title: The Orphan G Protein-coupled Receptor GPR17 Negatively Regulates Oligodendrocyte Differentiation via Gαi/o and Its Downstream Effector Molecules.
abstract: Recent studies have recognized G protein-coupled receptors as important regulators of oligodendrocyte development. GPR17, in particular, is an orphan G protein-coupled receptor that has been identified as oligodendroglial maturation inhibitor because its stimulation arrests primary mouse oligodendrocytes at a less differentiated stage. However, the intracellular signaling effectors transducing its activation remain poorly understood. Here, we use Oli-neu cells, an immortalized cell line derived from primary murine oligodendrocytes, and primary rat oligodendrocyte cultures as model systems to identify molecular targets that link cell surface GPR17 to oligodendrocyte maturation blockade. We demonstrate that stimulation of GPR17 by the small molecule agonist MDL29,951 (2-carboxy-4,6-dichloro-1H-indole-3-propionic acid) decreases myelin basic protein expression levels mainly by triggering the Gαi/o signaling pathway, which in turn leads to reduced activity of the downstream cascade adenylyl cyclase-cAMP-PKA-cAMP response element-binding protein (CREB). In addition, we show that GPR17 activation also diminishes myelin basic protein abundance by lessening stimulation of the exchange protein directly activated by cAMP (EPAC), thus uncovering a previously unrecognized role for EPAC to regulate oligodendrocyte differentiation. Together, our data establish PKA and EPAC as key downstream effectors of GPR17 that inhibit oligodendrocyte maturation. We envisage that treatments augmenting PKA and/or EPAC activity represent a beneficial approach for therapeutic enhancement of remyelination in those demyelinating diseases where GPR17 is highly expressed, such as multiple sclerosis.
authors.affiliation: From the Institute of Pharmaceutical Biology, Section Molecular, Cellular, and Pharmacobiology, University of Bonn, 53115 Bonn, Germany and.
authors.forename: Katharina
authors.initials: K
authors.lastname: Simon
authors.affiliation: From the Institute of Pharmaceutical Biology, Section Molecular, Cellular, and Pharmacobiology, University of Bonn, 53115 Bonn, Germany and.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hennen
authors.affiliation: From the Institute of Pharmaceutical Biology, Section Molecular, Cellular, and Pharmacobiology, University of Bonn, 53115 Bonn, Germany and.
authors.forename: Nicole
authors.initials: N
authors.lastname: Merten
authors.affiliation: From the Institute of Pharmaceutical Biology, Section Molecular, Cellular, and Pharmacobiology, University of Bonn, 53115 Bonn, Germany and.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Blättermann
authors.affiliation: UCB Pharma, CNS Research, 1420 Braine l'Alleud, Belgium.
authors.forename: Michel
authors.initials: M
authors.lastname: Gillard
authors.affiliation: From the Institute of Pharmaceutical Biology, Section Molecular, Cellular, and Pharmacobiology, University of Bonn, 53115 Bonn, Germany and kostenis@uni-bonn.de.
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
authors.affiliation: From the Institute of Pharmaceutical Biology, Section Molecular, Cellular, and Pharmacobiology, University of Bonn, 53115 Bonn, Germany and jgomeza@uni-bonn.de.
authors.forename: Jesus
authors.initials: J
authors.lastname: Gomeza
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D004676:Myelin Basic Protein / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology*; D010766:Phosphorylation / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: C000588735:2-carboxy-4,6-dichloro-(1H)-indole-3-propanoic acid; D017362:Cyclic AMP Response Element-Binding Protein; C534979:GPR17 protein, mouse; C514731:GPR17 protein, rat; D020662:Guanine Nucleotide Exchange Factors; D007211:Indoles; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D011422:Propionates; C526973:Rapgef3 protein, rat; D043562:Receptors, G-Protein-Coupled; D013873:Thionucleotides; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: EPAC; G protein; G protein-coupled receptor (GPCR); GPR17; cAMP response element-binding protein (CREB); cell signaling; label-free dynamic mass redistribution; multiple sclerosis; oligodendrocyte; protein kinase A (PKA)