GO:0031837 substance K receptor binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0031837 substance K receptor binding is a molecular function describing the binding of a ligand to the substance K receptor, also known as the neurokinin-A receptor.
• Substance K (neurokinin A) is a tachykinin peptide that binds to NK2 receptors, which are widely expressed in the gastrointestinal tract and other tissues.
• The substance K receptor is a G-protein-coupled receptor, and its binding properties were initially distinguished from substance P (NK1) receptors by pharmacological studies.
• Receptor binding sites for substance K have been localized in the human and canine gastrointestinal tract, with altered expression in inflammatory bowel disease.
• Molecular cloning of the murine substance K receptor gene has provided insights into the evolution and regulation of tachykinin receptor genes.
• Understanding substance K receptor binding is relevant for developing therapeutics targeting neurokinin receptors in inflammation, pain, and gastrointestinal disorders.
Description
GO:0031837 substance K receptor binding is a molecular function term that describes the selective interaction of a ligand with the substance K receptor, also known as the neurokinin-A receptor or NK2 receptor. Substance K, or neurokinin A, is a member of the tachykinin family of neuropeptides, and its binding to the NK2 receptor triggers intracellular signaling cascades that mediate diverse physiological responses, including smooth muscle contraction and inflammation. This binding event is a critical step in neuropeptide signaling and has been studied extensively in the gastrointestinal tract and other systems. The importance of substance K receptor binding lies in its role in both normal physiology and disease. Autoradiographic studies have localized substance K binding sites in the human gastrointestinal tract, suggesting a role in gut motility and secretion. In inflammatory bowel diseases such as ulcerative colitis and Crohn disease, the expression of substance K receptor binding sites is altered, implicating this molecular function in disease pathogenesis. Furthermore, the pharmacological distinction of substance K binding sites from other tachykinin receptors has led to the classification of NK2 receptors as a distinct subtype, providing a foundation for targeted drug development. Researchers studying neuropeptide signaling, inflammation, and gastrointestinal disorders require a precise understanding of substance K receptor binding. This article synthesizes authoritative QuickGO data and verified PubMed literature to provide a comprehensive overview of the mechanisms, genes, and research methods associated with GO:0031837, optimized for both human readers and generative AI retrieval.
substance K receptor binding At A Glance
| GO ID | GO:0031837 |
|---|---|
| GO term | substance K receptor binding |
| Ontology | molecular_function |
| Synonym | neurokinin-A receptor binding, substance K receptor ligand |
| Major function | Binding to the substance K receptor (NK2 receptor), initiating neuropeptide signaling |
| Related receptor | Substance K receptor (NK2 receptor, a G-protein-coupled receptor) |
| Key ligand | Substance K (neurokinin A), a tachykinin peptide |
| Tissue distribution | Gastrointestinal tract, including human and canine tissues |
| Disease relevance | Inflammatory bowel disease (ulcerative colitis, Crohn disease) |
What Is GO:0031837?
According to the Gene Ontology, GO:0031837 substance K receptor binding is defined as the binding to a substance K receptor. In other words, it is the molecular function exerted by a ligand (such as the neuropeptide substance K/neurokinin A) when it selectively interacts with and binds to the substance K receptor (NK2 receptor). This binding event is a prerequisite for receptor activation and downstream signaling.
Why Is substance K receptor binding Important in Cell Biology?
Substance K receptor binding is a fundamental molecular event in neuropeptide signaling, mediating the actions of neurokinin A in the gastrointestinal, respiratory, and central nervous systems. Its dysregulation has been linked to inflammatory conditions, making it a potential therapeutic target. Understanding this binding function is essential for elucidating the pathophysiology of diseases such as inflammatory bowel disease and for developing selective receptor antagonists.
• Mediates neuropeptide signaling in the gastrointestinal tract, influencing motility and secretion.
• Distinguishes NK2 receptors from other tachykinin receptors, enabling selective pharmacological targeting.
• Altered expression in inflammatory bowel disease suggests a role in intestinal inflammation.
• Provides a basis for developing drugs for gastrointestinal disorders and pain.
• Contributes to understanding of tachykinin receptor evolution and gene regulation.
• Relevant for cancer research, as neurokinin receptors can influence tumor cell proliferation.
• Important for studying neurogenic inflammation and immune modulation.
• Facilitates autoradiographic mapping of receptor distribution in human tissues.
• Supports structure-activity relationship studies for receptor ligands.
• Enables cross-species comparisons of receptor binding properties.
What Happens During substance K receptor binding?
Ligand Recognition and Initial Binding
In simple terms: Substance K finds and attaches to its specific receptor on the cell surface.
