GDNF family of ligands
Encyclopedia
The GDNF family of ligand
s (GFL) consists of four neurotrophic factors: glial cell line-derived neurotrophic factor
(GDNF), neurturin
(NRTN), artemin
(ARTN), and persephin
(PSPN). GFLs have been shown to play a role in a number of biological processes including cell survival, neurite outgrowth, cell differentiation and cell migration. In particular signalling by GDNF promotes the survival of dopaminergic neurons.
, a receptor tyrosine kinase
molecule RET
, and a cell surface-bound co-receptor that is a member of the GFRα protein family. The primary ligands for the co-receptors GFRα1, GFRα2, GFRα3, and GFRα4 are GDNF, NRTN, ARTN, and PSPN, respectively.
Upon initial GFL-GFRα complex formation, the complex then brings together two molecules of RET, triggering trans-autophosphorylation of specific tyrosine
residues within the tyrosine kinase
domain of each RET molecule. Phosphorylation
of these tyrosine
s then initiates intracellular signal transduction
processes.
It has been shown that in the case of GDNF, heparan sulfate
glycosaminoglycan
s are also required to be present at the cell surface in order for RET mediated GDNF signalling to occur.
Given a huge spectrum of possible therapeutic applications, the modulation of GFRα/RET receptor complex activity is of great interest. However, natural GDNF ligands are of a limited clinical use. As positively charged polypeptides GFLs are unable to penetrate the blood-brain barrier, and they have very small volume of distribution in the tissues. Therefore, the creation of small-molecule agonists is highly beneficial for the development of effective therapies against devastating neurological diseases.
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
s (GFL) consists of four neurotrophic factors: glial cell line-derived neurotrophic factor
Glial cell line-derived neurotrophic factor
Glial cell-derived neurotrophic factor, also known as GDNF is a protein that, in humans, is encoded by the GDNF gene.GDNF is a small protein that potently promotes the survival of many types of neurons.-Function:...
(GDNF), neurturin
Neurturin
Neurturin is a ligand used to bind to GFRA2 receptors. It is related to Glial cell line-derived neurotrophic factor....
(NRTN), artemin
Artemin
Artemin, also known as enovin or neublastin, is a protein that in humans is encoded by the ARTN gene.- Function :Artemin is a neurotrophin in the glial cell line-derived neurotophic factor family of ligands which are a group of ligands within the TGF-beta superfamily of signaling molecules...
(ARTN), and persephin
Persephin
Persephin is a neurotrophic factor in the Glial cell line-Derived Neurotrophic Factor family....
(PSPN). GFLs have been shown to play a role in a number of biological processes including cell survival, neurite outgrowth, cell differentiation and cell migration. In particular signalling by GDNF promotes the survival of dopaminergic neurons.
Signalling complex formation
At the cell surface of target cells, a signalling complex forms, composed of a particular GFL dimerProtein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
, a receptor tyrosine kinase
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
molecule RET
RET proto-oncogene
The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules....
, and a cell surface-bound co-receptor that is a member of the GFRα protein family. The primary ligands for the co-receptors GFRα1, GFRα2, GFRα3, and GFRα4 are GDNF, NRTN, ARTN, and PSPN, respectively.
Upon initial GFL-GFRα complex formation, the complex then brings together two molecules of RET, triggering trans-autophosphorylation of specific tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
residues within the tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
domain of each RET molecule. Phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of these tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
s then initiates intracellular signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
processes.
It has been shown that in the case of GDNF, heparan sulfate
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...
glycosaminoglycan
Glycosaminoglycan
Glycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...
s are also required to be present at the cell surface in order for RET mediated GDNF signalling to occur.
Clinical significance
GFLs are an important therapeutical target for several conditions:- GDNF has shown promising results in two Parkinson's diseaseParkinson's diseaseParkinson's disease is a degenerative disorder of the central nervous system...
clinical trial and in a number of animal trials. Although a different study later reported this as a 'placebo effect', work on perfecting the delivery of GDNF to the putamen is continuing. GDNF is a potent survival factor for central motoneurons and may have clinical importance for the treatment of ALS. Moreover, recent results highlight the importance of GDNF as a new target for drug addiction and alcoholism treatment.
- NRTN can also be used for Parkinson’s disease therapy and for epilepsyEpilepsyEpilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
treatment. NRTN promotes survival of basal forebrain cholinergic neurons and spinal motor neurons. Therefore, NRTN has a potential in the treatment of Alzheimer’s disease and ALS.
- ARTN also has a therapeutic perspective, for it is considered for chronic pain treatment.
- PSPN promotes the survival of mouse embryonic basal forebrain cholinergic neurons in vitro. Hence, PSPN may be used for the treatment of Alzheimer’s disease. PSPN may also have clinical applications in the treatment of the stroke.
Given a huge spectrum of possible therapeutic applications, the modulation of GFRα/RET receptor complex activity is of great interest. However, natural GDNF ligands are of a limited clinical use. As positively charged polypeptides GFLs are unable to penetrate the blood-brain barrier, and they have very small volume of distribution in the tissues. Therefore, the creation of small-molecule agonists is highly beneficial for the development of effective therapies against devastating neurological diseases.