NPY1R Gene

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

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

• 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:

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

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

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

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

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

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

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

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

Key Research Findings

Clinical Relevance

NPY1R represents a promising therapeutic target for multiple conditions:

See Also

• [Neuropeptide Y (NPY)](/proteins/neuropeptide-y)
• [G protein-coupled receptors](/search?type=page&query=GPCR)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Obesity](/search?type=disease&query=obesity)
• [Hippocampus](/brain-regions/hippocampus)
• [Amygdala](/brain-regions/amygdala)
• [Hypothalamus](/brain-regions/hypothalamus)

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

Pathway Diagram

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