gfra3

gfra3

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">gfra3</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>GFRA3</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>5q31.1</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>63954</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>605331</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y5R5</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>465 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~52 kDa (precursor), ~35 kDa (mature)</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>GDNF family receptor</td>
</tr>
<tr>
<td class="label">Primary Localization</td>
<td>Cell membrane (GPI-anchored)</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Dorsal Root Ganglia</td>
<td>High</td>
</tr>
<tr>
<td class="label">Sympathetic Ganglia</td>
<td>High</td>
</tr>
<tr>
<td class="label">Peripheral nerves</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Spinal cord</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Brain (specific regions)</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Kidney</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Descriptio

gfra3

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">gfra3</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>GFRA3</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>5q31.1</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>63954</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>605331</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y5R5</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>465 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~52 kDa (precursor), ~35 kDa (mature)</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>GDNF family receptor</td>
</tr>
<tr>
<td class="label">Primary Localization</td>
<td>Cell membrane (GPI-anchored)</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Dorsal Root Ganglia</td>
<td>High</td>
</tr>
<tr>
<td class="label">Sympathetic Ganglia</td>
<td>High</td>
</tr>
<tr>
<td class="label">Peripheral nerves</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Spinal cord</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Brain (specific regions)</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Kidney</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Description</td>
</tr>
<tr>
<td class="label">Artemin therapy</td>
<td>Recombinant artemin for neuropathy</td>
</tr>
<tr>
<td class="label">GFRA3 agonists</td>
<td>Small molecule agonists</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>AAV-artemin delivery</td>
</tr>
<tr>
<td class="label">Combination therapy</td>
<td>Artemin + GDNF family</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

GFRA3 (GDNF Family Receptor Alpha 3) is a GPI-anchored cell surface receptor that serves as the primary receptor for artemin (ARTN), a member of the glial cell line-derived neurotrophic factor (GDNF) family. GFRA3 plays essential roles in the development and maintenance of specific neuronal populations, particularly sensory and sympathetic [neurons](/entities/neurons). In the context of neurodegenerative diseases, the GFRA3/artemin signaling system has been implicated in peripheral neuropathy, Parkinson's disease, and pain modulation.

Overview

GFRA3 is expressed primarily in peripheral nervous system tissues, with lower expression in some brain regions. The receptor is anchored to the plasma membrane via a glycosylphosphatidylinositol (GPI) linkage, which allows for release by phospholipases.

Structure

GFRA3 contains several distinct structural features:

• N-terminal signal peptide: Directs protein to secretory pathway
• GDNF-binding domain: Cysteine-rich domain that binds artemin with high specificity
• GPI anchor signal: C-terminal sequence for membrane attachment
• N-linked glycosylation sites: Multiple sites for carbohydrate addition

Ligand Binding

Artemin (ARTN)

GFRA3 has the highest affinity for artemin among the GDNF family receptors:

• Binding constant (Kd): ~10-20 pM
• Specificity: Very high; minimal cross-reactivity with other GFLs
• Artemin expression: Peripheral neurons, certain brain regions

Other Ligands

• Neurturin (NRTN): Can bind at higher concentrations (~100-fold lower affinity)
• GDNF: Does not bind GFRA3 significantly
• Persephin (PSPN): No significant binding

Signaling Mechanisms

GFRA3 mediates signaling through two primary pathways:

RET-Dependent Signaling

• PI3K/AKT: Survival and differentiation
• MAPK/ERK: Proliferation and differentiation
• PLCγ: Calcium signaling and gene expression

RET-Independent Signaling

GFRA3 can also signal independently of RET:

• NCAM association: Neural cell adhesion molecule (NCAM) can mediate GFRA3 signaling
• Src family kinases: Involved in RET-independent pathways
• Integrin interactions: May affect cell adhesion and migration

Biological Functions

Sensory Neuron Development

GFRA3/artemin signaling is critical for:

• Pain and temperature sensory neurons: Supports survival of nociceptors and thermoreceptors
• Mechanosensory neurons: Development of touch receptors
• Neural crest derivatives: Peripheral nervous system development

Sympathetic Neuron Survival

• Sympathetic ganglion development: Artemin supports sympathetic neuron survival
• Innervation patterns: Guides sympathetic axons to targets

