The sphingolipid receptor S1PR2 is a receptor for Nogo-a repressing synaptic plasticity.
Nogo-A is a membrane protein of the central nervous system (CNS) restricting neurite growth and synaptic plasticity via two extracellular domains: Nogo-66 and Nogo-A-Δ20. Receptors transducing Nogo-A-Δ20 signaling remained elusive so far. Here we identify the G protein-coupled receptor (GPCR) sphingosine 1-phosphate receptor 2 (S1PR2) as a Nogo-A-Δ20-specific receptor. Nogo-A-Δ20 binds S1PR2 on sites distinct from the pocket of the sphingolipid sphingosine 1-phosphate (S1P) and signals via the G protein G13, the Rho GEF LARG, and RhoA. Deleting or blocking S1PR2 counteracts Nogo-A-Δ20- and myelin-mediated inhibition of neurite outgrowth and cell spreading. Blockade of S1PR2 strongly enhances long-term potentiation (LTP) in the hippocampus of wild-type but not Nogo-A(-/-) mice, indicating a repressor function of the Nogo-A/S1PR2 axis in synaptic plasticity. A similar increase in LTP was also observed in the motor cortex after S1PR2 blockade. We propose a novel signaling model in which a GPCR functions as a receptor for two structurally unrelated ligands, a membrane protein and a sphingolipid. Elucidating Nogo-A/S1PR2 signaling platforms will provide new insights into regulation of synaptic plasticity.
Brain Research Institute, University of Zurich, and Dept. of Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland.
Anissa
A
Kempf
Brain Research Institute, University of Zurich, and Dept. of Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland.
Bjoern
B
Tews
Brain Research Institute, University of Zurich, and Dept. of Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland.
Michael E
ME
Arzt
Brain Research Institute, University of Zurich, and Dept. of Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland.
Oliver
O
Weinmann
Brain Research Institute, University of Zurich, and Dept. of Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland.
Franz J
FJ
Obermair
Brain Research Institute, University of Zurich, and Dept. of Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland.
Vincent
V
Pernet
Zoological Institute, Division of Cellular Neurobiology, TU Braunschweig, Braunschweig, Germany.
Marta
M
Zagrebelsky
Zoological Institute, Division of Cellular Neurobiology, TU Braunschweig, Braunschweig, Germany.
Andrea
A
Delekate
Zoological Institute, Division of Cellular Neurobiology, TU Braunschweig, Braunschweig, Germany.
Cristina
C
Iobbi
Brain Research Institute, University of Zurich, and Dept. of Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland.
Ajmal
A
Zemmar
Brain Research Institute, University of Zurich, and Dept. of Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland.
Zorica
Z
Ristic
Brain Research Institute, University of Zurich, and Dept. of Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland.
Miriam
M
Gullo
School of Life Sciences, University of Applied Life Sciences Northwestern Switzerland, Muttenz, Switzerland.
Peter
P
Spies
Brain Research Institute, University of Zurich, and Dept. of Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland.
Dana
D
Dodd
School of Life Sciences, University of Applied Life Sciences Northwestern Switzerland, Muttenz, Switzerland.
Daniel
D
Gygax
Zoological Institute, Division of Cellular Neurobiology, TU Braunschweig, Braunschweig, Germany.
Martin
M
Korte
Brain Research Institute, University of Zurich, and Dept. of Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland.
Martin E
ME
Schwab
D000818:Animals; D049109:Cell Proliferation; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D017774:Long-Term Potentiation; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009044:Motor Cortex / Q000166:cytology / Q000378:metabolism*; D009185:Myelin Proteins / Q000172:deficiency / Q000235:genetics*; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism; D016501:Neurites / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics*; D000070798:Nogo Proteins; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D013569:Synapses / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
D008246:Lysophospholipids; D009185:Myelin Proteins; D000070798:Nogo Proteins; D049349:Receptors, Lysosphingolipid; C000603201:Rtn4 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; C533955:sphingosine-1-phosphate receptor-2, mouse; C060506:sphingosine 1-phosphate; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1; D044365:GTP-Binding Protein alpha Subunits, G12-G13; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D013110:Sphingosine