GDNF Family Ligands and Receptors

The GDNF Family: Neurotrophic Factors and Structural Characteristics

The GDNF (glial cell derived neurotrophic factor) family encompasses a group of neurotrophic factors that were first isolated and purified from the conditioned medium of the mouse glial cell line B49 by Lin et al. (1993), hence the name. The rat and human GDNF genes were subsequently cloned using the amino terminal sequence of the purified GDNF as a probe. The human GDNF precursor protein consists of 211 amino acid residues, including a 19-amino acid signal peptide. After processing, it forms a secreted mature protein comprising 134 amino acids. This protein is a glycosylated, disulfide-bonded homodimer with a molecular weight of 32-34 kD and is classified as a basic protein.

In 1996, another neurotrophic factor with structural and functional similarity to GDNF was discovered in the ovaries of Chinese golden hamsters and humans, named Neurturin (NTN). The amino acid sequence of NTN showed 42% identity to GDNF. Subsequently, primers were designed based on highly homologous regions of GDNF and NTN, leading to the discovery and cloning of two additional members of the GDNF family: Persephin (PSP) and Artemin (ART). GDNF, Neurturin, Persephin, and Artemin belong to a group of secreted proteins with similar structures and related functions. They share seven conserved cysteine residues, exhibit similar spatial structures, and demonstrate high nucleotide and amino acid sequence homology. Collectively, they form a subfamily within the transforming growth factor-β (TGF-β) superfamily, sharing similarities in physiological functions, receptors, and signal transduction pathways.

GDNF Receptor: Structure and Signal Transduction

1. Structure of GDNF Receptor

The GDNF receptor (GDNFR) is a multi-component complex composed of two main parts. One part is the GDNF family receptor α (GDNFRα, GFRα), which is anchored on the cell surface through a glycosylphosphatidylinositol (GPI) bond. The other part is the tyrosine kinase Ret protein. Ret, encoded by the c-ret proto-oncogene, is a functional receptor for GDNF and belongs to the receptor tyrosine kinase superfamily. GFRα specifically binds to GDNF family members, promoting the phosphorylation of Ret. Phosphorylated Ret activates downstream intracellular pathways, including mitogen-activated protein kinase (MAPK) and PI3 kinase, leading to the activation of various cellular processes and exerting the neurotrophic effects of the GDNF family factors.

Studies have identified four types of GFRα: GFRα1, GFRα2, GFRα3, and GFRα4. Different factors bind to these receptors with varying affinities. GFRα1 serves as a high-affinity receptor for GDNF, GFRα2 binds to NTN, GFRα3 interacts with ART, and GFRα4 is expressed exclusively in chicken tissues. Among these receptor molecules, GFRα1 and GFRα2 show the highest homology, while GFRα3 and GFRα4 display the lowest homology.

2. Signal Transduction of GDNF Receptor

As GFRα is an extracellular protein linked by GPI and lacks transmembrane and intracellular domains, it requires the transmembrane protein Ret to mediate signal transduction. Upon specific binding of GDNF homodimer molecules to single-subunit or double-subunit GFRα1, a complex is formed that interacts with Ret. This interaction leads to Ret dimerization, activation, and subsequent phosphorylation. Ret activates several canonical tyrosine kinase signaling pathways, including Ras-MAPK, PI-3K, JNK, and PLC-γ. Similar to the NTs signaling pathway, GDNF's effect on promoting neuron survival and neurite growth is mediated through the Ras-MAPK signaling pathway, while its effect on the growth and differentiation of cultured dopaminergic neurons is realized through the PI-3K signaling pathway.

It is generally understood that the presence of both GFRα and Ret is necessary for GDNF to function. However, recent experiments have shown that GDNF can also directly interact with Ret or activate intracellular signal transduction pathways through GFRα1 receptors without the involvement of Ret.

Clinical Significance of GDNF Family in Neurological Diseases

The GDNF family holds great clinical significance, particularly in the treatment of nervous system diseases, with Parkinson's disease being extensively studied. Research has shown that GDNF family members can promote the survival and functional recovery of dopaminergic neurons, significantly alleviating symptoms in Parkinson's disease patients. Clinical trials and animal models have demonstrated that GDNF family treatments improve motor function, reduce dyskinesia, and minimize drug side effects.

Furthermore, the GDNF family exhibits potential in the treatment of neurodegenerative diseases and nerve injuries. They facilitate neuron regeneration and repair, enhance nerve cell survival, and provide neuroprotective effects within the nervous system. As a result, extensive investigations are being conducted to explore the application of GDNF family members in the treatment of conditions such as spinal cord injury, Alzheimer's disease, Parkinson's disease, and peripheral nerve injury.

GDNF Family Summary

In summary, GDNF is considered to be one of the most powerful trophic factors for neurotrophic effects on midbrain dopaminergic neurons so far. Its role not only plays an important role in protecting and restoring the function of dopaminergic neurons, but also shows potential clinical significance in the treatment of related diseases such as Parkinson's disease. Further research and development may provide new opportunities and options for the treatment of neurological diseases.

References:
[1] Baloh, R. ,  Enomoto, H. ,  Johnson, E. , &  Milbrandt, J. . The GDNF family ligands and receptorsDimplications for neural development.
[2] Sukhanova, T., Runeberg-Roos, P., Lume, & M., et al. (2015). Gdnf-family growth factors in the treatment of neurodegenerative diseases. Febs Journal.