TACR1 (Tachykinin Receptor 1): A Key Mediator of Neurogenic Inflammation and Pain
Comprehensive genomic and functional overview of TACR1, encoding the NK1 receptor, with implications for pain signaling, inflammation, and psychiatric disorders.
Gene Information Card
| Symbol | TACR1 |
|---|---|
| Full Name | Tachykinin Receptor 1 |
| Gene Type | protein coding |
| Chromosomal Location | 2p12 |
| NCBI Gene ID | 6869 ncbi.nlm.nih.gov/gene/6869 |
| Ensembl ID | ENSG00000115353 |
| UniProt ID | P25103 |
| OMIM ID | 162450 |
| HGNC ID | 11526 |
| Aliases | NK1R, NK-1 receptor, SPR, TAC1R |
Description
The TACR1 gene encodes the tachykinin receptor 1 (NK1R), a G protein-coupled receptor that belongs to the tachykinin receptor family. This receptor is the primary target for the neuropeptide substance P (SP), as well as neurokinin A (NKA) and neurokinin B (NKB), with a higher affinity for substance P. TACR1 is widely expressed in the central and peripheral nervous systems and in various peripheral tissues, where it mediates a range of physiological processes including pain transmission, neurogenic inflammation, smooth muscle contraction, and emotional behavior. Activation of NK1R triggers intracellular signaling cascades, primarily through the Gq/11 family of G proteins, leading to the activation of phospholipase C and subsequent increases in intracellular calcium. Given its central role in pain and inflammation, TACR1 is a significant therapeutic target for the development of analgesics, anti-inflammatory drugs, and treatments for psychiatric conditions such as depression and anxiety.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Disease | Mechanism | Evidence |
| Major Depressive Disorder (MDD) | Dysregulation of substance P/NK1R signaling in brain regions involved in mood regulation (e.g., amygdala, hippocampus) is implicated in the pathophysiology of depression. Antagonists of NK1R have been investigated as potential antidepressants. | Genetic association studies have linked TACR1 polymorphisms to altered risk for MDD. Clinical trials with NK1R antagonists (e.g., aprepitant) have shown mixed but promising results in some patient subgroups. (Source: OMIM, PubMed) |
| Irritable Bowel Syndrome (IBS) | Increased expression and sensitivity of NK1R in the gut contribute to visceral hypersensitivity, altered motility, and increased secretion, leading to symptoms of IBS. Substance P-mediated neurogenic inflammation is a key mechanism. | Preclinical and clinical studies demonstrate that NK1R antagonists can reduce visceral pain and improve bowel function in IBS patients. (Source: PubMed, NCBI) |
| Chemotherapy-Induced Nausea and Vomiting (CINV) | Substance P released in the brainstem (nucleus tractus solitarius) activates NK1R to trigger the vomiting reflex. NK1R antagonists are effective in preventing both acute and delayed phases of CINV. | Large clinical trials have established the efficacy of NK1R antagonists (e.g., aprepitant, fosaprepitant) as a standard of care in CINV prophylaxis. (Source: PubMed, NCBI) |
| Asthma and Airway Inflammation | Substance P and NK1R signaling contribute to neurogenic inflammation in the airways, causing bronchoconstriction, mucus secretion, and plasma extravasation, which are features of asthma. | Animal models of asthma show that NK1R antagonists reduce airway hyperresponsiveness and inflammation. Human studies have shown increased NK1R expression in the airways of asthmatic patients. (Source: PubMed, NCBI) |
| Chronic Pain Conditions (e.g., Osteoarthritis, Neuropathic Pain) | Elevated substance P levels and NK1R expression in peripheral tissues and the spinal cord contribute to chronic pain states by sensitizing nociceptors and enhancing excitatory neurotransmission. | Preclinical studies demonstrate that NK1R antagonists have analgesic effects in various pain models. Clinical trials for chronic pain have shown limited efficacy as monotherapy, but combination approaches are being explored. (Source: PubMed, NCBI) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Tissue | nTPM | Level |
| Cerebral Cortex | 12.3 | Medium |
| Basal Ganglia | 8.5 | Low |
| Hypothalamus | 15.1 | Medium |
| Spinal Cord | 20.4 | Medium |
| Gastrointestinal Tract (Stomach, Small Intestine, Colon) | 5.2 - 9.8 | Low |
| Lung | 4.1 | Low |
| Urinary Bladder | 6.3 | Low |
| Skin | 2.5 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Cell Line | nTPM | Notes |
| SH-SY5Y (Neuroblastoma) | 18.7 | Neuronal-like cell line, used as a model for neurobiology and pain research. |
| U-87 MG (Glioblastoma) | 9.2 | Astrocytoma cell line, expresses NK1R, implicated in glioma progression. |
| IMR-90 (Lung Fibroblast) | 3.4 | Low expression, but can be upregulated under inflammatory conditions. |
| A549 (Lung Carcinoma) | 2.1 | Low basal expression; may be involved in tumor-associated inflammation. |
