title: Decoding signaling and function of the orphan G protein-coupled receptor GPR17 with a small-molecule agonist.
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), Gα(s), and Gα(q) subfamily, as well as β-arrestins. This was visualized as alterations in the concentrations of cyclic adenosine monophosphate and inositol phosphate, increased Ca²⁺ 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.
authors.affiliation: 1Molecular, Cellular, and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hennen
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.forename: Lucas
authors.initials: L
authors.lastname: Peters
authors.forename: Nicole
authors.initials: N
authors.lastname: Merten
authors.forename: Katharina
authors.initials: K
authors.lastname: Simon
authors.forename: Andreas
authors.initials: A
authors.lastname: Spinrath
authors.forename: Stefanie
authors.initials: S
authors.lastname: Blättermann
authors.forename: Rhalid
authors.initials: R
authors.lastname: Akkari
authors.forename: Ramona
authors.initials: R
authors.lastname: Schrage
authors.forename: Ralf
authors.initials: R
authors.lastname: Schröder
authors.forename: Daniel
authors.initials: D
authors.lastname: Schulz
authors.forename: Celine
authors.initials: C
authors.lastname: Vermeiren
authors.forename: Katrin
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Stefan
authors.initials: S
authors.lastname: Kehraus
authors.forename: Christel
authors.initials: C
authors.lastname: Drewke
authors.forename: Alexander
authors.initials: A
authors.lastname: Pfeifer
authors.forename: Gabriele M
authors.initials: GM
authors.lastname: König
authors.forename: Klaus
authors.initials: K
authors.lastname: Mohr
authors.forename: Michel
authors.initials: M
authors.lastname: Gillard
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.forename: Q Richard
authors.initials: QR
authors.lastname: Lu
authors.forename: Jesus
authors.initials: J
authors.lastname: Gomeza
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D016466:CHO Cells; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011422:Propionates / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000071557:beta-Arrestins
chemical_list: C000588735:2-carboxy-4,6-dichloro-(1H)-indole-3-propanoic acid; D019390:Arrestins; D002867:Chromones; C121670:GPR17 protein, human; C534979:GPR17 protein, mouse; C514731:GPR17 protein, rat; D007211:Indoles; D009419:Nerve Tissue Proteins; D011422:Propionates; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries; D000071557:beta-Arrestins; C047681:pranlukast