Recently, we have demonstrated  that phosphatidyl-β-D-glucoside derived lyso-phosphatidyl-β-D-glucoside (lyso-PtdGlc) is the first lipid derived regulator of central projections in nociceptive (pain) sensory afferents during embryonic development. This lyso-PtdGlc associated patterning is mediated by G-protein coupled receptor 55 (GPR55). GPR55 has originally been deorphanized as a cannabinoid receptor, but has later been described as lysophospholipid-responsive receptor. GPR55 upregulation has been reported in a variety of cancers, while GPR55 knock out mice show abnormal responses to inflammation and mechanical stimuli, suggesting a role of GPR55 in neuropathic pain and inflammatory processes. Furthermore, GPR55 has been linked to a variety of physiological and pathological processes, such as synaptic transmission, obesity, bone development and gastrointestinal functions.
To characterize lysolipid-GPR55 interaction and more specifically the ligand binding pocket, we established synthetic access to lyso-PtdGlc and prepared a variety of synthetic lyso-PtdGlc analogues. The biological activity of our synthetic analogues was evaluated using our previously developed functional assay, based on primary cultured DRG sensory neurons endogenously expressing GPR55. To overcome the lack of structural information of GPR55, we established and validated a GPR55 homology model  and performed molecular dynamics (MD) simulations of GPR55 in the presence of natural and synthetic lysolipid ligands. The results of our MD simulation were in good agreement with our biological assay results, providing novel insight into the ligand binding pocket specifics.
- A.T. Guy, Y. Nagatsuka, N. Ooashi, M. Inoue, A. Nakata, P. Greimel, A. Inoue, T. Nabetani, A. Murayama, K. Ohta, Y. Ito, J. Aoki, Y. Hirabayashi, H. Kamiguchi, Science 2015, 349(6251), 974-7.
- A.T. Guy, K. Kano, J. Ohyama, H. Kamiguchi, Y. Hirabayashi, Y. Ito, I. Matsuo, P. Greimel ACS Chem. Neurosci. 2019, 10, 716-727.