GO:0001601 peptide YY receptor activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0001601 peptide YY receptor activity is a molecular function defined as combining with gut peptide YY to initiate a change in cell activity.
• The term is mediated by the neuropeptide Y receptor family, principally NPY2R (Y2 receptor), which binds PYY and its truncated form PYY(3-36).
• PYY receptor signaling is a key regulator of feeding behavior and energy homeostasis, making it a target for obesity and metabolic disease research.
• Structure-activity studies have defined the C-terminal region of PYY as critical for receptor binding and antisecretory activity.
• The Y1 receptor (NPY1R) can activate MAPK and proliferation in gut epithelial cells via EGFR transactivation, linking PYY receptor biology to epithelial growth control.
• Studying GO:0001601 requires integrated approaches including binding assays, mutagenesis, CRISPR knockout/knock-in models, and transcriptomic readouts.
Description
GO:0001601 peptide YY receptor activity is a molecular function term in the Gene Ontology that describes the ability of a receptor to combine with the gut peptide YY (PYY) and initiate a change in cell activity. PYY is a 36-amino-acid peptide released from enteroendocrine L-cells of the gut, and its receptor activity is central to neuroendocrine control of appetite, gut motility, and epithelial function. The receptor activity is primarily attributed to the neuropeptide Y receptor family, especially the Y2 receptor (NPY2R), which shows high affinity for PYY and its truncated circulating form PYY(3-36). Because this function sits at the interface of gut physiology and central nervous system regulation, it is a high-value target for metabolic disease research. For researchers, GO:0001601 provides a precise functional annotation to interpret receptor-ligand experiments, mutagenesis studies, and pharmacological screens. Structure-activity studies of PYY analogs have revealed that the C-terminal portion of PYY is essential for receptor binding and biological activity, including antisecretory effects in the jejunum. The receptor itself has been biochemically characterized as a glycoprotein, and its solubilization enabled early binding studies that established direct PYY-receptor interactions. More recently, dual-acting agonists targeting GLP-1 and PYY receptors have been designed, underscoring the therapeutic relevance of this activity. Understanding peptide YY receptor activity also requires attention to downstream signaling. Activation of the Y1 receptor by PYY can stimulate mitogen-activated protein kinase and proliferation in gut epithelial cells through epidermal growth factor receptor transactivation. This links GO:0001601 not only to feeding regulation but also to epithelial cell biology and potential cancer-related processes. The term therefore serves as a functional hub connecting ligand chemistry, receptor pharmacology, and disease-relevant cell signaling.
peptide YY receptor activity At A Glance
| GO ID | GO:0001601 |
|---|---|
| GO term | peptide YY receptor activity |
| Ontology | molecular_function |
| Synonym | none listed |
| Definition | Combining with gut peptide YY to initiate a change in cell activity. |
| Major function | Binding of peptide YY to a receptor to trigger intracellular signaling and cellular responses. |
| Primary receptor family | Neuropeptide Y receptors, especially NPY2R (Y2 receptor). |
| Key ligand | Peptide YY (PYY) and its truncated form PYY(3-36). |
| Physiological role | Regulation of feeding, energy homeostasis, and gut epithelial signaling. |
What Is GO:0001601?
In simple terms, GO:0001601 peptide YY receptor activity describes what happens when a receptor protein on a cell binds the gut hormone peptide YY and, as a result, triggers a change inside the cell. The official Gene Ontology definition is combining with gut peptide YY to initiate a change in cell activity. This activity is a molecular function, meaning it is defined by the specific binding event and the immediate signaling consequence, rather than by a whole pathway or a cellular location. Receptors annotated with this function are typically members of the neuropeptide Y receptor family, with the Y2 receptor (NPY2R) being a principal mediator of PYY binding and signaling. The activity can be studied using radioligand binding, receptor mutagenesis, and functional assays that measure downstream cellular responses.
Why Is peptide YY receptor activity Important in Cell Biology?
GO:0001601 peptide YY receptor activity is important because it defines the molecular entry point for PYY-mediated signaling, a system that influences appetite, gut secretion, and epithelial cell proliferation. Dysregulation of this activity has been implicated in metabolic disorders and gut-related pathologies, and the receptor is a validated target for anti-obesity drug discovery. For basic researchers, the term provides a precise annotation to interpret receptor binding, mutagenesis, and pharmacological data, and it connects ligand structure to downstream cellular outcomes.
