Glial cell line-derived growth factor (GDNF), neurturin (NTN), persephin (PEP) and artemin (ART), distant members of the TGF-beta superfamily, are neurotrophic factors for a variety of neuronal populations in the central and peripheral nervous systems. The bioactivities of these neurotrophic factors are mediated through a receptor complex composed of the non ligand-binding signaling subunit (c-Ret receptor tyrosine kinase) and one of four ligand binding cysteine-rich glycosyl-phosphatidylinositol (GPI)-linked cell surface proteins (GFR alpha -1, 2, 3 or 4). These four GFR-alpha proteins share conserved placements of many of their cysteine residues. GFR alpha -1, 2, 3 or 4 have been shown to preferentially bind GDNF, NTN, ART and PSP, respectively. While the GFR alpha -3/Ret complex is highly specific for ART, the GFR alpha -1 /Ret complex is extremely promiscuous and may also be utilized by NTN and ART.
Human GFR alpha -3 cDNA encodes a 400 amino acid (aa) residue precursor protein with an N-terminal signal peptide and C-terminal hydrophobic domain. GFR alpha -3 is approximately 34% and 36% identical to GFR alpha -1 and GFR alpha -2, respectively. Human and mouse GFR alpha -3 share approximately 76% amino acid sequence homology. The gene encoding GFR alpha -3 has been localized to human chromosome 5. GFR alpha -3 is expressed at high levels only in the developing and adult sensory and sympathetic ganglia of the peripheral nervous system. In the trigeminal ganglions, the expression of GFR alpha -3 is found in a population of neurons distinct from those expressing GFR alpha -1 or 2.
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