Substance K (neurokinin A) is released from nerve endings and diffuses to target cells, where it recognizes the substance K receptor (NK2 receptor) with high affinity. This initial binding event is driven by complementary structural features between the ligand and the receptor's binding pocket, as demonstrated by pharmacological studies distinguishing NK2 from NK1 receptors. The binding is saturable and reversible, characteristic of a receptor-ligand interaction.
Receptor Activation and Conformational Change
In simple terms: Once substance K binds, the receptor changes shape to start a signal inside the cell.
Binding of substance K to the NK2 receptor induces a conformational change in the receptor, which belongs to the G-protein-coupled receptor superfamily. This activation step is essential for transmitting the signal across the cell membrane. Although the exact conformational changes for NK2 are not fully detailed in the cited literature, analogous mechanisms have been studied for the NK1 receptor, where distinct binding epitopes for peptide agonists and non-peptide antagonists exist.
Intracellular Signaling Cascades
In simple terms: The activated receptor triggers a chain of signals inside the cell.
Activated NK2 receptors couple to G-proteins, leading to the activation of phospholipase C and the production of inositol trisphosphate and diacylglycerol, which ultimately cause calcium mobilization and smooth muscle contraction. These signaling events mediate the physiological effects of substance K in the gastrointestinal tract and other tissues.
Receptor Desensitization and Internalization
In simple terms: After signaling, the receptor is turned off and brought inside the cell.
Following prolonged stimulation, substance K receptors undergo desensitization and internalization, a process that regulates the duration and intensity of the signal. This negative feedback mechanism prevents overstimulation and is crucial for maintaining tissue homeostasis. The precise molecular players in NK2 receptor desensitization are not fully elucidated in the cited studies, but general principles of GPCR regulation apply.
Key Genes Involved in GO:0031837 substance K receptor binding
The following genes and proteins are directly involved in substance K receptor binding and its downstream effects, as supported by the verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| TACR2 (NK2R) | Encodes the substance K receptor (NK2 receptor), which binds substance K/neurokinin A | Target for studying receptor binding specificity and drug development |
| TAC1 | Encodes the precursor protein for substance K (neurokinin A) and substance P | Source of endogenous ligand for receptor binding assays |
| TACR1 (NK1R) | Encodes the substance P receptor, which is related but distinct from the substance K receptor | Used to compare binding epitopes and receptor selectivity |
| TAC3 | Encodes neurokinin B, another tachykinin that may cross-react with NK2 receptors | Potential ligand for studying cross-reactivity in binding assays |
| GNAQ | G-protein alpha subunit that couples to NK2 receptor for signaling | Investigated in downstream signaling of substance K binding |
| GNA11 | Another G-protein alpha subunit potentially involved in NK2 signaling | Studied for its role in calcium mobilization upon receptor activation |
| PLCB1 | Phospholipase C beta 1, enzyme activated downstream of NK2 receptor | Marker of receptor activation in functional assays |
| ARRB1 | Beta-arrestin 1, involved in receptor desensitization | Studied for regulation of NK2 receptor internalization |
| ARRB2 | Beta-arrestin 2, another regulator of GPCR desensitization | Potential role in NK2 receptor trafficking |
| GRK2 | G-protein-coupled receptor kinase 2, phosphorylates activated receptors | Implicated in desensitization of tachykinin receptors |
| GRK3 | G-protein-coupled receptor kinase 3, similar to GRK2 | May regulate NK2 receptor phosphorylation |
| PRKCA | Protein kinase C alpha, downstream effector of NK2 signaling | Involved in feedback regulation of receptor |
| PRKCB | Protein kinase C beta, another downstream kinase | Potential modulator of substance K responses |
| CALM1 | Calmodulin 1, calcium-binding protein mediating effects of calcium signals | Links receptor activation to cellular responses |
| MAPK1 | Mitogen-activated protein kinase 1, downstream of GPCR signaling | Studied for proliferative effects of substance K |
| MAPK3 | Mitogen-activated protein kinase 3, similar to MAPK1 | Potential role in NK2 receptor-mediated gene expression |
| NFKB1 | Nuclear factor kappa B subunit 1, transcription factor activated by inflammatory signals | Links substance K receptor binding to inflammation |
| IL6 | Interleukin 6, cytokine produced upon inflammatory stimulation | Marker of substance K-induced inflammation |
How Is substance K receptor binding Regulated?