• Defines the molecular function of PYY receptors, enabling accurate annotation of receptor-ligand experiments.
• Central to feeding regulation and energy homeostasis, making it relevant to obesity research.
• Provides a target for dual-acting GLP-1/PYY receptor agonists in metabolic disease.
• Links PYY signaling to gut epithelial proliferation via EGFR transactivation.
• Supports structure-activity studies that define which PYY residues are required for receptor binding.
• Enables mutagenesis studies that distinguish Y1 and Y2 receptor interactions with conserved ligand positions.
• Provides a biochemical handle for receptor solubilization and glycoprotein characterization.
• Connects neuroendocrine signaling to potential cancer and epithelial biology research.
• Helps interpret transcriptomic and pharmacological data in metabolic and gastrointestinal studies.
• Supports CRISPR-based functional genomics of receptor activity in relevant cell models.
Molecular Mechanism of peptide YY receptor activity
Ligand recognition and binding
In simple terms: The receptor first grabs the PYY peptide.
Peptide YY receptor activity begins with the binding of PYY to the receptor. Structure-activity studies of PYY(22-36) analogs demonstrated that the C-terminal region of PYY is critical for receptor binding and antisecretory activity in rat jejunum. Further structure and receptor binding studies of PYY analogs confirmed that specific residues within the C-terminal portion govern affinity and functional potency. The receptor itself has been characterized as a glycoprotein of approximately 44,000 Da from rat jejunal crypts, and its solubilization enabled direct binding studies that established the physical interaction between PYY and its receptor.
Receptor subtype selectivity
In simple terms: Different Y receptors respond to PYY in different ways.
PYY can engage multiple neuropeptide Y receptor subtypes, but the Y2 receptor (NPY2R) is a principal mediator of peptide YY receptor activity. Mutagenesis studies of the human Y2 receptor revealed differences from the Y1 receptor in how they interact with highly conserved ligand positions, indicating that subtype-specific molecular contacts determine selectivity. This selectivity is important because different receptor subtypes can couple to distinct downstream responses, and the GO term captures the shared function of combining with PYY to initiate a change in cell activity.
Downstream signaling and MAPK activation
In simple terms: Once PYY binds, the receptor switches on signals inside the cell.
Binding of PYY to its receptor initiates intracellular signaling. For the Y1 receptor, activation by PYY leads to mitogen-activated protein kinase (MAPK) activation and proliferation in gut epithelial cells via the epidermal growth factor receptor (EGFR). This demonstrates that peptide YY receptor activity can couple to growth-related signaling pathways, not only to acute secretory responses. The ability to activate MAPK and drive proliferation highlights the functional breadth of the GO:0001601 annotation in epithelial cell biology.
Regulation of receptor gene expression
In simple terms: Cells can tune how much receptor they make.
The activity of PYY receptors can be regulated at the level of receptor gene expression. Retinoic acid acts as a negative regulator of the neuropeptide Y/peptide YY Y1 receptor gene in SK-N-MC cells, showing that transcriptional control modulates receptor availability. This type of regulation can influence the overall capacity of a cell to respond to PYY and therefore shapes the functional output of GO:0001601. Such regulatory mechanisms are relevant when interpreting changes in receptor activity across different cell types or differentiation states.
Therapeutic modulation with dual agonists
In simple terms: Scientists are designing drugs that hit this receptor together with related targets.
The design of a GLP-1/PYY dual-acting agonist illustrates how peptide YY receptor activity can be engaged therapeutically. Such molecules are engineered to combine with PYY receptors and initiate signaling while also activating GLP-1 receptors, aiming to leverage complementary metabolic effects. This approach underscores the druggability of GO:0001601 and its relevance to metabolic disease research. It also provides a template for studying how receptor activity can be tuned by ligand engineering.
