Mandel U, Brunak S, Wandall HH, Levery SB, Clausen H (2013) Precision mapping of the human O-GalNAc glycoproteome through SimpleCell technology. EMBO J 32:1478–1488. https://doi.org/10.1038/emboj.2013.79
Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, Stein TI, Nudel R, Lieder I, Mazor Y, Kaplan S, Dahary D, Warshawsky D, Guan-Golan Y, Kohn A, Rappaport N, Safran M, Lancet D (2016) The GeneCards suite: from gene data mining to disease genome sequence analyses. Curr Protoc Bioinform 54(1):1.30.1-1.30.33. https://doi.org/10.1002/cpbi.5
Succar R, Mitchell VA, Vaughan CW (2007) Actions of N-arachidonyl-glycine in a rat inflammatory pain model. Mol Pain 3:24. https://doi.org/10.1186/1744-8069-3-24
Sumida H, Cyster JG (2018) G-protein coupled receptor 18 contributes to establishment of the CD8 effector T cell compartment. Front Immunol 9:660. https://doi.org/10.3389/fimmu.2018.00660
Syed SK, Bui HH, Beavers LS, Farb TB, Ficorilli J, Chesterfield AK, Kuo MS, Bokvist K, Barrett DG, Efanov AM (2012) Regulation of GPR119 receptor activity with endocannabinoid-like lipids. Am J Physiol Endocrinol Metab 303(12):E1469–E1478. https://doi.org/10.1152/ajpendo.00269.2012
Takenouchi R, Inoue K, Kambe Y, Miyata A (2012) N-arachidonoyl glycine induces macrophage apoptosis via GPR18. Biochem Biophys Res Commun 418(2):366–371. https://doi.org/10.1016/j.bbrc.2012.01.027
Tanaka S, Ishii K, Kasai K, Yoon SO, Saeki Y (2007) Neural expression of G protein-coupled receptors GPR3, GPR6, and GPR12 up-regulates cyclic AMP levels and promotes neurite outgrowth. J Biol Chem 282(14):10506–10515. https://doi.org/10.1074/jbc.M700911200
Tanaka S, Miyagi T, Dohi E, Seki T, Hide I, Sotomaru Y, Saeki Y, Antonio Chiocca E, Matsumoto M, Sakai N (2014) Developmental expression of GPR3 in rodent cerebellar granule neurons is associated with cell survival and protects neurons from various apoptotic stimuli. Neurobiol Dis 68:215–227. https://doi.org/10.1016/j.nbd.2014.04.007
Tengholm A (2012) Cyclic AMP dynamics in the pancreatic β-cell. Ups J Med Sci 117(4):355–369. https://doi.org/10.3109/03009734.2012.724732
Thathiah A, Spittaels K, Hoffmann M, Staes M, Cohen A, Horré K, Vanbrabant M, Coun F, Baekelandt V, Delacourte A, Fischer DF, Pollet D, De Strooper B, Merchiers P (2009) The orphan G protein-coupled receptor 3 modulates amyloid-beta peptide generation in neurons. Science 323(5916):946–951. https://doi.org/10.1126/science.1160649
Thathiah A, Horre K, Snellinx A, Vandewyer E, Huang Y, Ciesielska M, De Kloe G, Munck S, De Strooper B (2013) β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer’s disease. Mol Neurodegener 8(Suppl 1):P41. https://doi.org/10.1186/1750-1326-8-S1-P41
Tudurí E, Imbernon M, Hernández-Bautista R, Tojo M, Fernø J, Diéguez C, Nogueiras R (2017) GPR55: a new promising target for metabolism? J Mol Endocrinol 58(3):R191–R202
Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson Å, Kampf C, Sjöstedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Pontén F (2015) Tissue-based map of the human proteome. Science 347(6220):1260419. https://doi.org/10.1126/science.1260419
Uhlenbrock K, Gassenhuber H, Kostenis E (2002) Sphingosine 1-phosphate is a ligand of the human gpr3, gpr6 and gpr12 family of constitutively active G protein-coupled receptors. Cell Signal 14(11):941–953. https://doi.org/10.1016/s0898-6568(02)00041-4
Vaccari S, Horner K, Mehlmann LM, Conti M (2008) Generation of mouse oocytes defective in cAMP synthesis and degradation: endogenous cyclic AMP is essential for meiotic arrest. Dev Biol 316(1):124–134. https://doi.org/10.1016/j.ydbio.2008.01.018
