Lysophospholipid stereoisomers exert distinct GPR55-mediated functions via different Gα subunits
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View abstract on PubMed
Summary
This summary is machine-generated.Stereoisomer configuration of lyso-phosphatidyl-β-d-glucoside (LysoPtdGlc) dictates its biological activity. R-LysoPtdGlc mediates axon repulsion and pain, while S-LysoPtdGlc induces attraction via distinct GPR55 signaling pathways.
Area Of Science
- Neuroscience
- Biochemistry
- Molecular Biology
Background
- Vertebrate glycerophospholipids typically have a glycerol-3-phosphate (G3P) backbone with R-configuration at the sn-2 chiral center.
- Lyso-phosphatidyl-β-d-glucoside (LysoPtdGlc) is an endogenous GPR55 ligand involved in axon guidance.
- Phosphatidyl-β-d-glucoside (PtdGlc) exists as a mixture of R-PtdGlc and S-PtdGlc stereoisomers.
Purpose Of The Study
- To investigate if LysoPtdGlc stereoconfiguration influences its biological activity.
- To elucidate the distinct signaling pathways and functions of R-LysoPtdGlc and S-LysoPtdGlc.
- To determine the role of LysoPtdGlc stereoisomers in nociception.
Main Methods
- Molecular dynamics simulations of GPR55 activation by R-LysoPtdGlc and S-LysoPtdGlc.
- In vitro and in vivo biological assays of GPR55-mediated functions in the nervous system.
- Assessment of axonal chemotropic responses and nociceptive phenotypes in mice.
Main Results
- Molecular dynamics predicted R-LysoPtdGlc binds to GPR55, but S-LysoPtdGlc does not.
- R-LysoPtdGlc induced axon repulsion (via GPR55-Gα<sub>13</sub>), while S-LysoPtdGlc induced chemoattraction (via GPR55-Gα<sub>S</sub>).
- Intrathecal R-LysoPtdGlc increased mechanical sensitivity in mice, dependent on GPR55, whereas S-LysoPtdGlc had no effect.
Conclusions
- LysoPtdGlc stereoconfiguration critically determines its biological activity and GPR55 signaling.
- R-LysoPtdGlc and S-LysoPtdGlc exert distinct GPR55-mediated functions through different Gα subunits.
- LysoPtdGlc stereoisomers represent potential therapeutic targets for pain modulation.
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