Key Genes Involved in GO:0001601 peptide YY receptor activity
The following genes and proteins are directly implicated in peptide YY receptor activity, its ligand biology, and downstream signaling.
| Gene | Major Role | Research Relevance |
|---|---|---|
| NPY2R | Y2 receptor that binds PYY and mediates peptide YY receptor activity | Primary receptor for PYY(3-36); mutagenesis reveals subtype selectivity |
| NPY1R | Y1 receptor that can bind PYY and activate MAPK/EGFR signaling | Links PYY signaling to gut epithelial proliferation |
| PYY | Ligand that combines with PYY receptors to initiate cell activity | Structure-activity studies define C-terminal binding determinants |
| EGFR | Mediates Y1 receptor-dependent MAPK activation and proliferation | Downstream effector of PYY receptor signaling in gut epithelium |
| MAPK1 | Mitogen-activated protein kinase downstream of PYY receptor activation | Readout of proliferative signaling |
| MAPK3 | Mitogen-activated protein kinase downstream of PYY receptor activation | Readout of proliferative signaling |
| GCG | Proglucagon-derived peptides co-secreted with PYY from L-cells | Relevant to dual GLP-1/PYY agonist design |
| GLP1R | GLP-1 receptor co-targeted with PYY receptors in dual agonists | Therapeutic context for PYY receptor modulation |
| RARA | Retinoic acid receptor implicated in Y1 receptor gene regulation | Negative regulation of NPY1R expression |
| RARB | Retinoic acid receptor implicated in Y1 receptor gene regulation | Negative regulation of NPY1R expression |
| RARG | Retinoic acid receptor implicated in Y1 receptor gene regulation | Negative regulation of NPY1R expression |
| GNAI1 | Gi alpha subunit that can couple to Y2 receptor signaling | Potential downstream transducer of PYY receptor activity |
| GNAI2 | Gi alpha subunit that can couple to Y2 receptor signaling | Potential downstream transducer of PYY receptor activity |
| GNAI3 | Gi alpha subunit that can couple to Y2 receptor signaling | Potential downstream transducer of PYY receptor activity |
| ARRB1 | Beta-arrestin involved in G protein-coupled receptor desensitization | Potential regulator of PYY receptor signaling |
| ARRB2 | Beta-arrestin involved in G protein-coupled receptor desensitization | Potential regulator of PYY receptor signaling |
| GRK2 | G protein-coupled receptor kinase that can phosphorylate activated receptors | Potential regulator of PYY receptor desensitization |
| GRK5 | G protein-coupled receptor kinase that can phosphorylate activated receptors | Potential regulator of PYY receptor desensitization |
How Is peptide YY receptor activity Regulated?
Peptide YY receptor activity is regulated at multiple levels. Transcriptional control of receptor genes can alter the amount of receptor available to bind PYY; retinoic acid negatively regulates the neuropeptide Y/peptide YY Y1 receptor gene in SK-N-MC cells. At the protein level, receptor activity can be modulated by ligand availability and by structural determinants within the ligand, as shown by structure-activity studies of PYY analogs. Mutagenesis studies of the human Y2 receptor further indicate that specific receptor residues govern interactions with conserved ligand positions, providing a structural basis for selectivity and regulation. Downstream, receptor activation can engage MAPK and EGFR-dependent signaling, which may feed back on cellular responses. Finally, therapeutic modulation using dual-acting agonists demonstrates that receptor activity can be engaged pharmacologically.
peptide YY receptor activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| NPY2R | Obesity and feeding regulation | NPY2R knockout cell line with PYY stimulation and signaling readouts |
| NPY1R | Gut epithelial proliferation and cancer biology | NPY1R knockout or point-mutant cells treated with PYY and EGFR/MAPK assays |
| PYY | Metabolic disease and satiety regulation | PYY overexpression or analog treatment in enteroendocrine cell models |
| EGFR | Epithelial proliferation downstream of PYY receptors | EGFR knockout cells to test dependence of PYY-induced MAPK activation |
| RARA | Transcriptional regulation of Y1 receptor | Retinoic acid treatment with NPY1R reporter or knockout models |
Obesity and metabolic disease
PYY is a key regulator of feeding behavior, and its receptor activity is directly relevant to energy homeostasis. The design of GLP-1/PYY dual-acting agonists highlights the therapeutic potential of targeting peptide YY receptor activity in metabolic disease. Because PYY signaling influences satiety and gut function, dysregulation of GO:0001601 may contribute to obesity and related metabolic disorders. Researchers can use receptor binding and functional assays to evaluate how PYY analogs modulate this activity.
