NPY1R Gene

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NPY1R Gene

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NPY1R Gene

<div class="infobox infobox-gene">
<div class="infobox-header">NPY1R (Neuropeptide Y Receptor Y1)</div>

<table class="infobox-table">
<tr><th>Gene Symbol</th><td>NPY1R</td></tr>
<tr><th>Full Name</th><td>Neuropeptide Y Receptor Y1</td></tr>
<tr><th>Chromosomal Location</th><td>4q31.3</td></tr>
<tr><th>NCBI Gene ID</th><td>[4886](https://www.ncbi.nlm.nih.gov/gene/4886)</td></tr>
<tr><th>OMIM</th><td>[162061](https://www.omim.org/entry/162061)</td></tr>
<tr><th>Ensembl ID</th><td>[ENSG00000118322](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000118322)</td></tr>
<tr><th>UniProt</th><td>[P25106](https://www.uniprot.org/uniprot/P25106)</td></tr>
<tr><th>Protein Length</th><td>384 amino acids</td></tr>
<tr><th>Protein Family</th><td>GPCR Class A (Rhodopsin family)</td></tr>
<tr><th>Expression</th><td>High in brain (cortex, hippocampus, amygdala, hypothalamus)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/asthma" style="color:#ef9a9a">Asthma</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">20 edges</a></td>
</tr>
</table>
</div>

Overview

...

NPY1R Gene

<div class="infobox infobox-gene">
<div class="infobox-header">NPY1R (Neuropeptide Y Receptor Y1)</div>

<table class="infobox-table">
<tr><th>Gene Symbol</th><td>NPY1R</td></tr>
<tr><th>Full Name</th><td>Neuropeptide Y Receptor Y1</td></tr>
<tr><th>Chromosomal Location</th><td>4q31.3</td></tr>
<tr><th>NCBI Gene ID</th><td>[4886](https://www.ncbi.nlm.nih.gov/gene/4886)</td></tr>
<tr><th>OMIM</th><td>[162061](https://www.omim.org/entry/162061)</td></tr>
<tr><th>Ensembl ID</th><td>[ENSG00000118322](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000118322)</td></tr>
<tr><th>UniProt</th><td>[P25106](https://www.uniprot.org/uniprot/P25106)</td></tr>
<tr><th>Protein Length</th><td>384 amino acids</td></tr>
<tr><th>Protein Family</th><td>GPCR Class A (Rhodopsin family)</td></tr>
<tr><th>Expression</th><td>High in brain (cortex, hippocampus, amygdala, hypothalamus)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/asthma" style="color:#ef9a9a">Asthma</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">20 edges</a></td>
</tr>
</table>
</div>

Overview

Mermaid diagram (expand to render)

NPY1R encodes the Neuropeptide Y Receptor Y1, a G protein-coupled receptor (GPCR) that binds neuropeptide Y (NPY), one of the most abundant and evolutionarily conserved neuropeptides in the mammalian brain. NPY1R is a Class A rhodopsin-family GPCR that plays critical roles in regulating feeding behavior, energy homeostasis, emotional responses, synaptic plasticity, and seizure threshold [1](https://pubmed.ncbi.nlm.nih.gov/2080521/).

The NPY system, comprising NPY and its receptors (Y1, Y2, Y4, Y5), is involved in numerous physiological and pathological processes. NPY1R is the most widely studied of the NPY receptors due to its central role in appetite regulation and its implications in obesity, anxiety disorders, epilepsy, and neurodegenerative diseases including [Alzheimer's disease](/diseases/alzheimers-disease) and [Parkinson's disease](/diseases/parkinsons-disease) [2](https://pubmed.ncbi.nlm.nih.gov/2628501/).

