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. 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, Parkinson's Disease, stroke, and other neurodegenerative conditions.
| Attribute |
Value |
| Gene Symbol |
NPY2R |
| Full Name |
Neuropeptide Y Receptor Y2 |
| Other Names |
Y2 receptor, NPY-Y2 receptor |
| Chromosomal Location |
4q31.3 |
| Gene ID |
4882 |
| Protein Class |
G Protein-Coupled Receptor (Class A) |
| Family |
Neuropeptide Y receptor family |
¶ Protein Structure and Function
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
Upon ligand binding, NPY2R activates multiple signaling cascades:
- Inhibition of adenylate cyclase: Reduces cAMP production
- Activation of GIRK channels: Causes hyperpolarization
- Inhibition of voltage-gated calcium channels: Reduces neurotransmitter release
- 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
NPY2R is widely expressed throughout the brain:
- 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
- Thalamus: Specific relay nuclei
- Striatum: Interneurons
- Substantia nigra: Substantia nigra pars compacta and reticulata
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
NPY2R plays a complex role in Alzheimer's Disease pathogenesis:
- 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
- NPY2R activation affects tau phosphorylation pathways
- Interaction with GSK-3β signaling has been reported
- May influence tau propagation between neurons
- NPY2R modulates long-term potentiation (LTP)
- Y2 receptor activation generally inhibits LTP in hippocampus
- NPY2R on GABAergic interneurons regulates excitatory/inhibitory balance
- NPY2R modulates microglial activation
- Anti-inflammatory effects of NPY2R activation reported
- May regulate cytokine production in AD brain
- NPY2R polymorphisms associated with AD risk in some populations
- Gene-wide association studies suggest possible links
- Further research needed to confirm genetic contributions
NPY2R involvement in Parkinson's Disease:
- NPY2R modulates dopamine release in striatum
- Y2 receptors located on dopaminergic terminals
- Alters dopamine transporter function
- NPY2R expression changes in dyskinetic models
- NPY system implicated in LID pathophysiology
- Y2 receptor modulators may reduce dyskinesia
- NPY2R activation can protect dopaminergic neurons
- Anti-apoptotic signaling through PI3K/Akt pathway
- May reduce oxidative stress in substantia nigra
¶ Stroke and Cerebral Ischemia
NPY2R plays important roles in stroke pathophysiology:
- NPY levels increase dramatically after ischemic stroke
- NPY2R mediates vasoconstriction during ischemia
- Contributes to cerebral blood flow regulation
- NPY2R activation reduces glutamate-induced neuronal damage
- Inhibits calcium influx through N-type calcium channels
- Provides endogenous neuroprotection
- NPY2R involved in preconditioning-induced protection
- Brief NPY2R activation can render neurons resistant to subsequent injury
- Therapeutic potential for stroke prevention
- NPY2R expression altered in HD models
- May modulate excitotoxicity
- Y2 receptor agonists under investigation
- NPY2R on motor neurons affected
- Modulates glutamate toxicity
- Potential therapeutic target
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
NPY2R as a therapeutic target:
- NPY(3-36) and selective Y2 agonists
- Potential for obesity treatment
- Neuroprotective applications under investigation
- Y2 receptor antagonists being developed
- Anxiolytic potential
- May have cognitive-enhancing effects
- Blood-brain barrier penetration important for CNS applications
- Peripheral vs central effects need differentiation
- Species differences in receptor pharmacology
| Partner |
Interaction Type |
Functional Consequences |
| NPY (Neuropeptide Y) |
Agonist |
Primary ligand, Gi signaling |
| PYY (Peptide YY) |
Agonist |
Satiety signaling |
| NPY(3-36) |
Selective agonist |
Preferentially activates Y2 |
| Gi/Go proteins |
G protein coupling |
Adenylate cyclase inhibition |
| β-arrestin |
Regulation |
Receptor internalization |
| GRK (G protein-coupled receptor kinases) |
Phosphorylation |
Desensitization |
| ERK1/2 |
Downstream signaling |
MAPK pathway activation |
| Akt |
Downstream signaling |
Pro-survival signaling |
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