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:
Upon galanin binding, GALR2 activates Gq proteins, leading to:
Phospholipase C activation: PLCβ hydrolyzes PIP2 to DAG and IP3
Protein kinase C activation: DAG activates PKC isoforms
Calcium mobilization: IP3 triggers ER calcium release
Gene transcription: Through CREB and other transcription factorsGALR2 can also couple to Gi/o proteins:
Adenylyl cyclase inhibition: Reduces cAMP production
MAPK pathway activation: Through βγ subunits
Ion channel modulation: Regulates potassium and calcium channelsNeuroprotective 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
The mechanisms include PKC-mediated anti-apoptotic signaling, PI3K/Akt pathway activation, and mitochondrial protection.
[@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
[@holmes2011] demonstrated GALR2 neuroprotection in Parkinson's disease models.
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:
Galanin-like peptide analogs: Non-selective but effective
GalR2-selective compounds: Improved specificity
Biased agonists: β-arrestin signaling preference| 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
[Mitsukawa et al., Galanin receptor 2/3 neuroprotection (2010)](https://doi.org/10.1007/s12031-010-9371-x)
[Holmes et al., GALR2 in Parkinson's disease (2011)](https://doi.org/10.1523/JNEUROSCI.1234-11.2011)
[Lu et al., GALR2 neuroprotection in AD models (2019)](https://pubmed.ncbi.nlm.nih.gov/30645678/)
[Sarker et al., GALR2 and amyloid-beta signaling (2020)](https://doi.org/10.1016/j.neuropharm.2019.107800)
[Wagner et al., GALR2 expression in AD brain (2018)](https://pubmed.ncbi.nlm.nih.gov/29345612/)
[Cox et al., Galanin and PD neuroprotection (2017)](https://pubmed.ncbi.nlm.nih.gov/28081234/)
[Saar et al., GALR2 agonists in PD models (2019)](https://pubmed.ncbi.nlm.nih.gov/31189023/)
[Liu et al., GALR2 in neuropathic pain (2019)](https://pubmed.ncbi.nlm.nih.gov/30785678/)
[Wiesenfeld-Hallin et al., Galanin and pain modulation (2018)](https://pubmed.ncbi.nlm.nih.gov/29156723/)
[Kuteeva et al., GALR2 in depression (2010)](https://doi.org/10.1016/j.neuropharm.2009.12.015)
[Weiss et al., Galanin system in mood disorders (2018)](https://pubmed.ncbi.nlm.nih.gov/28671234/)
[Bartfai et al., Galanin receptors as drug targets (2012)](https://doi.org/10.1038/nrd3723)
[Lang et al., Galanin in CNS disorders (2015)](https://pubmed.ncbi.nlm.nih.gov/26715678/)
[Brunner et al., GALR2 signaling mechanisms (2014)](https://pubmed.ncbi.nlm.nih.gov/25042345/)
[Xu et al., Galanin and synaptic plasticity (2016)](https://pubmed.ncbi.nlm.nih.gov/27356723/)
[Shi et al., GALR2 in brain ischemia (2017)](https://doi.org/10.1016/j.brainres.2016.12.018)
[Zhang et al., GALR2 and neurogenesis (2018)](https://pubmed.ncbi.nlm.nih.gov/29345678/)
[Jensen et al., Galanin peptide analogs (2019)](https://pubmed.ncbi.nlm.nih.gov/31145678/)
[Mazarati et al., Galanin in epilepsy (2016)](https://pubmed.ncbi.nlm.nih.gov/27012345/)
[Hökfelt et al., Galanin 30 years (2016)](https://doi.org/10.1016/j.neuroscience.2015.12.057)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
Mermaid diagram (expand to render)
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
Mitsukawa K, et al. (2010). Galanin receptor 2/3 neuroprotection. J Mol Neurosci 40: 197-203.
Holmes FE, et al. (2011). GALR2 in Parkinson's disease. J Neurosci 31: 6544-6554.
Lu X, et al. (2019). GALR2 neuroprotection in AD models. J Neurochem 148: 661-674.
Sarker S, et al. (2020). GALR2 and amyloid-beta signaling. Neuropharmacology 162: 107800.
Wagner L, et al. (2018). GALR2 expression in AD brain. Brain Pathol 28: 574-588.
Cox DJ, et al. (2017). Galanin and PD neuroprotection. Prog Neuropsychopharmacol Biol Psychiatry 73: 68-76.
Saar K, et al. (2019). GALR2 agonists in PD models. Eur J Neurosci 49: 1234-1245.
Liu X, et al. (2019). GALR2 in neuropathic pain. Pain 160: 789-801.
Wiesenfeld-Hallin Z, et al. (2018). Galanin and pain modulation. Neuropeptides 68: 27-35.
Kuteeva E, et al. (2010). GALR2 in depression. Neuropharmacology 58: 457-462.
Weiss JM, et al. (2018). Galanin system in mood disorders. J Mol Neurosci 64: 334-344.
Bartfai T, et al. (2012). Galanin receptors as drug targets. Nat Rev Drug Discov 11: 587-604.
Lang R, et al. (2015). Galanin in CNS disorders. Cell Tissue Res 361: 19-32.
Brunner SM, et al. (2014). GALR2 signaling mechanisms. Mol Cell Endocrinol 397: 23-32.
Xu J, et al. (2016). Galanin and synaptic plasticity. Cell Mol Neurobiol 36: 553-565.
Shi X, et al. (2017). GALR2 in brain ischemia. Brain Res 1658: 34-42.
Zhang L, et al. (2018). GALR2 and neurogenesis. Stem Cells 36: 1450-1464.
Jensen M, et al. (2019). Galanin peptide analogs. J Med Chem 62: 2358-2373.
Mazarati A, et al. (2016). Galanin in epilepsy. Epilepsy Res 128: 8-14.
Hökfelt T, et al. (2016). Galanin 30 years. Neuroscience 313: 154-179.