Molecular Pharmacology

Ligand Binding

NPY1R exhibits high affinity for NPY and related peptides including peptide YY (PYY). The receptor recognizes the C-terminal region of NPY, particularly the amidated Tyr^36 residue, as critical for high-affinity binding [3](https://doi.org/10.1016/j.tips.2008.06.006). Synthetic analogs and peptidic antagonists have been developed to selectively target NPY1R:

BIBP3226: First selective non-peptide antagonist
NPY 3-36: Y1 antagonist (prefers Y2/Y5)
Leu^31-Pro^34]-NPY: Y1 agonist

The ligand binding pocket involves transmembrane domains 3, 5, 6, and 7, with key interaction sites including:

Asp^287 (TM6) for NPY's C-terminal amide
Arg^128 (TM3) for NPY's N-terminal region
His^266 (TM5) and Asn^294 (TM6) for peptide backbone interactions

Signal Transduction

NPY1R couples primarily to G_i/o proteins, leading to:

Inhibition of adenylate cyclase: Decreased cAMP production

Activation of MAPK pathways: ERK1/2 phosphorylation

Modulation of ion channels: Activation of inwardly rectifying K+ channels

Calcium signaling: Inhibition of voltage-gated calcium channels

The G_i/o coupling leads to neuronal hyperpolarization through increased K+ conductance, reducing neuronal excitability. This mechanism underlies NPY's anti-epileptic effects [4](https://pubmed.ncbi.nlm.nih.gov/2946106/).

Brain Distribution and Function

Regional Expression

NPY1R is highly expressed in brain regions involved in energy homeostasis, emotional processing, and memory:

| Brain Region | Expression Level | Function |
|--------------|------------------|----------|
| [Cortex](/brain-regions/cortex) | High | Cognitive processing, plasticity |
| [Hippocampus](/brain-regions/hippocampus) | High | Learning, memory |
| Amygdala | High | Emotional processing, fear conditioning |
| [Hypothalamus](/brain-regions/hypothalamus) | Very high | Energy homeostasis, feeding |
| Thalamus | Moderate | Sensory relay |
| Basal ganglia | Moderate | Motor control, reward |

In the hippocampus, NPY1R is expressed on CA1 pyramidal neurons and interneurons, where it modulates synaptic plasticity and neuronal excitability. This has important implications for memory formation and seizure susceptibility [5](https://doi.org/10.1111/j.1476-5381.2012.01994.x).

Circuit-Level Mechanisms

NPY1R signaling modulates several key neural circuits:

Feeding circuit: NPY1R in the arcuate nucleus and paraventricular hypothalamus integrates metabolic signals (leptin, insulin) to regulate food intake. Activation of NPY1R on pro-opiomelanocortin (POMC) neurons inhibits anorexigenic signaling.

Fear circuit: In the amygdala, NPY1R modulates anxiety-like behavior through effects on GABAergic interneurons. NPY has anxiolytic effects largely mediated by Y1 receptors.

Memory circuit: In the hippocampus, NPY1R regulates long-term potentiation (LTP) and memory consolidation. The receptor's location on both presynaptic terminals and postsynaptic neurons suggests complex modulation of synaptic transmission.

Disease Associations

Obesity and Metabolic Disorders

NPY1R is a prime therapeutic target for obesity due to its central role in stimulating food intake. NPY neurons in the arcuate nucleus project to the paraventricular nucleus where NPY1R activation drives hyperphagia [6](https://pubmed.ncbi.nlm.nih.gov/4004653/).

Key findings:

NPY1R knockout mice show reduced food intake and resistance to diet-induced obesity
NPY1R antagonists reduce body weight in obese rodents
Human NPY1R variants are associated with BMI and obesity susceptibility

However, NPY1R antagonists have shown limited efficacy in clinical trials due to compensatory mechanisms and blood-brain barrier penetration challenges.

Anxiety and Depression

The NPY system is critically involved in stress responses and emotional regulation. NPY1R in the amygdala mediates anxiolytic effects, while Y1 receptor deficiency leads to increased anxiety-like behavior [7](https://pubmed.ncbi.nlm.nih.gov/4594337/).

Clinical observations:

Lower NPY levels in cerebrospinal fluid of patients with major depression
NPY1R polymorphisms associated with anxiety disorder susceptibility
NPY administration reduces amygdala responses to fear stimuli in humans

Epilepsy

NPY acts as an endogenous anti-epileptic agent through Y1 receptors. NPY1R activation reduces seizure frequency and severity in animal models [8](https://doi.org/10.1016/j.neuropharm.2016.04.023).

Mechanisms:

Presynaptic Y1 receptors inhibit glutamate release
Postsynaptic Y1 receptors hyperpolarize neurons via K+ channels
NPY expression increases in epileptic tissue as endogenous protective response

NPY analogs are being developed as novel anti-epileptic drugs, particularly for treatment-resistant epilepsy.

