2018 Fiscal Year Annual Research Report
First neuronal guidance lipid: Elucidation of biosynthesis and development of lead compounds to support neuronal recovery after injury
| Project/Area Number |
16K08259
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| Research Institution | Institute of Physical and Chemical Research |
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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)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | Phosphatidylglucoside / GPCR / Lipids / GPR55 |
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| Outline of Annual Research Achievements |
G protein-coupled receptor 55 (GPR55) is highly expressed in brain and peripheral nervous system. It was originally deorphanized as a cannabinoid receptor, but has recently been described as a lysophospholipid-responsive receptor, responsive to lysophosphatidylinositol and lysophosphatidyl-β-D-glucoside (LysoPtdGlc). To characterize lysolipid-GPR55 interaction a novel homology model of GPR55 was created, based on the human δ-opioid, human adenosine A2A, and CXCR4 receptor. Additionally synthetic access to LysoPtdGlc and selected analogues featuring not only modifications on the acyl chain, but also 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 embedded in a suitable lipid membrane and in presence of a variety 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.
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