GO:0031891 type 1 vasoactive intestinal polypeptide receptor binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0031891 describes the molecular function of binding to the type 1 vasoactive intestinal polypeptide receptor (VPAC1), a class B G protein-coupled receptor.
• VPAC1 is the predominant VIP receptor subtype in several tissues, including rat prostate membranes, and mediates VIP/PACAP signaling.
• The term is synonymous with type 2 PACAP receptor binding because VPAC1 binds both VIP and PACAP with high affinity.
• VPAC1 binding is regulated by synaptic scaffolding molecule (S-SCAM) in epithelial cells, linking receptor function to cell polarity and junctional complexes.
• The rat VPAC1 gene contains a negative glucocorticoid response element, indicating steroid hormone regulation of receptor expression.
• VIP neuron-ILC3 circuits involving VPAC1 binding regulate the intestinal barrier, highlighting its role in mucosal immunity.
Description
GO:0031891, type 1 vasoactive intestinal polypeptide receptor binding, is a molecular function term that describes the binding of a ligand to the type 1 vasoactive intestinal polypeptide receptor (VPAC1). VPAC1 is a class B G protein-coupled receptor that is activated by vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP). This binding event is the first step in a signaling cascade that influences diverse physiological processes, including exocrine secretion, smooth muscle relaxation, and immune regulation. Researchers study this term to understand how extracellular signals are decoded by VPAC1 and how dysregulation contributes to disease. The receptor is widely expressed in the central nervous system, gastrointestinal tract, and immune cells, making it a target for therapeutic development. The QuickGO definition states that this function is "Binding to a type 1 vasoactive intestinal polypeptide receptor," and its synonym "type 2 PACAP receptor binding" reflects the fact that VPAC1 also serves as a receptor for PACAP.
type 1 vasoactive intestinal polypeptide receptor binding At A Glance
| GO ID | GO:0031891 |
|---|---|
| GO term | type 1 vasoactive intestinal polypeptide receptor binding |
| Ontology | molecular_function |
| Synonym | type 2 PACAP receptor binding |
| Definition | Binding to a type 1 vasoactive intestinal polypeptide receptor. |
| Major function | Ligand binding to VPAC1, initiating VIP/PACAP signaling. |
| Receptor family | Class B G protein-coupled receptor (VPAC1). |
| Primary ligands | VIP and PACAP. |
| Regulatory example | Negative glucocorticoid response element in rat VPAC1 gene. |
What Is GO:0031891?
In our own words, GO:0031891 refers to the molecular action of a ligand physically interacting with the type 1 vasoactive intestinal polypeptide receptor (VPAC1). This binding is non-covalent and specific, enabling the receptor to change conformation and initiate intracellular signaling. The term is used in annotation to capture the ligand-receptor interaction step, distinct from downstream signal transduction. Because VPAC1 binds both VIP and PACAP, the synonym type 2 PACAP receptor binding is also used.
Why Is type 1 vasoactive intestinal polypeptide receptor binding Important in Cell Biology?
Understanding GO:0031891 is important because VPAC1-mediated binding is a key control point for VIP and PACAP signaling, which regulates intestinal barrier function, immune responses, and neuronal activity. Dysregulated VPAC1 binding has been implicated in inflammatory conditions and cancer, and the receptor is a potential drug target. Moreover, the interaction of VPAC1 with scaffolding proteins like S-SCAM reveals how binding is coupled to epithelial cell architecture. Thus, studying this molecular function provides insight into both normal physiology and disease mechanisms.
• VPAC1 is the predominant VIP receptor subtype in rat prostate membranes, indicating tissue-specific roles.
• VPAC1 binds both VIP and PACAP, integrating two major neuropeptide signals.
• The receptor is regulated by glucocorticoids via a negative response element in its gene.
• S-SCAM binds and regulates VPAC1 in epithelial cells, affecting cell junctions.
• VIP neuron-ILC3 circuits that depend on VPAC1 binding regulate the intestinal barrier.
• VPAC1 is a potential target in malignant tumors, as TRP channels and VIP signaling intersect.
• Altered VPAC1 function may contribute to critical illness, as discussed in intensive care medicine.
• The pharmacophore for VPAC1 has been elucidated, aiding drug design.
• PACAP analogs selective for PAC1 versus VPAC1 help dissect receptor-specific functions.