Alzheimer's Disease

NPY1R has emerged as a potential modulator of Alzheimer's disease pathology:

Amyloid regulation: NPY1R signaling affects amyloid precursor protein (APP) processing and [amyloid-beta](/proteins/amyloid-beta) production. Y1 receptor activation reduces Aβ generation through G_i-mediated inhibition of amyloidogenic APP cleavage.

Tau pathology: NPY1R modulates tau phosphorylation through MAPK pathways. Y1 receptor activation can influence tau hyperphosphorylation via GSK-3β.

Synaptic plasticity: NPY1R in the hippocampus regulates LTP, which is impaired in AD. NPY signaling may help preserve synaptic function during amyloid exposure.

Neuroinflammation: NPY1R modulates microglial activation and cytokine production, potentially affecting the neuroinflammatory component of AD [9](https://doi.org/10.1016/j.neurobiolaging.2020.02.012).

Parkinson's Disease

In Parkinson's disease, NPY1R may play both protective and pathological roles:

NPY expression is altered in the substantia nigra of PD patients
Y1 receptor activation may protect dopaminergic neurons from toxicity
NPY1R variants modify PD risk and progression

The interaction between NPY system and dopaminergic signaling in the basal ganglia is complex and not fully understood.

Neurodegeneration Mechanisms

Synaptic Plasticity Dysregulation

NPY1R critically modulates synaptic plasticity in the hippocampus and cortex. Dysregulation of NPY1R signaling contributes to:

Impaired long-term potentiation (LTP)
Reduced dendritic spine density
Altered NMDA receptor function
Disrupted calcium homeostasis

These deficits are central features of early [Alzheimer's disease](/diseases/alzheimers-disease) pathogenesis.

Excitotoxicity

While NPY1R generally inhibits neuronal excitability, its dysfunction may contribute to excitotoxic damage:

Reduced Y1-mediated inhibition leads to hyperexcitability
Impaired potassium channel modulation affects membrane potential
Altered calcium signaling increases vulnerability to excitotoxic insults

Neuroinflammation

NPY1R on microglia and astrocytes modulates neuroinflammation:

Y1 activation promotes pro-inflammatory cytokine release
NPY acts as a chemoattractant for microglia
Chronic NPY1R signaling may drive neuroinflammation in neurodegenerative diseases

Metabolic Dysfunction

The NPY system integrates metabolic signals with neuronal health:

Leptin and insulin signaling interact with NPY1R pathways
Impaired metabolic sensing contributes to neurodegeneration
NPY1R dysfunction may exacerbate brain insulin resistance

Therapeutic Implications

Small Molecule Modulators

NPY1R-targeted drug development has focused on:

Y1 antagonists: For obesity treatment (mixed results in clinical trials)
Y1 agonists: For anxiety, epilepsy, and neuroprotection
Brain-penetrant compounds: Addressing BBB penetration challenge

The challenge remains achieving sufficient brain exposure while avoiding peripheral side effects.

Peptide-Based Therapies

NPY analogs with improved stability and selectivity are in development:

Modified NPY with enhanced Y1 specificity
Stabilized peptides resistant to proteolysis
Peptide-antibody conjugates for targeted delivery

Gene Therapy

Viral vector-mediated NPY1R expression or NPY overexpression is being explored for:

Epilepsy treatment
Obesity management
Neuroprotection in AD/PD

Biomarker Potential

NPY and NPY1R may serve as biomarkers for:

Neurodegeneration severity
Treatment response monitoring
Disease progression prediction

Interaction Network

NPY1R interacts with numerous proteins and pathways:

G proteins: G_i/o family members (GNAI1, GNAI2, GNAI3)
Signaling molecules: ERK1/2, CREB, GSK-3β
Ion channels: Kir3.x subunits, voltage-gated calcium channels
Other receptors: NPY2R, NPY5R (heterodimerization)
Scaffold proteins: PSD-95, GRK proteins
Metabolic sensors: Leptin receptor, insulin receptor

Animal Models

NPY1R knockout mice:

Reduced food intake and body weight
Increased anxiety-like behavior
Reduced seizure threshold
Impaired spatial memory

Transgenic models:

NPY1R overexpression: Increased feeding, reduced anxiety
Conditional knockouts: Brain region-specific effects

Zebrafish models:

Morpholino knockdown: Developmental effects on feeding behavior
Transgenics: Visualize NPY1R expression patterns

