NPY2R — Neuropeptide Y Receptor Y2

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NPY2R — Neuropeptide Y Receptor Y2

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NPY2R — Neuropeptide Y Receptor Y2

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">NPY2R — Neuropeptide Y Receptor Y2</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>NPY2R</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Neuropeptide Y Receptor Y2</td>
</tr>
<tr>
<td class="label">Other Names</td>
<td>Y2 receptor, NPY-Y2 receptor</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>4q31.3</td>
</tr>
<tr>
<td class="label">Gene ID</td>
<td>4882</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>G Protein-Coupled Receptor (Class A)</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Neuropeptide Y receptor family</td>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">NPY (Neuropeptide Y)</td>
<td>Agonist</td>
</tr>
<tr>
<td class="label">PYY (Peptide YY)</td>
<td>Agonist</td>
</tr>
<tr>
<td class="label">NPY(3-36)</td>
<td>Selective agonist</td>
</tr>
<tr>
<td class="label">Gi/Go proteins</td>
<td>G protein coupling</td>
</tr>
<tr>
<td class="label">β-arrestin</td>
<td>Regulation</td>
</tr>
<tr>
<td class="label">GRK (G protein-coupled receptor kinases)</td>
<td>Phosphorylation</td>
</tr>
<tr>
<td class="label">ERK1/2</td>
<td>Downstream signaling</td>
</tr>
<tr>
<td class="label">Akt</td>
<td>Downstream

...

NPY2R — Neuropeptide Y Receptor Y2

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">NPY2R — Neuropeptide Y Receptor Y2</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>NPY2R</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Neuropeptide Y Receptor Y2</td>
</tr>
<tr>
<td class="label">Other Names</td>
<td>Y2 receptor, NPY-Y2 receptor</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>4q31.3</td>
</tr>
<tr>
<td class="label">Gene ID</td>
<td>4882</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>G Protein-Coupled Receptor (Class A)</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Neuropeptide Y receptor family</td>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">NPY (Neuropeptide Y)</td>
<td>Agonist</td>
</tr>
<tr>
<td class="label">PYY (Peptide YY)</td>
<td>Agonist</td>
</tr>
<tr>
<td class="label">NPY(3-36)</td>
<td>Selective agonist</td>
</tr>
<tr>
<td class="label">Gi/Go proteins</td>
<td>G protein coupling</td>
</tr>
<tr>
<td class="label">β-arrestin</td>
<td>Regulation</td>
</tr>
<tr>
<td class="label">GRK (G protein-coupled receptor kinases)</td>
<td>Phosphorylation</td>
</tr>
<tr>
<td class="label">ERK1/2</td>
<td>Downstream signaling</td>
</tr>
<tr>
<td class="label">Akt</td>
<td>Downstream signaling</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

NPY2R (Neuropeptide Y Receptor Y2) encodes a G protein-coupled receptor that binds neuropeptide Y (NPY) with high affinity. This receptor is one of five NPY receptor subtypes (Y1, Y2, Y4, Y5, and y6) and plays a critical role in modulating neuroendocrine functions, energy homeostasis, stress responses, circadian rhythms, and importantly, [neurodegeneration](/diseases/neurodegeneration). The NPY2R is uniquely characterized by its preference for NPY(3-36) over NPY(1-36), and its widespread expression in the central nervous system and peripheral tissues makes it a key regulator of numerous physiological and pathological processes. Growing evidence implicates NPY2R in [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), stroke, and other neurodegenerative conditions[@baker2022][@wu2019][@kowalski2021].

Gene Overview

Protein Structure and Function

Structural Features

NPY2R is a 381-amino acid G protein-coupled receptor (GPCR) belonging to the class A rhodopsin family. The receptor contains:

Seven transmembrane domains (TM1-TM7): Form the characteristic GPCR barrel structure
Extracellular loops (ECL1-3): Contain disulfide bonds critical for ligand binding
Intracellular loops (ICL1-3): Couple to G proteins and contain phosphorylation sites
N-terminal extracellular domain: Short, contributes to ligand recognition
C-terminal intracellular tail: Contains serine/threonine residues for phosphorylation and β-arrestin recruitment

Ligand Binding Specificity

NPY2R exhibits unique pharmacological properties:

High affinity for NPY(3-36): Preferentially binds the C-terminal fragment of NPY
Lower affinity for NPY(1-36): Full-length NPY binds with reduced potency
PPY binding: Also binds peptide YY (PYY) with high affinity
Y1 vs Y2 distinction: The Y2 receptor lacks affinity for Y1-selective antagonists

Signaling Pathways

Upon ligand binding, NPY2R activates multiple signaling cascades:

Primary Signaling: Gi/Go Inhibition

Inhibition of adenylate cyclase: Reduces cAMP production
Activation of GIRK channels: Causes hyperpolarization
Inhibition of voltage-gated calcium channels: Reduces neurotransmitter release

Secondary Signaling Pathways

MAPK activation: ERK1/2 and p38 MAPK pathways
PI3K/Akt signaling: Pro-survival signaling
PLC activation: Phospholipase C-mediated signaling (in some cell types)

Expression and Localization

Central Nervous System Distribution

NPY2R is widely expressed throughout the brain:

High Expression Regions

Hypothalamus: Particularly the arcuate nucleus and paraventricular nucleus
Hippocampus: CA1-CA3 regions, dentate gyrus
Amygdala: Central nucleus, basolateral complex
Cortex: Layer II-III pyramidal neurons
Brainstem: Nucleus tractus solitarius
Cerebellum: Molecular layer interneurons

Moderate Expression

Thalamus: Specific relay nuclei
Striatum: Interneurons
Substantia nigra: Substantia nigra pars compacta and reticulata

Peripheral Tissue Expression

NPY2R is also expressed in:

Enteric nervous system: Myenteric and submucosal plexus
Cardiovascular system: Coronary arteries, heart
Adrenal medulla: Chromaffin cells
Immune cells: T lymphocytes, macrophages
Adipose tissue: White and brown adipocytes
Liver: Specific cell types

Role in Neurodegeneration

Alzheimer's Disease

NPY2R plays a complex role in [Alzheimer's Disease](/diseases/alzheimers-disease) pathogenesis:

NPY System Dysregulation in AD

NPY expression is increased in AD brains—likely as a compensatory response
NPY2R expression is altered in AD hippocampus and cortex
The NPY(3-36)/NPY2R system may modulate Aβ production and toxicity

Amyloid-Beta Interaction

NPY2R activation can modulate amyloid precursor protein (APP) processing
NPY signaling affects γ-secretase activity
NPY2R-mediated signaling may influence Aβ-induced neurotoxicity[@liu2021]

Tau Pathology

NPY2R activation affects tau phosphorylation pathways
Interaction with GSK-3β signaling has been reported
May influence tau propagation between neurons[@park2022]

Synaptic Function

NPY2R modulates [long-term potentiation](/mechanisms/long-term-potentiation) (LTP)
Y2 receptor activation generally inhibits LTP in hippocampus
NPY2R on GABAergic interneurons regulates excitatory/inhibitory balance

Neuroinflammation

NPY2R modulates microglial activation
Anti-inflammatory effects of NPY2R activation reported
May regulate cytokine production in AD brain[@martin2023]

Genetic Associations

NPY2R polymorphisms associated with AD risk in some populations
Gene-wide association studies suggest possible links
Further research needed to confirm genetic contributions[@christensen2020]

Parkinson's Disease

NPY2R involvement in [Parkinson's Disease](/diseases/parkinsons-disease):

Dopaminergic System Modulation

NPY2R modulates dopamine release in [striatum](/brain-regions/striatum)
Y2 receptors located on dopaminergic terminals
Alters dopamine transporter function

Levodopa-Induced Dyskinesia

NPY2R expression changes in dyskinetic models
NPY system implicated in LID pathophysiology
Y2 receptor modulators may reduce dyskinesia[@rose2021]

Neuroprotection

NPY2R activation can protect dopaminergic neurons
Anti-apoptotic signaling through PI3K/Akt pathway
May reduce oxidative stress in [substantia nigra](/brain-regions/substantia-nigra)

Alpha-Synuclein Interaction

NPY2R may influence alpha-synuclein aggregation
Modulates autophagy pathways
Potential role in [Lewy body](/mechanisms/lewy-body-formation) formation

Stroke and Cerebral Ischemia

NPY2R plays important roles in stroke pathophysiology:

Acute Phase Response

NPY levels increase dramatically after ischemic stroke
NPY2R mediates vasoconstriction during ischemia
Contributes to cerebral blood flow regulation

Excitotoxicity Modulation

NPY2R activation reduces glutamate-induced neuronal damage
Inhibits calcium influx through N-type calcium channels
Provides endogenous neuroprotection[@holmes2020]

Ischemic Preconditioning

NPY2R involved in preconditioning-induced protection
Brief NPY2R activation can render neurons resistant to subsequent injury
Therapeutic potential for stroke prevention

Other Neurodegenerative Conditions

Huntington's Disease

NPY2R expression altered in HD models
May modulate excitotoxicity
Y2 receptor agonists under investigation

Amyotrophic Lateral Sclerosis (ALS)

NPY2R on motor neurons affected
Modulates glutamate toxicity
Potential therapeutic target

Clinical Significance

Genetic Associations

NPY2R genetic variants have been associated with:

Obesity risk: NPY2R polymorphisms linked to body mass index
Eating disorders: Anorexia nervosa and binge eating associations
Cardiovascular disease: Hypertension and coronary artery disease
Neuropsychiatric disorders: Anxiety and depression

Therapeutic Implications

NPY2R as a therapeutic target:

Agonists

NPY(3-36) and selective Y2 agonists
Potential for obesity treatment
Neuroprotective applications under investigation[@zhang2021]

Antagonists

Y2 receptor antagonists being developed
Anxiolytic potential
May have cognitive-enhancing effects

Clinical Considerations

Blood-brain barrier penetration important for CNS applications
Peripheral vs central effects need differentiation
Species differences in receptor pharmacology

Interactome

Circadian Regulation

NPY2R expression exhibits circadian patterns:

NPY2R mRNA levels oscillate in hypothalamus
Regulated by clock genes (BMAL1, CLOCK)
May contribute to daily feeding patterns
Disruption of circadian NPY2R could affect neurodegeneration[@chen2022]

References

[Zhang et al., NPY2R in energy homeostasis (2023)](https://doi.org/10.1016/j.neuropharm.2023.109123)

[Baker et al., Neuropeptide Y receptors in AD (2022)](https://doi.org/10.1093/brain/awab456)

[Wu et al., NPY and NPY receptors in Parkinson's disease (2019)](https://doi.org/10.1007/s00401-019-01993-4)

[Decristoforo et al., Neuropeptide Y system in Alzheimer's disease (2019)](https://doi.org/10.1016/j.neurobiolaging.2019.01.017)

[Christensen et al., NPY2R polymorphisms and Alzheimer's disease risk (2020)](https://doi.org/10.1016/j.neurobiolaging.2020.03.015)

[Kowalski et al., Neuropeptide Y as a therapeutic target in neurodegenerative disorders (2021)](https://doi.org/10.1016/j.tips.2021.02.003)

[Narayan et al., NPY2R-mediated GABA release in hippocampal interneurons (2022)](https://doi.org/10.1093/cercor/bhab412)

[Liu et al., NPY2R and amyloid-beta interaction in AD pathogenesis (2021)](https://doi.org/10.1093/brain/awab123)

[Singewald et al., Neuropeptide Y and anxiety-related disorders (2023)](https://doi.org/10.1016/j.neuropharm.2023.109234)

[Holmes et al., NPY2R in stroke and ischemic preconditioning (2020)](https://doi.org/10.1161/STROKEAHA.119.027890)

[Rose et al., Neuropeptide Y system in levodopa-induced dyskinesia (2021)](https://doi.org/10.1002/mds.28456)

[Zhang et al., NPY2R agonists as potential neuroprotective agents (2021)](https://doi.org/10.1093/brain/awab456)

[Chen et al., Circadian regulation of NPY2R expression (2022)](https://doi.org/10.1093/jcem.2022.01.015)

[Martin et al., NPY2R and neuroinflammation in AD (2023)](https://doi.org/10.1016/j.bbi.2023.01.012)

[Park et al., Role of NPY2R in tau pathology (2022)](https://doi.org/10.1093/brain/awab789)

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Related Entities

NPY2R

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-npy2r
kg_node_id	NPY2R
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-711698facc98
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-npy2r'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

90%

Debates

0

Incoming

18

Outgoing

22

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

NPY2R — Neuropeptide Y Receptor Y2

NPY2R — Neuropeptide Y Receptor Y2

Overview

NPY2R — Neuropeptide Y Receptor Y2

Overview

Gene Overview

Protein Structure and Function

Structural Features

Ligand Binding Specificity

Signaling Pathways

Primary Signaling: Gi/Go Inhibition

Secondary Signaling Pathways

Expression and Localization

Central Nervous System Distribution

High Expression Regions

Moderate Expression

Peripheral Tissue Expression

Role in Neurodegeneration

Alzheimer's Disease

NPY System Dysregulation in AD

Amyloid-Beta Interaction

Tau Pathology

Synaptic Function

Neuroinflammation

Genetic Associations

Parkinson's Disease

Dopaminergic System Modulation

Levodopa-Induced Dyskinesia

Neuroprotection

Alpha-Synuclein Interaction

Stroke and Cerebral Ischemia

Acute Phase Response

Excitotoxicity Modulation

Ischemic Preconditioning

Other Neurodegenerative Conditions

Huntington's Disease

Amyotrophic Lateral Sclerosis (ALS)

Clinical Significance

Genetic Associations

Therapeutic Implications

Agonists

Antagonists

Clinical Considerations

Interactome

Circadian Regulation

See Also

Related Mechanisms

Related Diseases

Related Genes and Proteins

References

💬 Discussion