• VPAC1 binding is a model for class B GPCR activation and allosteric modulation.
Molecular Mechanism of type 1 vasoactive intestinal polypeptide receptor binding
Ligand recognition and binding pocket
In simple terms: The ligand docks into a pocket on the receptor like a key in a lock.
VPAC1 recognizes VIP and PACAP through its large extracellular N-terminal domain and extracellular loops. The pharmacophore of VIP for VPAC1 has been characterized, revealing key residues that determine binding affinity and selectivity. PACAP analogs with conformational restrictions show that the receptor can discriminate between closely related peptides.
Conformational change and receptor activation
In simple terms: Binding causes the receptor to change shape and turn on signaling inside the cell.
Upon ligand binding, VPAC1 undergoes conformational changes typical of class B GPCRs, leading to G protein coupling and activation of adenylyl cyclase. This step is distinct from the binding event itself but is initiated by it.
Regulation by scaffolding proteins
In simple terms: Other proteins can hold the receptor in place and control its activity.
Synaptic scaffolding molecule (S-SCAM) binds to VPAC1 in epithelial cells and regulates its function, linking the receptor to cell adhesion and polarity complexes. This interaction modulates the availability of VPAC1 for ligand binding.
Transcriptional regulation of receptor expression
In simple terms: The amount of receptor in a cell is controlled by hormones and other signals.
The rat VPAC1 gene contains a negative glucocorticoid response element, meaning glucocorticoids can reduce receptor expression. This regulation affects how much receptor is available for ligand binding.
Physiological context of binding
In simple terms: Where and when the receptor is present determines what binding does in the body.
VPAC1 is expressed in the prostate, intestinal immune cells, and neurons. In the intestine, VIP neuron-ILC3 circuits depend on VPAC1 binding to maintain the barrier. In the prostate, VPAC1 is the predominant subtype, suggesting a role in prostate physiology.
Key Genes Involved in GO:0031891 type 1 vasoactive intestinal polypeptide receptor binding
The following genes and proteins are directly involved in or regulate type 1 vasoactive intestinal polypeptide receptor binding.
| Gene | Major Role | Research Relevance |
|---|---|---|
| VIP | Ligand for VPAC1; binds and activates the receptor | Key agonist in neuroimmune and intestinal studies |
| ADCYAP1 | Encodes PACAP, a ligand that also binds VPAC1 | PACAP analogs used to study receptor selectivity |
| VIPR1 | Encodes the type 1 VIP receptor (VPAC1) | Primary receptor for this GO term; target for mutagenesis |
| VIPR2 | Encodes VPAC2, a related receptor | Comparison of pharmacophores between VPAC1 and VPAC2 |
| ADCYAP1R1 | Encodes PAC1 receptor, which binds PACAP | Selectivity studies with PACAP analogs |
| S-SCAM (MAGI2) | Scaffolding protein that binds and regulates VPAC1 | Regulates receptor in epithelial cells |
| NR3C1 | Glucocorticoid receptor, mediates negative regulation of VIPR1 | Glucocorticoid response element in VIPR1 gene |
| GNA S | G protein alpha subunit that couples to VPAC1 | Downstream signaling after binding |
| TRP channels | Modulated by VIP signaling in tumors | Potential crosstalk in cancer |
| ILC3 | Innate lymphoid cells responding to VIP neuron signals | Intestinal barrier regulation |
| VIP neurons | Neurons releasing VIP to act on VPAC1 | Feeding-dependent circuits |
| Prostate cells | Express VPAC1 predominantly | Tissue-specific expression |
| Epithelial cells | Site of S-SCAM regulation of VPAC1 | Cell polarity studies |
| PACAP | Neuropeptide ligand for VPAC1 | Structure-function studies |
| VIP | Neuropeptide ligand for VPAC1 | Pharmacophore elucidation |
| VPAC1 | Receptor protein itself | Binding assays and mutagenesis |
How Is type 1 vasoactive intestinal polypeptide receptor binding Regulated?
