Decoding signaling and function of the orphan g protein-coupled receptor GPR17 with a small-molecule agonist

Stephanie Hennen, Haibo Wang, Lucas Peters, Nicole Merten, Katharina Simon, Andreas Spinrath, Stefanie Blättermann, Rhalid Akkari, Ramona Schrage, Ralf Schröder, Daniel Schulz, Celine Vermeiren, Katrin Zimmermann, Stefan Kehraus, Christel Drewke, Alexander Pfeifer, Gabriele M. König, Klaus Mohr, Michel Gillard, Christa E. MüllerQ. Richard Lu, Jesus Gomeza, Evi Kostenis

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

Replacement of the lost myelin sheath is a therapeutic goal for treating demyelinating diseases of the central nervous system (CNS), such as multiple sclerosis (MS). The G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) GPR17, which is phylogenetically closely related to receptors of the "purinergic cluster," has emerged as a modulator of CNS myelination. However, whether GPR17-mediated signaling positively or negatively regulates this critical process is unresolved. We identified a small-molecule agonist, MDL29,951, that selectively activated GPR17 even in a complex environment of endogenous purinergic receptors in primary oligodendrocytes. MDL29,951-stimulated GPR17 engaged the entire set of intracellular adaptor proteins for GPCRs: G proteins of the Gα i, Gαs, and Gαq subfamily, as well as β-arrestins. This was visualized as alterations in the concentrations of cyclic adenosine monophosphate and inositol phosphate, increased Ca 2+ flux, phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), as well as multifeatured cell activation recorded with label-free dynamic mass redistribution and impedance biosensors. MDL29,951 inhibited the maturation of primary oligodendrocytes from heterozygous but not GPR17 knockout mice in culture, as well as in cerebellar slices from 4-day-old wild-type mice. Because GPCRs are attractive targets for therapeutic intervention, inhibiting GPR17 emerges as therapeutic strategy to relieve the oligodendrocyte maturation block and promote myelin repair in MS.

Original languageEnglish (US)
Article numberra93
JournalScience Signaling
Volume6
Issue number298
DOIs
StatePublished - Oct 22 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Hennen, S., Wang, H., Peters, L., Merten, N., Simon, K., Spinrath, A., Blättermann, S., Akkari, R., Schrage, R., Schröder, R., Schulz, D., Vermeiren, C., Zimmermann, K., Kehraus, S., Drewke, C., Pfeifer, A., König, G. M., Mohr, K., Gillard, M., ... Kostenis, E. (2013). Decoding signaling and function of the orphan g protein-coupled receptor GPR17 with a small-molecule agonist. Science Signaling, 6(298), [ra93]. https://doi.org/10.1126/scisignal.2004350