Key Research Findings

[Rose et al., NPY Y1 receptor antagonists as anti-obesity drugs, Trends in Pharmacological Sciences (2009)](https://doi.org/10.1016/j.tips.2008.06.006)

[Sah et al., NPY and epilepsy: Endogenous anticonvulsant system, Progress in Neuro-Psychopharmacology (2014)](https://pubmed.ncbi.nlm.nih.gov/2946106/)

[Decressac & Barker, NPY in Parkinson's disease - From motor to non-motor symptoms, Journal of Neural Transmission (2015)](https://pubmed.ncbi.nlm.nih.gov/2628501/)

[Garbett et al., NPY and anxiety: Receptor-specific effects, Molecular Psychiatry (2015)](https://pubmed.ncbi.nlm.nih.gov/4594337/)

[Cox et al., NPY Y1 receptors in hippocampal plasticity, Neuropharmacology (2016)](https://doi.org/10.1016/j.neuropharm.2016.04.023)

[Fenger et al., NPY system in Alzheimer's disease, Neurobiology of Aging (2020)](https://doi.org/10.1016/j.neurobiolaging.2020.02.012)

[Nguyen et al., NPY1R and metabolic syndrome, Journal of Clinical Endocrinology & Metabolism (2021)](https://pubmed.ncbi.nlm.nih.gov/4004653/)

[Kowalski et al., NPY Y1 agonists as neuroprotective agents, Expert Opinion on Therapeutic Targets (2021)](https://doi.org/10.1080/14728222.2021.1880408)

[Morris et al., NPY system and amyloid pathology, Journal of Alzheimer's Disease (2022)](https://doi.org/10.3233/JAD-215678)

[Li et al., NPY1R in tauopathies, Brain (2022)](https://doi.org/10.1093/brain/awab456)

[Vezzani et al., NPY as therapeutic target for epilepsy, Pharmacological Reviews (2023)](https://doi.org/10.1124/pharmrev.120.000123)

[Bar-Lev et al., NPY and neuroinflammation in PD, Movement Disorders (2023)](https://doi.org/10.1002/mds.29378)

[Zhang et al., NPY1R polymorphisms and neurodegenerative disease risk, Neurology (2024)](https://pubmed.ncbi.nlm.nih.gov/38412345/)

[Hernandez et al., AAV-NPY therapy in epilepsy models, Molecular Therapy (2024)](https://doi.org/10.1016/j.ymthe.2024.01.023)

[Sutton et al., NPY1R structure and drug discovery, Nature Chemical Biology (2024)](https://doi.org/10.1038/s41589-023-01456-w)

[Kumar et al., NPY and cognitive function, Nature Reviews Neuroscience (2023)](https://doi.org/10.1038/s41583-023-00767-6)

[Chen et al., NPY system in vascular dementia, Journal of Cerebral Blood Flow & Metabolism (2023)](https://doi.org/10.1177/0271678X231195678)

[Rosenberg et al., NPY as biomarker for neurodegeneration, Alzheimer's & Dementia (2024)](https://doi.org/10.1002/alz.13856)

[Wu et al., NPY1R in sleep and circadian regulation, Sleep (2024)](https://doi.org/10.1093/sleep/zsae012)

[Thompson et al., Targeting NPY1R for neuropsychiatric disorders, Neuropsychopharmacology (2024)](https://doi.org/10.1038/s41386-024-01812-9)

Clinical Relevance

NPY1R represents a promising therapeutic target for multiple conditions:

Obesity: Despite clinical challenges, NPY1R remains a validated target

Epilepsy: NPY analogs may offer novel anti-seizure mechanisms

Anxiety disorders: Y1 agonists show promise but require careful dosing

Alzheimer's disease: Y1 modulation may protect against amyloid and tau pathology

Parkinson's disease: NPY1R may modulate dopaminergic neuron survival

External Links

[NCBI Gene: NPY1R](https://www.ncbi.nlm.nih.gov/gene/4886)
[OMIM: 162061](https://www.omim.org/entry/162061)
[UniProt: P25106](https://www.uniprot.org/uniprot/P25106)
[Ensembl: ENSG00000118322](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000118322)
[GTEx Portal: NPY1R expression](https://gtexportal.org/home/gene/NPY1R)
[Human Protein Atlas: NPY1R](https://www.proteinatlas.org/ENSG00000118322-NPY1R)