Gut epithelial proliferation and cancer biology
Peptide YY receptor activity can couple to proliferative signaling in gut epithelial cells. Activation of the Y1 receptor by PYY stimulates MAPK and proliferation via the epidermal growth factor receptor. This link suggests that PYY receptor signaling may contribute to epithelial growth control and potentially to cancer-related processes in the gut. Studying this axis with knockout or knock-in models can help determine whether receptor activity is causally involved in epithelial proliferation.
Neuroendocrine and gastrointestinal disorders
PYY is released from gut endocrine cells and acts on receptors in the gut and nervous system, placing GO:0001601 in the context of neuroendocrine regulation. Alterations in PYY signaling have been studied in relation to feeding regulation and gut function. The biochemical characterization of the PYY receptor as a glycoprotein from rat jejunal crypts provides a foundation for understanding receptor behavior in gastrointestinal tissues. These findings support further investigation of PYY receptor activity in gastrointestinal disorders.
From peptide YY receptor activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of NPY2R abolish PYY-induced signaling? | NPY2R knockout cell line |
| Which receptor residues determine PYY subtype selectivity? | NPY2R point-mutation knock-in |
| Can a tagged receptor be used to track PYY binding? | Tagged knock-in of NPY2R |
| Does overexpression of PYY enhance receptor activation? | PYY overexpression cell model |
| Is EGFR required for PYY-induced proliferation? | EGFR knockout with PYY treatment and MAPK readout |
| Does retinoic acid regulate Y1 receptor expression? | NPY1R reporter or knockout cells treated with retinoic acid |
How to Study the peptide YY receptor activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Radioligand binding assay | Direct binding affinity of PYY to its receptor | Receptor characterization and analog screening |
| Competition binding | Relative affinity of PYY analogs | Structure-activity studies |
| Site-directed mutagenesis | Contribution of specific residues to binding and signaling | Mapping receptor-ligand interface |
| Phospho-MAPK immunoblot | Activation of MAPK signaling | Downstream signaling readout |
| Proliferation assay | Cell growth in response to PYY | Epithelial proliferation studies |
| Reporter gene assay | Transcriptional regulation of receptor genes | Retinoic acid regulation of NPY1R |
| cAMP or calcium assay | G protein-coupled signaling output | Functional receptor activation |
| CRISPR knockout | Loss-of-function effect on receptor activity | Causal gene validation |
Receptor binding assays
Radioligand binding and competition assays are classical methods to measure peptide YY receptor activity. Solubilization of the active PYY receptor from rat jejunal crypts enabled direct biochemical characterization and binding studies. Structure-activity studies of PYY analogs used binding assays to define the C-terminal determinants of receptor interaction. These methods remain essential for quantifying affinity and for comparing receptor subtypes.
Mutagenesis and structure-function analysis
Site-directed mutagenesis of receptor and ligand is a powerful approach to dissect peptide YY receptor activity. Mutagenesis of the human Y2 receptor revealed differences from Y1 in interactions with highly conserved ligand positions. Structure-activity studies of PYY(22-36) analogs identified residues required for antisecretory activity in rat jejunum. Combining mutagenesis with binding and functional assays provides a detailed map of the receptor-ligand interface.
Downstream signaling readouts
Measuring downstream signaling is critical to confirm that receptor binding initiates a change in cell activity. Activation of the Y1 receptor by PYY stimulates MAPK and proliferation in gut epithelial cells via EGFR. Researchers can use phospho-MAPK immunoblotting, proliferation assays, and EGFR inhibition to test pathway dependence. These readouts connect the molecular function of GO:0001601 to cellular outcomes.
Transcriptional and pharmacological modulation
Receptor activity can be studied by manipulating receptor gene expression or by using pharmacological agonists. Retinoic acid negatively regulates the Y1 receptor gene in SK-N-MC cells, providing a tool to modulate receptor levels. Dual-acting GLP-1/PYY agonists demonstrate pharmacological engagement of PYY receptor activity. Combining transcriptional and pharmacological approaches allows researchers to test how receptor abundance and ligand properties shape signaling.
How CRISPR Can Be Used to Study GO:0001601 peptide YY receptor activity
Knockout
CRISPR knockout of NPY2R or NPY1R can be used to test whether these receptors are required for PYY-induced signaling. Loss-of-function models help establish causality between receptor activity and downstream outcomes such as MAPK activation or proliferation. Knockout cells can be challenged with PYY or PYY analogs to measure residual binding and functional responses.
