GALR2 Gene

GALR2 — Galanin Receptor 2

<div class="infobox infobox-gene">
<div class="infobox-header">GALR2 — Galanin Receptor 2</div>

Overview

GALR2 (Galanin Receptor 2) is a G protein-coupled receptor that mediates the neuroprotective and modulatory effects of the neuropeptide galanin in the central and peripheral nervous systems. Unlike its sibling receptor GALR1, GALR2 couples to both Gq and Gi/o proteins, enabling diverse signaling pathways relevant to neurodegeneration, neuroprotection, and synaptic plasticity. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegenerative diseases.

<table>
<tr><th>Symbol</th><td><strong>GALR2</strong></td></tr>
<tr><th>Full Name</th><td>Galanin Receptor 2</td></tr>
<tr><th>Chromosomal Location</th><td>17q25.3</td></tr>
<tr><th>NCBI Gene ID</th><td>[9512](https://www.ncbi.nlm.nih.gov/gene/9512)</td></tr>
<tr><th>OMIM</th><td>[607311](https://www.omim.org/entry/607311)</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000141404</td></tr>
<tr><th>UniProt</th><td>O43603</td></tr>
<tr><th>Associated Diseases</th><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), Neuropathic Pain, Depression, Epilepsy, Stroke</td></tr>
</table>
</div>

Gene Structure and Evolution

GALR2 — Galanin Receptor 2

<div class="infobox infobox-gene">
<div class="infobox-header">GALR2 — Galanin Receptor 2</div>

Overview

GALR2 (Galanin Receptor 2) is a G protein-coupled receptor that mediates the neuroprotective and modulatory effects of the neuropeptide galanin in the central and peripheral nervous systems. Unlike its sibling receptor GALR1, GALR2 couples to both Gq and Gi/o proteins, enabling diverse signaling pathways relevant to neurodegeneration, neuroprotection, and synaptic plasticity. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegenerative diseases.

<table>
<tr><th>Symbol</th><td><strong>GALR2</strong></td></tr>
<tr><th>Full Name</th><td>Galanin Receptor 2</td></tr>
<tr><th>Chromosomal Location</th><td>17q25.3</td></tr>
<tr><th>NCBI Gene ID</th><td>[9512](https://www.ncbi.nlm.nih.gov/gene/9512)</td></tr>
<tr><th>OMIM</th><td>[607311](https://www.omim.org/entry/607311)</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000141404</td></tr>
<tr><th>UniProt</th><td>O43603</td></tr>
<tr><th>Associated Diseases</th><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), Neuropathic Pain, Depression, Epilepsy, Stroke</td></tr>
</table>
</div>

Gene Structure and Evolution

The GALR2 gene is located on chromosome 17q25.3 and encodes a 369 amino acid GPCR belonging to the galanin receptor family. The gene structure includes 4 exons spanning approximately 25 kb, with multiple transcription start sites and alternative splicing generating variant isoforms.

GALR2 is evolutionarily conserved across vertebrates, sharing structural features with other galanin receptors: seven transmembrane domains, extracellular N-terminus, and intracellular C-terminus with phosphorylation sites.

Function

Signaling Pathways

GALR2 exhibits unique signaling properties compared to GALR1:

Gq-Mediated Signaling

Upon galanin binding, GALR2 activates Gq proteins, leading to:

Gi/o-Mediated Signaling

GALR2 can also couple to Gi/o proteins:

Neuroprotective Mechanisms

Against Excitotoxicity

GALR2 activation provides robust neuroprotection against excitotoxic insults:

• Glutamate-induced toxicity: GALR2 agonists reduce neuronal death
• NMDA receptor modulation: Alters NMDA receptor function
• Calcium homeostasis: Stabilizes intracellular calcium levels

[@mitsukawa2010] demonstrated the neuroprotective effects of GALR2 activation.

Against Oxidative Stress

GALR2 neuroprotection extends to oxidative stress models through Nrf2/ARE pathway activation, antioxidant gene expression, and mitochondrial biogenesis.

Synaptic Function

GALR2 regulates synaptic transmission and plasticity:

• Glutamate release: Modulated by GALR2
• GABA release: Enhanced by GALR2 activation
• Synaptic plasticity: Both LTP and LTD are modulated

Expression Pattern

Brain Region Distribution

GALR2 exhibits widespread but distinct expression:

| Brain Region | Expression Level | Primary Cell Types |
|--------------|-----------------|-------------------|
| Hippocampus | High | CA1/CA3 pyramidal neurons, dentate gyrus granule cells |
| Hypothalamus | High | Paraventricular nucleus, supraoptic nucleus neurons |
| Amygdala | Moderate-High | Principal neurons, interneurons |
| Spinal Cord | Moderate-High | Dorsal horn neurons, motor neurons |
| Dorsal Root Ganglion | High | Sensory neurons |

In neurons, GALR2 localizes to dendrites and dendritic spines, axon terminals, postsynaptic densities, and soma.

Disease Associations

Alzheimer's Disease

GALR2 plays complex roles in AD pathogenesis:

• Amyloid-beta toxicity: GALR2 activation reduces Aβ-induced neuronal death
• Tau pathology: GALR2 signaling modulates tau phosphorylation
• Synaptic dysfunction: GALR2 preserves synaptic markers

Parkinson's Disease

GALR2 has emerged as a significant neuroprotective target in PD:

• Dopaminergic neuron survival: GALR2 activation protects substantia nigra neurons
• Alpha-synuclein toxicity: Modulates synucleinopathy
• Mitochondrial function: Preserves mitochondrial integrity

Neuropathic Pain

GALR2 is a key mediator of pain modulation:

• Dorsal horn transmission: GALR2 reduces nociceptive signaling
• Primary sensory neurons: Express GALR2 in DRG

Depression and Mood Disorders

GALR2 is implicated in depression pathophysiology:

• Hypothalamic-pituitary-adrenal axis: Modulates stress response
• Serotonin system: Cross-talk with 5-HT signaling
• Neurogenesis: GALR2 supports hippocampal neurogenesis

Therapeutic Implications

Drug Development

GALR2 Agonists

Small molecule and peptide agonists are under development:

| Condition | Therapeutic Approach | Status |
|-----------|---------------------|--------|
| Alzheimer's Disease | GALR2 agonists | Preclinical |
| Parkinson's Disease | GALR2 agonists | Preclinical |
| Neuropathic Pain | GALR2 agonists | Phase I/II |
| Depression | GALR2 agonists | Preclinical |

Key Publications

Interaction Network

• GNAQ: Gq protein coupling
• GNAI2: Gi/o protein coupling
• ARRB1/2: β-arrestin recruitment
• PLCβ: Downstream effector
• AKT1: Pro-survival signaling
• MAPK1/3: MAPK pathway

Animal Models

Galr2 knockout mice exhibit enhanced anxiety-like behavior, deficits in spatial memory, and altered pain threshold. GALR2 overexpression provides enhanced neuroprotection in disease models.

See Also

• [Galanin](/proteins/galanin)
• [GALR1](/genes/galr1)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [G-Protein Coupled Receptor Signaling](/mechanisms/gpcr-signaling)
• [Neuroinflammation](/mechanisms/neuroinflammation)
• [Synaptic Plasticity](/mechanisms/synaptic-plasticity)

External Links

• [NCBI Gene: GALR2](https://www.ncbi.nlm.nih.gov/gene/9512)
• [Ensembl: ENSG00000141404](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000141404)
• [UniProt: O43603](https://www.uniprot.org/uniprot/O43603)
• [OMIM: 607311](https://www.omim.org/entry/607311)

References