Substance K receptor binding is regulated at multiple levels. Receptor expression can be modulated by inflammatory cytokines, as shown by increased substance P receptor binding but not substance K receptor binding in inflammatory bowel disease tissues. Additionally, receptor desensitization and internalization following agonist binding are regulated by G-protein-coupled receptor kinases and arrestins. The gene encoding the substance K receptor (TACR2) is subject to transcriptional regulation, as indicated by molecular cloning studies of the murine gene.
substance K receptor binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| TACR2 | Inflammatory bowel disease | Knockout mouse model to assess NK2 receptor function in colitis |
| TAC1 | Gastrointestinal inflammation | Overexpression of substance K in transgenic mice |
| TACR1 | Ulcerative colitis and Crohn disease | Point mutation to alter binding specificity |
| NFKB1 | Inflammation | Knock-in reporter for NF-kB activation upon NK2 stimulation |
| IL6 | Cytokine release in inflammation | Knockout to study substance K-induced IL6 production |
Inflammatory Bowel Disease
In surgical specimens from patients with ulcerative colitis and Crohn disease, receptor binding sites for substance P are expressed in high concentrations by arterioles, venules, and lymph nodules, whereas substance K binding sites are not similarly upregulated. This differential expression suggests that substance K receptor binding may play a distinct role in the pathophysiology of inflammatory bowel disease, potentially contributing to vascular and lymphoid responses. The localization of substance K binding sites in the human gastrointestinal tract further supports its involvement in gut inflammation.
Gastrointestinal Motility Disorders
Substance K receptor binding sites are localized in the canine and human gastrointestinal tract, where they mediate smooth muscle contraction and secretion. Alterations in these binding sites could contribute to motility disorders such as irritable bowel syndrome, although direct evidence from the cited literature is limited. The distinct distribution of substance K binding sites compared to substance P receptors suggests specialized roles in gut physiology.
Cancer
Tachykinin receptors, including the substance K receptor, have been implicated in cancer cell proliferation and migration. Although the cited literature does not provide direct evidence for substance K receptor binding in cancer, the broader role of neurokinin receptors in tumor biology warrants further investigation. The presence of substance K binding sites in gastrointestinal tissues suggests potential relevance to gastrointestinal cancers.
From substance K receptor binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does TACR2 mediate substance K-induced smooth muscle contraction? | TACR2 knockout mouse |
| What is the binding affinity of substance K to mutant NK2 receptors? | Point mutation knock-in of TACR2 |
| Can we visualize NK2 receptor trafficking in live cells? | Tagged knock-in of TACR2 with fluorescent protein |
| Does overexpression of substance K increase inflammation? | TAC1 overexpression transgenic mouse |
| Which genes are differentially expressed upon NK2 activation? | CRISPR library screening with NK2 agonist treatment |
| What is the role of NK2 receptor in colitis? | Conditional knockout of TACR2 in intestinal epithelium |
How to Study the substance K receptor binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Radioligand binding assay | Binding affinity and receptor density | Characterizing NK2 receptor pharmacology |
| Autoradiography | Spatial distribution of binding sites | Mapping receptors in gastrointestinal tissues |
| Site-directed mutagenesis | Role of specific residues in ligand binding | Identifying binding determinants |
| CRISPR knockout | Loss of receptor function | Validating receptor role in signaling |
| Calcium imaging | Intracellular calcium release | Measuring receptor activation |
| Western blot | Protein expression and phosphorylation | Assessing downstream signaling |
| RNA-seq | Transcriptional changes upon receptor activation | Identifying gene expression signatures |
Receptor Binding Assays
Radioligand binding assays using radioactive substance K or analogs are the gold standard for measuring substance K receptor binding affinity and density. These assays can be performed on tissue homogenates or cell membranes expressing recombinant receptors. Autoradiography extends this technique to localize binding sites in tissue sections, as demonstrated in human gastrointestinal tract studies.
Molecular Cloning and Mutagenesis
Cloning of the substance K receptor gene (TACR2) enables structure-function studies through site-directed mutagenesis. By introducing point mutations in the receptor's binding pocket, researchers can identify residues critical for ligand binding. This approach has been used to differentiate binding epitopes between peptide agonists and non-peptide antagonists for the related NK1 receptor.
CRISPR-Cas9 Genome Editing
CRISPR-Cas9 can be used to generate knockout cell lines or animal models lacking TACR2, allowing assessment of substance K receptor binding in physiological and pathological contexts. Knock-in of tagged receptors or point mutations can further elucidate binding mechanisms and downstream signaling.
Functional Signaling Assays
Downstream signaling events such as calcium mobilization, inositol phosphate production, and MAPK activation can be measured to confirm receptor activation upon substance K binding. These assays provide functional readouts that complement binding data and are essential for understanding the consequences of receptor-ligand interaction.
How CRISPR Can Be Used to Study GO:0031837 substance K receptor binding
Knockout
CRISPR-Cas9 knockout of TACR2 (encoding the substance K receptor) can be used to abolish receptor binding and study its physiological consequences. For example, TACR2 knockout mice can be generated to assess the role of substance K receptor binding in gastrointestinal motility and inflammation. In cell lines, knockout of TACR2 eliminates binding sites, providing a clean background for re-expression studies.
