• Anissa Kempf, Bjoern Tews, Michael E Arzt, Oliver Weinmann, Franz J Obermair, Vincent Pernet, Marta Zagrebelsky, Andrea Delekate, Cristina Iobbi, Ajmal Zemmar, Zorica Ristic, Miriam Gullo, Peter Spies, Dana Dodd, Daniel Gygax, Martin Korte, and Martin E Schwab.
• Brain Research Institute, University of Zurich, and Dept. of Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland.
• Plos Biol. 2014 Jan 1;12(1):e1001763.

AbstractNogo-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.

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