Netrin is a secreted ligand involved in directing axon growth. The deleted in colorectal cancer protein (DCC) has been postulated to be a netrin receptor, on the basis of similarities in phenotypes of mutants for these two proteins; however, DCC and netrin do not appear to interact directly. Corset et al. identified the adenosine 2b receptor (A2bR) as a binding partner for DCC in a yeast two-hybrid screen. In cotransfected cells, netrin enhanced DCC and A2bR interactions, as detected by coimmunoprecipitation. Netrin stimulated cAMP production in cells expressing both proteins, even in the presence of agents that metabolize adenosine, indicating that netrin is activating the A2bR directly, not acting to increase adenosine release. The coapplication of netrin and an A2bR agonist led to higher levels of cAMP than those produced by either agonist alone, suggesting that the two ligands bind to separate sites on the A2bR. Antagonists of A2bR blocked the ability of netrin to stimulate axon outgrowth in dorsal spinal cord explants, providing evidence for an interaction between netrin and A2bR in axon growth. These results suggest that netrin may be the native ligand for the A2bR, which has a very low affinity for adenosine, and provide a mechanism by which cAMP levels can be modulated to affect axon growth.
Corset, V., Nguyen-Ba-Charvet, K.T., Forcet, C., Moyse, E., Chédotal, A., Mehlen, P. (2000) Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor. Nature 407: 747-750. [Online Journal]