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
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • Apart from the different assays used

    2022-05-18

    Apart from the different assays used, biased agonism could also explain the inconsistent pharmacology of GPR55. Indeed, one study compared the effect of LPIs and Virodhamine in HEK293 GANT61 stably transfected with human GPR55. They found that the effect of both ligands on intracellular Ca2+ was blocked by CID16020046, a GPR55 antagonist. However, the effect of Virodhamine was mediated by Gα13, Rho, ROCK, and PLCε while the effect of LPI was more dependent on Gαq and PLCβ [23]. However, in another study with HEK293 cells transfected with human GPR55, LPIs activated the Gα13, Rho, ROCK pathway [21]. Another example of potentially biased agonism comes from a study that found that LPIs, but not the cannabinoid receptor antagonists SR141716A and AM251, could induce ERK phosphorylation in hGPR55-transfected U2OS cells, despite all three ligands inducing β-arrestin recruitment and receptor internalization [24]. Additionally, some cannabinoids have been suggested to be allosteric modulators of GPR55, which could explain the complex pharmacology of cannabinoids at GPR55. Indeed, allosteric modulation is often dependent on the probe, system, and assay used, which could explain the inconsistent data [25]. While it is gradually emerging that GPR55 is not a cannabinoid receptor, there is a clear crosstalk between GPR55 and the cannabinoid receptors (CB1 and CB2), either through modulation of integrin clustering [26] or through heteromerization 27, 28. Indeed, like numerous GPCRs, GPR55 was found to oligomerize, notably with the cannabinoid receptors, leading to alterations in signaling. However the consequences of this interaction were different depending on the cannabinoid receptor considered (Box 3).
    Pathophysiological Actions of LPIs and GPR55 GPR55 is ubiquitously expressed 29, 30, 31, 32, 33, 34, 35, therefore, despite its relatively recent deorphanization and complex pharmacology, it is implicated in many physiological and pathological processes, including inflammation, nociception, cancer, bone development, metabolic disturbances, synaptic transmission, and anxiety (Figure 2, Key Figure). In the following section, we discuss the effects of either LPIs or GPR55 in several settings. Some studies in the literature attribute effects to GPR55 following the use of atypical cannabinoid ligands, such as oleoylethanolamide, palmitoylethanolamide, O-1602, and abnormal cannabidiol or the blockade of some effects by putative antagonists such as O-1918. However, as mentioned previously, there is no consensus as to whether some of these compounds are indeed GPR55 ligands and if they are, their selectivity is questionable. They were shown to have GPR55-independent targets and to retain their effects in GPR55-/- mice 36, 37, 38. Therefore we elected to review the effects directly attributable to GPR55, as well as the effects of LPIs, and discuss if the latter were GPR55-dependent or not.
    Concluding Remarks and Future Perspectives While it is now widely accepted that LPIs are GPR55 ligands and that some of the cannabinoid ligands are also GPR55 ligands, many of the compounds tested in the literature as GPR55 ligands lack selectivity and have GPR55-independent effects. This has led to contradictory observations and possible misinterpretations and hinders the discovery of the pathophysiological roles of GPR55 (see Outstanding Questions). Moreover, it is possible that GPR55 could have other endogenous ligands than LPIs and that LPIs have other targets than GPR55. Despite these hurdles, GPR55 was implicated in many physiological and pathological processes that deserve further exploration. The recent development of selective agonists and antagonists of this receptor could help in moving the field forward. For instance, using antagonists to confirm the effects obtained with knock-out animals would provide further evidence of the druggability of GPR55 in inflammation and cancer. Another potential hurdle in the way to understanding the role of GPR55 in human physiology is the difference in results between humans and rodents, notably when it comes to obesity and metabolic diseases. Finally, it should be noted that while GPR55 activation seems beneficial in some settings, such as obesity and diabetes, it is rather deleterious in other settings, such as cancer. Therefore, antagonists of GPR55 might prove effective as cancer treatments. However, as GPR55 seems to be implicated in the control of mood and behavior, caution should be taken with the development and use of compounds targeting GPR55 and their potential side effects. Therefore, as it is often the case with receptors having multiple functions, delineating which diseases could actually benefit from a modulation of LPI and GPR55 will be a key question in the future.