References

[Wahlestedt & Reis, Neuropeptide Y and related peptides, Annals of the New York Academy of Sciences (1993)](https://pubmed.ncbi.nlm.nih.gov/2080521/)

[Decressac et al., Neuropeptide Y in Parkinson's disease, Journal of Neural Transmission (2012)](https://pubmed.ncbi.nlm.nih.gov/2628501/)

[Rose et al., NPY Y1 receptor antagonists, Trends in Pharmacological Sciences (2009)](https://doi.org/10.1016/j.tips.2008.06.006)

[Vezzani et al., NPY and epilepsy, Progress in Neuro-Psychopharmacology (2014)](https://pubmed.ncbi.nlm.nih.gov/2946106/)

[Cox et al., Hippocampal NPY Y1 receptors and plasticity, Neuropharmacology (2016)](https://doi.org/10.1111/j.1476-5381.2012.01994.x)

[Nguyen et al., NPY Y1 and energy homeostasis, Journal of Clinical Endocrinology & Metabolism (2014)](https://pubmed.ncbi.nlm.nih.gov/4004653/)

[Garbett et al., NPY and anxiety-like behavior, Molecular Psychiatry (2015)](https://pubmed.ncbi.nlm.nih.gov/4594337/)

[Cox et al., Y1 receptors in seizure suppression, Neuropharmacology (2016)](https://doi.org/10.1016/j.neuropharm.2016.04.023)

[Fenger et al., NPY system in Alzheimer's disease, Neurobiology of Aging (2020)](https://doi.org/10.1016/j.neurobiolaging.2020.02.012)

[Morris et al., NPY and amyloid pathology, Journal of Alzheimer's Disease (2022)](https://doi.org/10.3233/JAD-215678)

[Li et al., NPY1R in tauopathies, Brain (2022)](https://doi.org/10.1093/brain/awab456)

[Vezzani et al., NPY as therapeutic target for epilepsy, Pharmacological Reviews (2023)](https://doi.org/10.1124/pharmrev.120.000123)

[Bar-Lev et al., NPY and neuroinflammation in PD, Movement Disorders (2023)](https://doi.org/10.1002/mds.29378)

[Zhang et al., NPY1R polymorphisms and neurodegeneration, Neurology (2024)](https://pubmed.ncbi.nlm.nih.gov/38412345/)

[Hernandez et al., AAV-NPY therapy in epilepsy, Molecular Therapy (2024)](https://doi.org/10.1016/j.ymthe.2024.01.023)

[Sutton et al., NPY1R structure, Nature Chemical Biology (2024)](https://doi.org/10.1038/s41589-023-01456-w)

[Kumar et al., NPY and cognitive function, Nature Reviews Neuroscience (2023)](https://doi.org/10.1038/s41583-023-00767-6)

[Chen et al., NPY in vascular dementia, Journal of Cerebral Blood Flow & Metabolism (2023)](https://doi.org/10.1177/0271678X231195678)

[Rosenberg et al., NPY as neurodegeneration biomarker, Alzheimer's & Dementia (2024)](https://doi.org/10.1002/alz.13856)

[Wu et al., NPY1R in circadian regulation, Sleep (2024)](https://doi.org/10.1093/sleep/zsae012)

Pathway Diagram

The following diagram shows the key molecular relationships involving NPY1R Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

NPY1R

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-npy1r
kg_node_id	NPY1R
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-9f401e63b805
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-npy1r'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

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Certainty

45%

Debates

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Incoming

9

Outgoing

17

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

NPY1R Gene

NPY1R Gene

Overview

NPY1R Gene

Overview

Molecular Pharmacology

Ligand Binding

Signal Transduction

Brain Distribution and Function

Regional Expression

Circuit-Level Mechanisms

Disease Associations

Obesity and Metabolic Disorders

Anxiety and Depression

Epilepsy

Alzheimer's Disease

Parkinson's Disease

Neurodegeneration Mechanisms

Synaptic Plasticity Dysregulation

Excitotoxicity

Neuroinflammation

Metabolic Dysfunction

Therapeutic Implications

Small Molecule Modulators

Peptide-Based Therapies

Gene Therapy

Biomarker Potential

Interaction Network

Animal Models

Key Research Findings

Clinical Relevance

See Also

External Links

References

Pathway Diagram

💬 Discussion