Glial Cell Line-Derived Neurotrophic Factor (GDNF) Receptor α-1 (GFRα1) Is Highly Selective for GDNF versus Artemin†

To clarify whether glial cell line-derived neurotrophic factor (GDNF) receptor α-1 (GFRα1), the glycosylphosphatidylinositol (GPI)-linked coreceptor for GDNF, is also a functional coreceptor for artemin (ART), we have studied receptor binding, signaling, and neuronal survival. In cell-free binding studies, GFRα1−Ig displayed strong preferential binding to GDNF, though in the presence of soluble RET, weak binding to ART could also be detected. However, using GFRα1-transfected NB41A3 cells, ART showed no detectable competition against the binding of 125I-labeled GDNF. Moreover, ART failed to induce phosphorylation of extracellular signal-related kinase (ERK) and Akt in these cells and was >104-fold less potent than GDNF in stimulating RET phosphorylation. When rat primary dorsal root ganglion (DRG) neurons were used, only the survival promoting activity of GDNF and not that of ART was blocked by an anti-GFRα1 antibody. These results indicate that although ART can interact weakly with soluble GFRα1 construct...