Profiling the activity of GPR55 antagonists against recombinant and endogenous GPR55

  • Orla Haugh

    Student thesis: Master's ThesisMaster of Science


    GPR55 is a putative novel cannabinoid receptor that is capable of being activated by a subset of cannabinoid ligands and the endogenous lipid, L-α-lysophosphatidylinositol (LPI). GPR55 mRNA is expressed widely throughout the body, particularly in the brain, bone and immune tissue, and is also expressed at high levels in certain types of tumour. Understanding the physiological and pathological role of GPR55 has been challenging due to the absence of selective pharmacological tools. However, novel antagonists have recently been developed, allowing for the determination of GPR55-selective effects. The objective of the present study was to utilise molecular imaging techniques to evaluate the effectiveness of two previously published novel GPR55 antagonists on LPI-mediated GPR55 responses, in a HEK293 cell line stably expressing GPR55 (hGPR55-HEK293) and also in a prostate cancer cell line that expresses GPR55 endogenously at high levels (DU145). Antagonist effectiveness was also examined in a neuronal model of Alzheimer’s disease (AD). The effects of the antagonists on LPI-mediated calcium (Ca2+) responses and cAMP-response element-binding protein (CREB) phosphorylation were evaluated. In hGPR55-HEK293 cells, treatment with antagonists at varying concentrations did not have an effect on intracellular Ca2+ levels or alter CREB phosphorylation when applied alone. However, both inhibited increases in Ca2+ signal induced by GPR55 agonists when applied at 3 µM. Overall, this data suggests that the GPR55 antagonists are active in in vitro models that over-express GPR55. Such pharmacological tools will help to advance the research on the physiological function of GPR55.
    Date of Award2015
    Original languageEnglish
    SupervisorAndrew Irving (Supervisor)

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