| HCT 116 (Colorectal Carcinoma) | 1.8 | Low expression; role in gut motility and inflammation is context-dependent. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| Variant | Type | Frequency | Effect |
| rs3771829 (Intronic) | SNV | Minor allele frequency (MAF) ~0.2-0.4 in global populations | Associated with altered risk for major depressive disorder and response to antidepressant treatment in some studies. |
| rs6715729 (3' UTR) | SNV | MAF ~0.1-0.3 | Potential impact on mRNA stability or microRNA binding, possibly affecting receptor expression levels. |
| rs1477157 (Missense, p.Leu322Pro) | SNV | Rare (MAF < 0.01) | Located in a transmembrane domain; may alter receptor conformation and ligand binding affinity, potentially affecting signaling efficacy. |
| rs1041801 (Synonymous, p.Pro387Pro) | SNV | MAF ~0.3-0.5 | No change in amino acid sequence; may affect mRNA splicing or stability, but functional significance is unclear. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in TACR1 are rare and not well-documented in large population databases. However, complete knockout of the TACR1 gene in mice results in reduced pain sensitivity, decreased neurogenic inflammation, and altered emotional behavior. In humans, rare non-synonymous variants that disrupt receptor binding or G-protein coupling would be predicted to cause a loss of function, potentially leading to reduced pain perception but also possible effects on mood and immune function.
Gain of Function (GOF)
Gain-of-function mutations in TACR1 are also rare. A constitutively active receptor or one with increased affinity for substance P could lead to heightened and prolonged signaling. This would be predicted to result in increased pain sensitivity, enhanced neurogenic inflammation, and potentially contribute to chronic inflammatory conditions. No specific gain-of-function mutations have been definitively characterized in human disease, but they are a theoretical possibility.
Dominant Negative (DN)
Given that TACR1 functions as a monomeric GPCR, a dominant-negative effect is less likely. However, if a mutant receptor could form non-functional heterodimers with the wild-type receptor or sequester essential G proteins, it could exert a dominant-negative effect. This has not been demonstrated for TACR1 in a physiological context.
View complete mutation data：
Gene Ontology (GO)
| • G protein-coupled receptor activity | • substance P receptor activity |
| • tachykinin receptor activity | • peptide binding |
| • signal transducer activity | • plasma membrane |
| • integral component of plasma membrane | • cell surface receptor signaling pathway |
| • G protein-coupled receptor signaling pathway | • phospholipase C-activating G protein-coupled receptor signaling pathway |
| • chemical synaptic transmission | • inflammatory response |
| • response to pain | • positive regulation of cytosolic calcium ion concentration |
| • smooth muscle contraction |
Pathways
• Neuroactive ligand-receptor interaction
• Calcium signaling pathway
• G alpha (q) signalling events
• Substance P-mediated signaling pathway
• Inflammatory mediator regulation of TRP channels
• Regulation of lipolysis in adipocytes
Protein Summary
The TACR1 protein, also known as the NK1 receptor (NK1R), is a 407-amino acid G protein-coupled receptor with seven transmembrane domains. It is a member of the rhodopsin-like GPCR family. The receptor has a large extracellular N-terminus and an intracellular C-terminus. The ligand-binding pocket is formed by the transmembrane helices, with the extracellular loops contributing to ligand selectivity. Substance P binds with high affinity, while neurokinin A and B bind with lower affinity. Upon agonist binding, the receptor undergoes a conformational change, activating heterotrimeric G proteins of the Gq/11 family. This leads to the activation of phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 triggers the release of calcium from intracellular stores, while DAG activates protein kinase C (PKC). These events lead to various cellular responses, including smooth muscle contraction, neuronal excitation, and the release of inflammatory mediators. The receptor is also subject to desensitization and internalization upon prolonged agonist exposure, which is mediated by G protein-coupled receptor kinases (GRKs) and arrestins.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| TACR1 Knockout HEK293 Cell Line | EDC90448 | Human | 6869 | Details Get a Quote |
| TACR1 Knockout HeLa Cell Line | EDJ-KQ54607 | Human | 6869 | Details Get a Quote |
| TACR1 Knockout A-549 Cell Line | EDJ-KQ63087 | Human | 6869 | Details Get a Quote |
| TACR1 Knockout HCT 116 Cell Line | EDJ-KQ71560 | Human | 6869 | Details Get a Quote |
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