Preference for Glucose over Inositol Headgroup during Lysolipid Activation of G Protein-Coupled Receptor 55

G protein-coupled
receptor 55 (GPR55) is highly expressed in brain
and peripheral nervous system. Originally deorphanized as a cannabinoid
receptor, recently GPR55 has been described as a lysophospholipid-responsive
receptor, specifically toward lysophosphatidylinositol and lysophosphatidyl-β-d-glucoside (LysoPtdGlc). To characterize lysolipid-GPR55 interaction,
synthetic access to LysoPtdGlc and selected analogues was established
utilizing a phosphorus­(III)-based chemical approach. The biological
activity of each synthetic lipid was assessed using a GPR55-dependent
chemotropism assay in primary sensory neurons. Combined with molecular
dynamics simulations the potential ligand entry port and binding pocket
specifics are discussed. These results highlight the preference for
gluco- over inositol- and galacto-configured headgroups.