Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor

Nature. 2000 Oct 12;407(6805):747-50. doi: 10.1038/35037600.


The netrins, a family of laminin-related secreted proteins, are critical in controlling axon elongation and pathfinding. The DCC (for deleted in colorectal cancer) protein was proposed as a receptor for netrin-1 in the light of many observations including the inhibition of netrin-1-mediated axon outgrowth and attraction in the presence of an anti-DCC antiserum, the similitude of nervous system defects in DCC and netrin-1 knockout mice and the results of receptor swapping experiments. Previous studies have failed to show a direct interaction of DCC with netrin-1 (ref. 10), suggesting the possibility of an additional receptor or co-receptor. Here we show that DCC interacts with the membrane-associated adenosine A2b receptor, a G-protein-coupled receptor that induces cAMP accumulation on binding adenosine. We show that A2b is actually a netrin-1 receptor and induces cAMP accumulation on binding netrin-1. Finally, we show that netrin-1-dependent outgrowth of dorsal spinal cord axons directly involves A2b. Together our results indicate that the growth-promoting function of netrin-1 may require a receptor complex containing DCC and A2b.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / physiology*
  • Brain / physiology
  • Cell Adhesion Molecules / metabolism
  • Cell Division
  • Cell Line
  • Chickens
  • Culture Techniques
  • Cyclic AMP / biosynthesis*
  • DCC Receptor
  • Growth Cones
  • Humans
  • Mutagenesis, Site-Directed
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / physiology*
  • Netrin Receptors
  • Netrin-1
  • Rats
  • Receptor, Adenosine A2B
  • Receptors, Cell Surface / physiology*
  • Receptors, Purinergic P1 / genetics
  • Receptors, Purinergic P1 / physiology*
  • Spinal Cord / cytology
  • Tumor Suppressor Proteins*
  • Two-Hybrid System Techniques


  • Cell Adhesion Molecules
  • DCC Receptor
  • DCC protein, human
  • NTN1 protein, human
  • Nerve Growth Factors
  • Netrin Receptors
  • Ntn1 protein, mouse
  • Ntn1 protein, rat
  • Receptor, Adenosine A2B
  • Receptors, Cell Surface
  • Receptors, Purinergic P1
  • Tumor Suppressor Proteins
  • Netrin-1
  • Cyclic AMP