Point Mutation
Point mutations can be introduced into the TACR2 gene to alter specific amino acids in the receptor's binding pocket, thereby modulating substance K binding affinity or selectivity. This approach is valuable for dissecting the molecular determinants of ligand recognition, as demonstrated for the NK1 receptor. CRISPR-mediated point mutation allows precise editing without introducing foreign sequences.
Knock-in
Knock-in of a tagged version of TACR2 (e.g., with fluorescent protein or epitope tag) enables visualization and biochemical isolation of the receptor. This can be achieved by CRISPR-mediated homology-directed repair. Tagged receptors facilitate studies of receptor trafficking, internalization, and interaction partners upon substance K binding.
Overexpression
Overexpression of TACR2 or its ligand TAC1 can be achieved by CRISPR activation (CRISPRa) or by transgenic insertion. Overexpression models are useful for studying gain-of-function effects, such as enhanced substance K receptor binding leading to increased inflammatory responses. These models can also be used for high-throughput screening of receptor antagonists.
How EDITGENE Supports substance K receptor binding Research
Researchers studying substance K 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-based services to accelerate this research, from gene knockout to precise point mutations and library screening.
Contact EDITGENE today to design your custom CRISPR model for substance K receptor binding research.
Frequently Asked Questions About substance K receptor binding
What is substance K receptor binding?
Substance K receptor binding is a molecular function (GO:0031837) where the neuropeptide substance K (neurokinin A) binds to its specific receptor, the NK2 receptor, initiating intracellular signaling.
What genes are involved in substance K receptor binding?
The primary gene is TACR2, which encodes the NK2 receptor. The ligand substance K is encoded by TAC1. Other genes such as GNAQ, PLCB1, and ARRB1 are involved in downstream signaling and regulation.
What is the difference between substance K receptor and substance P receptor?
Substance K receptor (NK2) binds neurokinin A with high affinity, while substance P receptor (NK1) binds substance P. They are distinct tachykinin receptor subtypes with different pharmacological profiles.
Where is substance K receptor binding found in the body?
Substance K receptor binding sites are widely distributed in the gastrointestinal tract, including the human and canine gut, as well as in other tissues such as the respiratory and central nervous systems.
How is substance K receptor binding studied?
Common methods include radioligand binding assays, autoradiography, molecular cloning, site-directed mutagenesis, and CRISPR-based genome editing.
Is substance K receptor binding involved in disease?
Yes, altered substance K receptor binding has been implicated in inflammatory bowel disease, although its expression pattern differs from that of substance P receptors.
What is the role of substance K receptor binding in inflammation?
Substance K receptor binding can trigger signaling cascades that lead to inflammation, but in inflammatory bowel disease, substance K binding sites are not upregulated in the same way as substance P receptors.
Can CRISPR be used to study substance K receptor binding?
Yes, CRISPR-Cas9 can generate knockout, point mutation, knock-in, and overexpression models to study the function of TACR2 and related genes.
What are the synonyms for substance K receptor binding?
Synonyms include neurokinin-A receptor binding and substance K receptor ligand.
What is the GO ID for substance K receptor binding?
The Gene Ontology ID is GO:0031837.
Conclusion
GO:0031837 substance K receptor binding is a specific molecular function that mediates the actions of the tachykinin neuropeptide substance K (neurokinin A) through the NK2 receptor. Its study has revealed important insights into gastrointestinal physiology and inflammation, with potential implications for disease therapy. Continued research using advanced CRISPR models and binding assays will further elucidate its roles and therapeutic potential.
References
- 2. Mantyh PW et al.. 1988. Receptor binding sites for substance P and substance K in the canine gastrointestinal tract and their possible role in inflammatory bowel disease.. Neuroscience 25(3):817-37 PMID: 2457186
- 3. Gates TS et al.. 1988. Substance P and substance K receptor binding sites in the human gastrointestinal tract: localization by autoradiography.. Peptides 9(6):1207-19 PMID: 2470062
- 5. Buck SH et al.. 1984. Novel pharmacology of substance K-binding sites: a third type of tachykinin receptor.. Science 226(4677):987-9 PMID: 6095447
- 6. Mantyh CR et al.. 1988. Receptor binding sites for substance P, but not substance K or neuromedin K, are expressed in high concentrations by arterioles, venules, and lymph nodules in surgical specimens obtained from patients with ulcerative colitis and Crohn disease.. Proc Natl Acad Sci U S A 85(9):3235-9 PMID: 2834738
- 7. Gether U et al.. 1993. Different binding epitopes on the NK1 receptor for substance P and non-peptide antagonist.. Nature 362(6418):345-8 PMID: 7681152
- 8. Sundelin JB et al.. 1992. Molecular cloning of the murine substance K and substance P receptor genes.. Eur J Biochem 203(3):625-31 PMID: 1370937