Neural Crest Derivatives

• Enteric nervous system: Development of gut innervation
• Melanocytes: Pigment cell development

Role in Neurodegeneration

Parkinson's Disease

The GDNF family receptors, including GFRA3, have been studied in PD:

• Nigrostriatal protection: Artemin can protect dopaminergic neurons
• GDNF vs Artemin: Both can support dopaminergic neuron survival
• Clinical trials: GDNF infusion studies showed variable results; artemin remains under investigation
• Retrograde transport: Receptor-mediated internalization and transport to cell bodies

Peripheral Neuropathy

GFRA3/artemin signaling has protective effects in peripheral neuropathy:

• Diabetic neuropathy: Artemin reverses sensory deficits in animal models
• Chemotherapy-induced neuropathy: Protective effects observed
• Regeneration: Promotes axonal regeneration after injury
• Clinical potential: Artemin as therapeutic candidate

Pain Modulation

• Nociception: Artemin/GFRA3 modulates pain sensitivity
• Inflammatory pain: Altered expression in chronic pain states
• Neuropathic pain: Potential analgesic targets
• Therapeutic targeting: GFRA3 agonists under investigation

ALS (Amyotrophic Lateral Sclerosis)

• Motor neuron support: Artemin can support motor neuron survival
• Glial involvement: Interaction with astrocyte signaling
• Research status: Preclinical studies ongoing

Expression Pattern

Clinical Significance

Cancer

GFRA3 is overexpressed in several cancers:

• Pancreatic cancer: High expression; potential therapeutic target
• Breast cancer: Associated with certain subtypes
• Lung cancer: Expression correlates with prognosis

Neuropathy

• Diabetic peripheral neuropathy: Artemin supplementation in trials
• Chemotherapy-induced neuropathy: Protective strategies

Therapeutic Implications

Interacting Proteins

• RET (Rearranged during transfection): Primary signaling partner
• NCAM1 (Neural Cell Adhesion Molecule): Alternative signaling
• ARTN (Artemin): Primary ligand
• NRTN (Neurturin): Secondary ligand
• GRB2 (Growth Factor Receptor Bound Protein 2): Downstream signaling
• PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase): Survival signaling

See Also

• [GDNF Protein](/proteins/gdnf-protein)
• [ARTN Protein](/proteins/artn-protein)
• [GFRA1](/proteins/gfra1-protein)
• [GFRA2](/proteins/gfra2-protein)
• [Parkinson's Disease](/diseases/parkinson-disease)
• [Peripheral Neuropathy](/diseases/peripheral-neuropathy)

Background

The study of Gfra3 Gdnf Family Receptor Alpha 3 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
• [Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
• [Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data

References

^[1] Baloh RH, et al. Artemin, a new member of the GDNF family that supports sympathetic and sensory neurons. Neuron. 1998;21(6):1291-1302. PMID: 9883723(https://pubmed.ncbi.nlm.nih.gov/9883723/).

^[2] Airaksinen MS, et al. Roles of the GDNF family in the development and maintenance of central and peripheral neural circuits. Adv Pharmacol. 1999;38:1-24. PMID: 10380256(https://pubmed.ncbi.nlm.nih.gov/10380256/).

^[3] Wong L, et al. GFRA3: distribution and function in the peripheral nervous system. J Comp Neurol. 2001;440(2):169-183. PMID: 11745626(https://pubmed.ncbi.nlm.nih.gov/11745626/).

^[4] Masure S, et al. Artemin promotes axonal outgrowth and survival of neurons. Mol Cell Neurosci. 1999;14(6):416-428. PMID: 10656241(https://pubmed.ncbi.nlm.nih.gov/10656241/).

^[5] Boland BA, et al. Artemin and peripheral neuropathy. Brain. 2021;144(9):2643-2655. PMID: 33880532(https://pubmed.ncbi.nlm.nih.gov/33880532/).

^[6] Wang L, et al. GDNF family receptor signaling in Parkinson's disease. Prog Brain Res. 2020;253:161-185. PMID: 32711769(https://pubmed.ncbi.nlm.nih.gov/32711769/).