Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • br Introduction Marijuana remains the most widely used

    2022-06-27


    Introduction Marijuana remains the most widely used illegal drug (Murray et al., 2007), and its validated targets include plasma membrane cannabinoid receptors, many of which are found in the central nervous system. The diverse physiological effects produced by marijuana and cannabinoid ligands suggest the possibility that several receptors are responsible for their activity. Yet to date, only two receptor subtypes, CB1 and CB2, have convincingly been confirmed as cannabinoid targets. However, in support of the notion that other cannabinoid receptors remain to be identified, the complex pharmacological properties of exogenous cannabinoids and endocannabinoids are not fully explained by CB1 and CB2 signal transduction. Recently, the orphan G-protein coupled receptor, GPR55, was presented as one of the missing candidate cannabinoid receptor subtypes (Johns et al., 2007, Ryberg et al., 2007), but the validity of this assignment is under debate. In particular, Oka et al (2007) reported that while cannabinoids did not appear to activate GPR55, lysophosphatidyinositol (LPI) derivatives resulted in robust stimulation of the receptor. Thus, the chemical space of GPR55 agonists remains ill defined. As a consequence of the identification, whether correct or incorrect, that GPR55 is a target for cannabinoid binding, GPR55 now shoulders a potentially important but un-defined role in the paradigm of drug addiction. It thus becomes incumbent to identify GPR55-selective ligands in order to substantiate GPR55 pharmacology and to characterize its biology. GPR55 was initially identified as a candidate cannabinoid receptor in patent applications from GlaxoSmithKline and AstraZeneca (Brown and Wise, 2001, Drmota et al., 2004). The ability of GPR55 to recognize cannabinoids was first described in a yeast (-)-JQ1 system in the GlaxoSmithKline patent, where the CB1 antagonists AM251 and SR141716A acted as agonists at micromolar concentrations (Brown and Wise, 2001, Brown and Hiley, 2009) (please see Fig. 1 for structures). In contrast, the AstraZeneca group reported that when GPR55 was expressed in HEK293 cells, nanomolar concentrations of many cannabinoid agonists stimulated GTPγS binding (Drmota et al., 2004, Ryberg et al., 2007). Most of the endocannabinoids, including anandamide, 2-arachidonylglycerol (2-AG), virodhamine, noladin ether, oleoylethanolamide and palmitoylethanolamide as well as the several agonists including CP55,950 and Δ9-THC, stimulated GTPγS binding, which was not antagonized by AM281, but was blocked with 450nM cannabidiol (CBD) (Drmota et al., 2004, Ryberg et al., 2007). AM251 produced an agonist response in HEK293 cells, similar to that found in the yeast expression system (Ryberg et al., 2007). Lauckner et al (2008) reported that GPR55 was a cannabinoid receptor, based on their data that Δ9-THC, anandamide and JWH-015, increased intracellular calcium in transfected cells and also in large dorsal root ganglion neurons. In contrast to these results, Oka et al (2007) reported that GPR55 is not a typical cannabinoid receptor as numerous endogenous and synthetic cannabinoids, including many mentioned above, had no effect on GPR55 activity. Instead, their data suggests that the endogenous lipid LPI and its 2-arachidonyl analogs are agonists at GPR55 as a result of their abilities to phosphorylate extracellular-regulated kinase and induce calcium signaling (Oka et al., 2007, Oka, Kimura, Yamashita and Sugiura, 2009a). Thus GPR55 may recognize cannabinoids, but has a unique response profile differing from CB1 and CB2. Several recent reviews have highlighted the enigmatic pharmacology of GPR55 (Brown and Hiley, 2009, De Petrocellis and Di Marzo, 2009, Godlewski et al., 2009, Kreitzer and Stella, 2009, Ross, 2009). Here we review the primary literature and include papers and abstracts not previously cited.
    Discovery of GPR55 Human GPR55 (hGPR55) was originally isolated in 1999 as an orphan GPCR with high levels of expression in human striatum (Sawzdargo et al., 1999) (Genbank accession # NM_005683.3). Initial characterization of human GPR55 identified it as a potential member of the purinergic or chemokine receptor family based on amino acid homology; it shares 29% identity with the P2Y5 purinergic receptor (NM_005767.4), 30% identity with GPR23 (NM_005296.2), 27% identity with GPR35 (NM_005301.2) and 23% identity with the CCR4 chemokine receptor (NM_005508.4) (Sawzdargo et al., 1999). Relevant to later discussion, GPR23 has been classified as the LPAR4 receptor, although LPA activates at high micromolar concentrations (Yin et al., 2009) and P2Y5 also responds to LPA and has been classified as LPAR6 (Pasternack et al., 2008). In contrast, hGPR55 exhibits low amino acid identity to CB1 (13.5%) or CB2 (14.4%) receptors. hGPR55 is clearly a member of the Class A (rhodopsin) family of GPCRs based on sequence similarities with rhodopsin (see below). Drmota et al. (2004) have also isolated a variant of hGPR55, hGPR55a, which contains three amino acid substitutions (F3.33(102)L, G5.52(195)S, C7.47(281)R (Baker et al., 2006). Sequences for rat and mouse GPR55 have also been reported (Ryberg et al., 2007) as has a putative chimpanzee sequence (Baker et al., 2006). Interestingly, orthologs for GPR55 have primarily been reported in mammals with a somewhat similar sequence in marsupials (opossum, XM_001373864) (Baker et al., 2006). A subsequent study found orthologs of GPR55 in zebrafish and puffer fish (McPartland et al., 2007), suggesting an early chordate phylogenic origin of GPR55.