First neuronal guidance lipid: Elucidation of biosynthesis and development of lead compounds to support neuronal recovery after injury

• Project/Area Number: 16K08259
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Greimel Peter 国立研究開発法人理化学研究所, 脳神経科学研究センター, 専任研究員 (60525541)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Phosphatidylglucoside / GPCR / Lipids / GPR55 / GPRC / Biosynthesis / lipid-biosynthesis

Outline of Final Research Achievements

To characterize lysolipid-GPR55 interaction a novel homology model of GPR55 was created. Synthetic access to LysoPtdGlc and selected analogues featuring modifications on the acyl chain and on the phosphate moiety were established. The biological activity of each synthetic lipid was assessed using a GPR55-dependent chemotropism assay in primary sensory neurons. Molecular dynamics simulations of the GPR55 homology model in presence of synthetic lysolipid ligands have been performed and assessed. Combination of the molecular dynamics simulations and biological experiments provided insight into the potential ligand entry port and binding pocket specifics of GPR55. These results highlight the preference for gluco- over inositol- and galacto-configured headgroups. Furthermore, the specific acyl chain length required for GPR55 activation has been determined and is in good agreement with the created homology model of GPR55.

Academic Significance and Societal Importance of the Research Achievements

Detailed characterization of the GPR55 ligand binding pocket is an essential per-requisite for rational design of novel GPR55 specific antagonists, which have a high potential to be applied in neuropathic pain relieve treatments in the future.

Research Products

• [Journal Article] Formation of tubules and helical ribbons by ceramide phosphoethanolamine-containing membranes. (2019)
  • Author(s): Inaba T., Murate M., Tomishige N., Lee Y.-F., Hullin-Matsuda F., Pollet B., Humbert N., Mely Y., Sako Y., Greimel P. and Kobayashi T.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 5812-5812
  • DOI: 10.1038/s41598-019-42247-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Biophysical Properties of Phosphtidylglucoside and Phosphatidylinositol: Specific Differences in Head Group Interaction (2018)
  • Author(s): Greimel Peter
  • Journal Title: Trends in Glycoscience and Glycotechnology Volume: 30 Issue: 171 Pages: E1-E13
  • DOI: 10.4052/tigg.1704.1E
  • NAID: 130006319125
  • ISSN: 0915-7352, 1883-2113
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Squaryl group modified phosphoglycolipid analogs as potential modulators of GPR55 (2018)
  • Author(s): Ding Feiqing、Guy Adam T.、Greimel Peter、Hirabayashi Yoshio、Kamiguchi Hiroyuki、Ito Yukishige
  • Journal Title: Chemical Communications Volume: 54 Issue: 61 Pages: 8470-8473
  • DOI: 10.1039/c8cc04467h
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] GPRC5B-Mediated Sphingomyelin Synthase 2 Phosphorylation Plays a Critical Role in Insulin Resistance (2018)
  • Author(s): Kim Yeon-Jeong、Greimel Peter、Hirabayashi Yoshio
  • Journal Title: iScience Volume: 8 Pages: 250-266
  • DOI: 10.1016/j.isci.2018.10.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Preference for Glucose over Inositol Headgroup during Lysolipid Activation of G Protein-Coupled Receptor 55 (2018)
  • Author(s): Guy Adam T.、Kano Koki、Ohyama Jyunpei、Kamiguchi Hiroyuki、Hirabayashi Yoshio、Ito Yukishige、Matsuo Ichiro、Greimel Peter
  • Journal Title: ACS Chemical Neuroscience Volume: 10 Issue: 1 Pages: 716-727
  • DOI: 10.1021/acschemneuro.8b00505
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Eudicot plant-specific sphingolipids determine host selectivity of microbial NLP cytolysins (2017)
  • Author(s): Lenarcic T., Albert I.、Boehm H.、Hodnik V.、Pirc K.、Zavec A. B.、Podobnik M.、Pahovnik D.、Zagar E.a、Pruitt R.、Greimel P.、Yamaji-Hasegawa A.、Kobayashi T.、Zienkiewicz A.、Goemann J.、Mortimer J. C.、Fang L.、Mamode-Cassim A.、Deleu M.、Lins L.、Oecking C.、Feussner I.、Mongrand S.、Anderluh G.、Nuernberger T.
  • Journal Title: Science Volume: 358 Issue: 6369 Pages: 1431-1434
  • DOI: 10.1126/science.aan6874
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Photoswitchable phospholipid FRET acceptor: Detergent free intermembrane transfer assay of fluorescent lipid analogs (2017)
  • Author(s): Sumi Mariko、Makino Asami、Inaba Takehiko、Sako Yasushi、Fujimori Fumihiro、Greimel Peter、Kobayashi Toshihide
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 1-10
  • DOI: 10.1038/s41598-017-02980-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel spingomyeling/cholesterol specific probe reveals the dynamics of the membrane domain during virus and in Nieman-Pick type C (2016)
  • Author(s): Makino, A., Sako, Y. et al.
  • Journal Title: FASEB J. Volume: 31 Issue: 4 Pages: 1301-1322
  • DOI: 10.1096/fj.201500075r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Phosphatidyl-β-D-glucoside: From Biosynthesis to Biological Activity of Synthetic Analogues (2018)
  • Author(s): P. Greimel, A.T. Guy, H.H. Hung, Y. Nagatsuka, I. Matsuo, Y. Ito, H. Kamiguchi, Y. Hirabayashi
  • Organizer: 29th International Carbohydrate Conference
  • Int'l Joint Research
• [Presentation] GPR55 Ligands: From Endocanabinoids to Lysolipids (2018)
  • Author(s): Greimel Peter
  • Organizer: RIKEN Symposium, Wako, Japan
  • Invited
• [Presentation] Probing Lipid-Cholesterol Interaction (2017)
  • Author(s): Greimel Peter
  • Organizer: International Membrane Seminar, Osaka, Japan
  • Invited
• [Presentation] Lyso-Phosphatidyl-β-D-glucoside Analogues as GPR55 Agonists: Synthesis and Modality-Specific Repulsive Guidance of Nociceptive Neurons (2017)
  • Author(s): Adam T. Guy, Yukishige Ito, Hiroyuki Kamiguchi, Yoshio Hirabayashi, Peter Greimel
  • Organizer: 19th European Carbohydrate Symposium; EUROCARB2017
• [Funded Workshop] 57th International Conference on the Bioscience of Lipids (2016)
  • Place of Presentation: France
  • Year and Date: 2016-09-04