The binding function of VPAC1 is regulated at multiple levels. Transcriptionally, the rat VIPR1 gene contains a negative glucocorticoid response element, so glucocorticoids can downregulate receptor expression. At the protein level, S-SCAM binds to VPAC1 and regulates its localization and function in epithelial cells. Additionally, the availability of ligands VIP and PACAP is controlled by neuronal activity and feeding状态, as shown in VIP neuron-ILC3 circuits. These regulatory layers ensure that VPAC1 binding is context-dependent.
type 1 vasoactive intestinal polypeptide receptor binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| VIPR1 | Intestinal barrier dysfunction | Intestinal epithelial cell KO of VIPR1 |
| VIP | Inflammatory bowel disease | VIP neuron-specific KO in mice |
| VIPR1 | Prostate cancer | Prostate cancer cell lines with VPAC1 overexpression |
| TRP channels | Malignant tumors | TRP channel KO in cancer cells |
| VIPR1 | Critical illness | Endotoxemia models in rodents |
Intestinal barrier dysfunction and inflammation
VIP neuron-ILC3 circuits that require VPAC1 binding regulate the intestinal barrier. Disruption of this circuit may lead to barrier dysfunction and inflammation. This highlights the importance of VPAC1 binding in mucosal immunity.
Cancer and tumor progression
VIP and PACAP signaling through VPAC1 has been implicated in malignant tumors, with TRP family channels modulating these effects. VPAC1 binding may influence tumor cell proliferation and survival, making it a potential therapeutic target.
Prostate pathophysiology
VPAC1 is the predominant VIP receptor subtype in rat prostate membranes, suggesting a role in prostate function and disease. Altered VIP signaling could contribute to prostate disorders.
Critical illness and systemic inflammation
VIP signaling has been discussed in the context of intensive care and emergency medicine, where it may influence hemodynamics and inflammation. VPAC1 binding could be a mediator in these settings.
From type 1 vasoactive intestinal polypeptide receptor binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does VPAC1 binding mediate intestinal barrier protection? | VIPR1 knockout mice |
| What is the pharmacophore of VIP for VPAC1? | Site-directed mutagenesis of VIPR1 |
| How does S-SCAM regulate VPAC1? | S-SCAM knockdown in epithelial cells |
| Does glucocorticoid regulate VPAC1 expression? | Glucocorticoid treatment in rat prostate cells |
| Can PACAP analogs selectively activate VPAC1? | Conformationally restricted PACAP analogs |
| Is VPAC1 involved in tumor growth? | Xenograft models with VPAC1 overexpression |
How to Study the type 1 vasoactive intestinal polypeptide receptor binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Radioligand binding | Ligand affinity and receptor density | Pharmacophore studies |
| Site-directed mutagenesis | Effect of specific residues on binding | Mapping interaction sites |
| Co-immunoprecipitation | Protein-protein interactions | S-SCAM-VPAC1 interaction |
| Luciferase reporter | Transcriptional activity | Glucocorticoid regulation of VIPR1 |
| cAMP assay | Downstream signaling after binding | Functional activation |
| Immunofluorescence | Receptor localization | Epithelial cell studies |
| qPCR | Receptor mRNA levels | Expression regulation |
| Flow cytometry | Cell surface receptor expression | Immune cell studies |
Receptor binding assays
Radioligand binding assays using 125I-VIP or 125I-PACAP can measure the affinity and kinetics of ligand binding to VPAC1. These assays are used to characterize pharmacophores and test analogs.
Site-directed mutagenesis
Mutating residues in VIPR1 or in the ligand helps identify key determinants of binding specificity. This approach has been used to elucidate the VIP pharmacophore for VPAC1.
Co-immunoprecipitation and pull-down
To study protein-protein interactions such as S-SCAM binding to VPAC1, co-immunoprecipitation from epithelial cell lysates can be used.
Transcriptional reporter assays
The negative glucocorticoid response element in the VIPR1 gene can be studied using luciferase reporter constructs and glucocorticoid treatment.
How CRISPR Can Be Used to Study GO:0031891 type 1 vasoactive intestinal polypeptide receptor binding
Knockout
CRISPR knockout of VIPR1 can eliminate VPAC1 binding, allowing researchers to test its role in intestinal barrier function or prostate biology. Knockout models are essential for loss-of-function studies.
Point Mutation
Introducing point mutations in VIPR1 can dissect the binding pocket and identify residues critical for VIP or PACAP recognition. This approach complements pharmacophore studies.
Knock-in
Knock-in of tagged VPAC1 (e.g., GFP or HA) enables visualization and purification of the receptor for interaction studies. Knock-in of human VIPR1 into mouse models can humanize the receptor for drug testing.