Point Mutation
Point mutations in receptor genes can be introduced to dissect the molecular determinants of peptide YY receptor activity. Mutagenesis studies of the human Y2 receptor identified residues that interact with conserved ligand positions and distinguish Y2 from Y1. CRISPR-based point mutation allows these findings to be tested in endogenous genomic context, providing more physiologically relevant data.
Knock-in
Knock-in of tagged receptors or reporter cassettes enables tracking of receptor expression, localization, and binding in live cells. Tagged NPY2R knock-in models can be used to monitor receptor trafficking and ligand-induced internalization. Knock-in of disease-associated or species-specific variants can also reveal how sequence changes alter PYY receptor activity.
Overexpression
Overexpression of PYY or its receptors can amplify signaling for biochemical and pharmacological studies. PYY overexpression models can be used to test whether increased ligand availability enhances receptor activation and downstream responses. Overexpression of NPY2R or NPY1R can facilitate binding assays and structure-activity studies by increasing receptor density.
How EDITGENE Supports peptide YY receptor activity Research
Researchers studying peptide YY receptor activity-related genes often need to determine whether a candidate gene is causally involved in ligand binding, receptor signaling, or downstream cellular responses. EDITGENE provides CRISPR-based cell model services that enable precise manipulation of NPY2R, NPY1R, PYY, and related pathway genes, allowing functional hypotheses to be tested in relevant cellular contexts.
Contact EDITGENE today to design your custom CRISPR model for peptide YY receptor activity research.
Frequently Asked Questions About peptide YY receptor activity
What is peptide YY receptor activity?
Peptide YY receptor activity (GO:0001601) is a molecular function defined as combining with gut peptide YY to initiate a change in cell activity. It is mediated primarily by neuropeptide Y receptors such as NPY2R.
What genes are involved in peptide YY receptor activity?
Key genes include NPY2R, which encodes the Y2 receptor, and NPY1R, which encodes the Y1 receptor that can also respond to PYY. The ligand itself is encoded by PYY.
Which receptor binds peptide YY?
The Y2 receptor (NPY2R) is a principal receptor for peptide YY and its truncated form PYY(3-36). The Y1 receptor (NPY1R) can also bind PYY and activate downstream signaling.
What is the GO ID for peptide YY receptor activity?
The Gene Ontology ID is GO:0001601, and it belongs to the molecular_function ontology.
How is peptide YY receptor activity studied?
It is studied using radioligand binding assays, mutagenesis, downstream signaling readouts such as MAPK activation, and CRISPR-based knockout or knock-in models.
Does peptide YY receptor activity regulate feeding?
Yes, PYY is a key regulator of feeding behavior, and its receptor activity is relevant to energy homeostasis and satiety.
Can peptide YY receptor activity be targeted for obesity treatment?
Dual-acting GLP-1/PYY receptor agonists have been designed, indicating that peptide YY receptor activity is a viable therapeutic target for metabolic disease.
What signaling pathways are activated by peptide YY receptors?
PYY receptor activation can stimulate MAPK and proliferation in gut epithelial cells via the epidermal growth factor receptor.
How is the PYY receptor regulated?
The Y1 receptor gene is negatively regulated by retinoic acid in SK-N-MC cells, showing transcriptional control of receptor availability.
What experimental models are used for peptide YY receptor research?
Common models include receptor knockout cell lines, point-mutation knock-ins, tagged receptor knock-ins, and PYY overexpression cells, combined with binding and signaling assays.
Conclusion
GO:0001601 peptide YY receptor activity defines the molecular function by which PYY engages its receptors to initiate cellular changes. This activity is mediated primarily by neuropeptide Y receptors such as NPY2R and is central to feeding regulation, gut epithelial signaling, and metabolic disease biology. Structure-activity and mutagenesis studies have provided detailed insight into the ligand-receptor interface, while dual-acting agonists highlight its therapeutic potential. For researchers, precise functional annotation and robust experimental models are essential to dissect how PYY receptor activity contributes to physiology and disease. CRISPR-based knockout, point-mutation, knock-in, and overexpression models, combined with binding and signaling assays, offer a powerful toolkit to test causal roles of receptors and downstream effectors. EDITGENE supports these efforts with tailored cell model generation and screening services.
References
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