2. Academic Validation
  3. The sphingolipid receptor S1PR2 is a receptor for Nogo-a repressing synaptic plasticity

The sphingolipid receptor S1PR2 is a receptor for Nogo-a repressing synaptic plasticity

  • PLoS Biol. 2014 Jan;12(1):e1001763. doi: 10.1371/journal.pbio.1001763.
Anissa Kempf 1,  Bjoern Tews 1,  Michael E Arzt 1,  Oliver Weinmann 1,  Franz J Obermair 1,  Vincent Pernet 1,  Marta Zagrebelsky 2,  Andrea Delekate 2,  Cristina Iobbi 2,  Ajmal Zemmar 1,  Zorica Ristic 1,  Miriam Gullo 1,  Peter Spies 3,  Dana Dodd 1,  Daniel Gygax 3,  Martin Korte 2,  Martin E Schwab 1
Affiliations

Affiliations

  • 1 Brain Research Institute, University of Zurich, and Dept. of Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland.
  • 2 Zoological Institute, Division of Cellular Neurobiology, TU Braunschweig, Braunschweig, Germany.
  • 3 School of Life Sciences, University of Applied Life Sciences Northwestern Switzerland, Muttenz, Switzerland.
PMID: 24453941 DOI: 10.1371/journal.pbio.1001763
Abstract

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.

Figures