Abstract
G protein-coupled receptor 55 (GPR55) is a recently deorphanized lipid- and peptide-sensing receptor. Its lipidic endogenous agonists belong to lysoglycerophospholipids, with lysophosphatidylinositol (LPI) being the most studied. Peptide agonists derive from fragmentation of pituitary adenylate cyclase-activating polypeptide (PACAP). Although GPR55 and its ligands were implicated in several physiological and pathological conditions, their biological function remains unclear. Thus, the aim of the study was to conduct a large-scale re-analysis of publicly available gene expression datasets to identify physiological and pathological conditions affecting the expression of GPR55 and the production of its ligands. The study revealed that regulation of GPR55 occurs predominantly in the context of immune activation pointing towards the role of the receptor in response to pathogens and in immune cell lineage determination. Additionally, it was revealed that there is almost no overlap between the experimental conditions affecting the expression of GPR55 and those modulating agonist production. The capacity to synthesize LPI was enhanced in various types of tumors, indicating that cancer cells can hijack the motility-related activity of GPR55 to increase aggressiveness. Conditions favoring accumulation of PACAP-derived peptides were different than those for LPI and were mainly related to differentiation. This indicates a different function of the two agonist classes and possibly the existence of a signaling bias.
Highlights
G protein-coupled receptor 55 (GPR55) is a seven transmembrane receptor (7TM), initially recognized as a sensor for phytocannabinoids, pharmacologically active compounds of Cannabis sativa [1,2]
Intensified signaling downstream of GPR55 can occur in cells experiencing upregulation of the receptor or in cells exposed to increased agonist load
Transcriptomic datasets were queried for conditions leading to GPR55 upregulation (Figure 2A)
Summary
G protein-coupled receptor 55 (GPR55) is a seven transmembrane receptor (7TM), initially recognized as a sensor for phytocannabinoids, pharmacologically active compounds of Cannabis sativa [1,2]. The lyso prefix indicates that one of the two fatty acid chains was removed from the phospholipid molecule by hydrolysis. The hydrophobic tail of LGPLs contains only one esterified fatty acid chain to a glycerol core. Glycerol is further bound to a phosphate group linked to an alcohol or a carbohydrate (Figure 1A). Different species of LGPLs exist depending on the (I) type of acyl chain attached to the glycerol moiety, (II) attachment point of the acyl chain, and (III) nature of the chemical group linked to a phosphate moiety. Initial screens revealed that GPR55 is selective regarding the lipid structure, as only a limited number of endogenous phospholipids managed to activate the receptor [11].
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