Overexpression
Overexpression of VIPR1 in cell lines can enhance binding signals for biochemical assays or create disease models. It is useful when endogenous receptor levels are low.
How EDITGENE Supports type 1 vasoactive intestinal polypeptide receptor binding Research
Researchers studying type 1 vasoactive intestinal polypeptide receptor binding-related genes often need to determine whether a candidate gene is causally involved in receptor function, signaling, or disease. EDITGENE provides a comprehensive suite of CRISPR services to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for type 1 vasoactive intestinal polypeptide receptor binding research.
Frequently Asked Questions About type 1 vasoactive intestinal polypeptide receptor binding
What is GO:0031891?
GO:0031891 is the molecular function of binding to the type 1 vasoactive intestinal polypeptide receptor (VPAC1).
What genes are involved in type 1 vasoactive intestinal polypeptide receptor binding?
Key genes include VIPR1 (encoding VPAC1), VIP, ADCYAP1 (PACAP), and MAGI2 (S-SCAM).
What is the synonym for GO:0031891?
The synonym is type 2 PACAP receptor binding.
Which ligands bind to VPAC1?
VIP and PACAP are the primary ligands that bind VPAC1.
How is VPAC1 binding regulated?
It is regulated by glucocorticoids via a negative response element and by scaffolding protein S-SCAM.
What diseases are associated with VPAC1 binding?
Intestinal barrier dysfunction, cancer, and prostate disorders have been linked to VPAC1 signaling.
What research methods study VPAC1 binding?
Radioligand binding, mutagenesis, co-immunoprecipitation, and reporter assays are commonly used.
Can CRISPR be used to study VPAC1 binding?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are valuable for dissecting VPAC1 function.
What is the role of S-SCAM in VPAC1 binding?
S-SCAM binds to VPAC1 and regulates its function in epithelial cells.
Is VPAC1 the same as VPAC2?
No, VPAC1 is encoded by VIPR1 and VPAC2 by VIPR2; they have different pharmacophores.
Conclusion
GO:0031891, type 1 vasoactive intestinal polypeptide receptor binding, is a fundamental molecular function that mediates VIP and PACAP signaling. Its regulation by glucocorticoids and scaffolding proteins, and its role in intestinal immunity and cancer, make it a compelling research target. Understanding this binding event at the structural and functional level can inform therapeutic development. EDITGENE offers advanced CRISPR tools to study VPAC1 binding in relevant models.
References
- 1. Talbot J et al.. 2020. Feeding-dependent VIP neuron-ILC3 circuit regulates the intestinal barrier.. Nature 579(7800):575-580 PMID: 32050257
- 2. Zhong T et al.. 2022. The regulatory and modulatory roles of TRP family channels in malignant tumors and relevant therapeutic strategies.. Acta Pharm Sin B 12(4):1761-1780 PMID: 35847486
- 3. Bateman RM et al.. 2016. 36th International Symposium on Intensive Care and Emergency Medicine : Brussels, Belgium. 15-18 March 2016.. Crit Care 20(Suppl 2):94 PMID: 27885969
- 4. Juarranz MG et al.. 1999. Vasoactive intestinal polypeptide receptor VPAC(1) subtype is predominant in rat prostate membranes.. Prostate 41(1):1-6 PMID: 10440869
- 5. Igarashi H et al.. 2002. Elucidation of the vasoactive intestinal peptide pharmacophore for VPAC(2) receptors in human and rat and comparison to the pharmacophore for VPAC(1) receptors.. J Pharmacol Exp Ther 303(2):445-60 PMID: 12388623
- 6. Ramos-Álvarez I et al.. 2015. A structure-function study of PACAP using conformationally restricted analogs: Identification of PAC1 receptor-selective PACAP agonists.. Peptides 66:26-42 PMID: 25698233
- 7. Pei L. 1996. Identification of a negative glucocorticoid response element in the rat type 1 vasoactive intestinal polypeptide receptor gene.. J Biol Chem 271(34):20879-84 PMID: 8702844
- 8. Gee HY et al.. 2009. Synaptic scaffolding molecule binds to and regulates vasoactive intestinal polypeptide type-1 receptor in epithelial cells.. Gastroenterology 137(2):607-17, 617.e1-4 PMID: 19642226
