Archives

  • 2018-07
  • 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
  • 2024-04
  • 2024-05
  • 2024-06
  • 2024-07
  • 2024-08
  • 2024-09
  • 2024-10
  • Human GPR hGPR was originally isolated in

    2022-06-13

    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). hGPR55 was mapped to human chromosome 2q37, and in the human CNS it is predominantly localized to the caudate, putamen, and striatum (Sawzdargo et al., 1999). In rats, in situ hybridization indicated expression in hippocampus, thalamus and regions of the midbrain (Sawzdargo et al., 1999). Ryberg et al. (2007) reported mRNA expression levels in the mouse. They found the level of expression to be highest in the adrenals>frontal cortex>striatum≅jejunem and ileum>hypothalamus, brainstem>hippocampus, cerebellum, spleen>spinal cord≫lung, liver, uterus, bladder, stomach, kidney>esophagus>adipose (Ryberg et al., 2007). Thus GPR55 mRNA is found in a number of tissues outside the CNS, where it is broadly expressed, albeit at levels significantly lower than those of CB1, perhaps the most highly expressed GPCR in the CNS (Howlett et al., 2002, Ryberg et al., 2007).
    Ligands: structurally distinct but with deep connections To date, kynurenic AH 7614 and 2-acyl lysophosphatidic acid have been postulated to be natural ligands for GPR35. Kynurenic acid was found to be able to elevate intracellular calcium in CHO cells expressing human GPR35 and a mixture of promiscuous and chimeric G proteins (Wang et al., 2006). Kynurenic acid is a metabolite of tryptophan; however, its precursors, kynurenine and tryptophan, failed to activate GPR35, suggesting the probable importance of the acidic moiety of kynurenic acid (Wang et al., 2006). In other functional assays, kynurenic acid stimulated GTPγS binding, which can be prevented by pretreatment with pertusis toxin (Wang et al., 2006). Using engineered βarrestin2 as reporters, kynurenic acid activated GPR35 in GPR35-expressing cells by two independent research groups (Jenkins et al., 2010, Zhao et al., 2010). Though kynurenic acid has been consistently shown to be able to activate GPR35, it showed a very low potency for human GPR35 compared with relative high potency for rat GPR35 (reviewed in (Milligan, 2011)). This suggests that kynurenic acid might be an effective agonist in rat, but not in human. A second group of postulated endogenous ligands for GPR35 receptors are lysophosphatidic acids, especially 2-acyl lysophosphatidic acids (Fig. 1) (Oka et al., 2010). GPR35 is related to GPR23 which has been reported to be a lysophosphatidic acid receptor (LPA4); previously referred to as P2Y9 (Noguchi et al., 2003). Unlike kynurenic acid, 2-acyl LPA activated human GPR35 with high potency. Thus, 2-acyl LPA is more likely to be the endogeneous ligand for human GPR35 instead of kynurenic acid. Many surrogate ligands have been reported for GPR35. Zaprinast, and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), have been identified as GPR35 agonists (Taniguchi et al., 2006, Wang et al., 2006). Tyrphostin analogs, the orphan asthma drugs cromolyn disodium and nedocromil sodium, bumetanide and furosemide, pamoic acid and its derivatives have all been reported to be GPR35 agonists (Deng et al., 2011a, Deng et al., 2011b, Yang et al., 2010, Zhao et al., 2010). The first antagonist for GPR35 described was methyl-5-[(tertbutylcarbamothioylhydrazinylidene) methyl]-1-(2,4-difluorophenyl) pyrazole-4-carboxylate (CID2745687), which inhibits in both the β-arrestin trafficking and ERK phosphorylation assays (Zhao et al., 2010). Subsequently, additional antagonists have been reported for GPR35 (Heynen-Genel et al., 2010c). To date, the pharmacology of the GPR55 receptor remains controversial. GPR55 does recognize certain cannabinoid ligands, so it has been suggested to be a third cannabinoid receptor (Sharir and Abood, 2010). Whether GPR55 responds to the endocannabinoid ligands, anandamide and 2-arachidonylglycerol, and the phytocannabinoids, delta-9-tetrahydrocannabidiol and cannabidiol, is cell-type and tissue-dependent (Pertwee et al., 2010, Ross, 2009). The consensus is that LPI is an endogenous ligand for GPR55 (Pertwee et al., 2010), but LPI has actions at sites other than GPR55 as well (Bondarenko et al., 2011). The 2-arachidonyl-LPI isoform is the most potent endogenous ligand described for GPR55 (Fig. 1) (Oka et al., 2009).