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Identification and characterization of select oxysterols as ligands for Gpr17
  • +10
  • Anthony Harrington,
  • Changlu Liu,
  • Naomi Phillips,
  • Diane Nepomuceno,
  • Chester Kuei,
  • Joseph Chang,
  • Weixuan Chen,
  • Steven Sutton,
  • Daniel O'malley,
  • Ly Pham,
  • Xiang Yao,
  • Siquan Sun,
  • Pascal Bonaventure
Anthony Harrington
Janssen Research and Development La Jolla

Corresponding Author:[email protected]

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Changlu Liu
Janssen Research and Development La Jolla
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Naomi Phillips
Janssen Research and Development La Jolla
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Diane Nepomuceno
Janssen Research and Development La Jolla
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Chester Kuei
Janssen Research and Development La Jolla
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Joseph Chang
Janssen Research and Development La Jolla
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Weixuan Chen
Janssen Research and Development La Jolla
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Steven Sutton
Janssen Research and Development La Jolla
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Daniel O'malley
Janssen Research and Development La Jolla
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Ly Pham
Janssen Research and Development La Jolla
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Xiang Yao
Janssen Research and Development La Jolla
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Siquan Sun
Janssen Research and Development La Jolla
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Pascal Bonaventure
Janssen Research and Development La Jolla
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Abstract

Abstract Background and Purpose: Gpr17 is an orphan receptor involved in the process of myelination due to its ability to inhibit the maturation of oligodendrocyte progenitor cells into myelinating oligodendrocytes. Despite multiple claims that the biological ligand has been identified, it remains an orphan receptor. Experimental Approach: Seventy-seven oxysterols were screened in a cell-free [35S]- GTPgS binding assay using membranes from cells expressing Gpr17. The positive hits were characterised using cAMP, IP1, and calcium mobilisation assays, with results confirmed in rat primary oligodendrocytes. Rat and pig brain extracts were separated by HPLC chromatography and endogenous activator(s) were identified in receptor activation assays. Gene expression studies of Gpr17 and Cyp46a1, the enzymes responsible for the conversion of cholesterol into specific oxysterols, were performed using quantitative real time PCR. Key Results: Eight oxysterols were able to stimulate Gpr17 activity, including the brain cholesterol, 24(S)-hydroxycholesterol. A specific brain fraction from rat and pig extracts containing 24S-HC activates Gpr17 in vitro assays. Expression of Gpr17 during mouse brain development correlates with the expression of Cyp46a1 and the levels of 24S-HC itself. Other active oxysterols have low brain concentrations below effective ranges. Conclusions and Implications: Oxysterols, including but not limited to 24S-HC, could be physiological activators for Gpr17 and thus potentially regulate OPC differentiation and myelination through activation of the receptor.
04 May 2022Submitted to British Journal of Pharmacology
12 May 2022Submission Checks Completed
12 May 2022Assigned to Editor
15 May 2022Reviewer(s) Assigned
11 Jun 2022Review(s) Completed, Editorial Evaluation Pending
16 Jun 2022Editorial Decision: Revise Minor
24 Aug 20221st Revision Received
26 Aug 2022Submission Checks Completed
26 Aug 2022Assigned to Editor
30 Aug 2022Reviewer(s) Assigned
15 Sep 2022Review(s) Completed, Editorial Evaluation Pending
19 Sep 2022Editorial Decision: Revise Minor
26 Sep 20222nd Revision Received
29 Sep 2022Submission Checks Completed
29 Sep 2022Assigned to Editor
30 Sep 2022Editorial Decision: Accept
14 Nov 2022Published in British Journal of Pharmacology. 10.1111/bph.15969