Valverde O, Célérier E, Baranyi M, Vanderhaeghen P, Maldonado R, Sperlagh B, Vassart G, Ledent C (2009) GPR3 receptor, a novel actor in the emotional-like responses. PLoS ONE 4(3):e4704. https://doi.org/10.1371/journal.pone.0004704
van der Stelt M, van Kuik JA, Bari M, van Zadelhoff G, Leeflang BR, Veldink GA, Finazzi-Agrò A, Vliegenthart JF, Maccarrone M (2002) Oxygenated metabolites of anandamide and 2-arachidonoylglycerol: conformational analysis and interaction with cannabinoid receptors, membrane transporter, and fatty acid amide hydrolase. J Med Chem 45(17):3709–3720. https://doi.org/10.1021/jm020818q
Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison JS, Marnett LJ, Di Marzo V, Pittman QJ, Patel KD, Sharkey KA (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310(5746):329–332. https://doi.org/10.1126/science
Waldeck-Weiermair M, Zoratti C, Osibow K, Balenga N, Goessnitzer E, Waldhoer M, Malli R, Graier WF (2008) Integrin clustering enables anandamide-induced Ca2+ signaling in endothelial cells via GPR55 by protection against CB1-receptor-triggered repression. J Cell Sci 121(Pt 10):1704–1717. https://doi.org/10.1242/jcs.020958
Wang X, Sumida H, Cyster JG (2014) GPR18 is required for a normal CD8αα intestinal intraepithelial lymphocyte compartment. J Exp Med 211(12):2351–2359. https://doi.org/10.1084/jem.20140646
Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, Heer FT, de Beer TAP, Rempfer C, Bordoli L, Lepore R, Schwede T (2018) SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res 46(W1):W296–W303. https://doi.org/10.1093/nar/gky427
Williams JR, Khandoga AL, Goyal P, Fells JI, Perygin DH, Siess W, Parrill AL, Tigyi G, Fujiwara Y (2009) Unique ligand selectivity of the GPR92/LPA5 lysophosphatidate receptor indicates role in human platelet activation. J Biol Chem 284(25):17304–17319. https://doi.org/10.1074/jbc.M109.003194
Xue Y, Liu Z, Cao J, Ma Q, Gao X, Wang Q, Jin C, Zhou Y, Wen L, Ren J (2011) GPS 2.1: enhanced prediction of kinase-specific phosphorylation sites with an algorithm of motif length selection. Protein Eng Des Sel 24:255–260. https://doi.org/10.1093/protein/gzq094
Ye C, Zhang Z, Wang Z, Hua Q, Zhang R, Xie X (2014) Identification of a novel small-molecule agonist for human G protein-coupled receptor 3. J Pharmacol Exp Ther 349(3):437–443. https://doi.org/10.1124/jpet.114.213082
Yin H, Chu A, Li W, Wang B, Shelton F, Otero F, Nguyen DG, Caldwell JS, Chen YA (2009) Lipid G protein-coupled receptor ligand identification using beta-arrestin PathHunter assay. J Biol Chem 284(18):12328–12338. https://doi.org/10.1074/jbc.M806516200
Zhang BL, Li Y, Ding JH, Dong FL, Hou YJ, Jiang BC, Shi FX, Xu YX (2012) Sphingosine 1-phosphate acts as an activator for the porcine Gpr3 of constitutively active G protein-coupled receptors. J Zhejiang Univ Sci B 13(7):555–566. https://doi.org/10.1631/jzus.B1100353
Zhang L, Qiu C, Yang L, Zhang Z, Zhang Q, Wang B, Wang X (2019) GPR18 expression on PMNs as biomarker for outcome in patient with sepsis. Life Sci 217:49–56. https://doi.org/10.1016/j.lfs.2018.11.061
Zou S, Kumar U (2018) Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci 19(3):833. https://doi.org/10.3390/ijms19030833
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Biringer, R.G. Endocannabinoid signaling pathways: beyond CB1R and CB2R. J. Cell Commun. Signal. 15, 335–360 (2021). https://doi.org/10.1007/s12079-021-00622-6
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DOI: https://doi.org/10.1007/s12079-021-00622-6