Affinage

TACR1

Substance-P receptor · UniProt P25103

Round 2 corrected
Length
407 aa
Mass
46.3 kDa
Annotated
2026-04-28
130 papers in source corpus 34 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TACR1 (NK-1R) is a Gq-coupled seven-transmembrane receptor for substance P and related tachykinins that transduces nociceptive, emetic, affective, and neuroinflammatory signals across central and peripheral tissues. The receptor binds peptide agonists via its N-terminal domain and first/second extracellular loops, while non-peptide antagonists occupy a distinct transmembrane pocket centered on His197 in TM5; after agonist stimulation it activates phospholipase C/PKC signaling from lipid-raft microdomains at the plasma membrane and, following clathrin/dynamin/β-arrestin–dependent endocytosis, sustains cytosolic PKC and nuclear ERK activation from endosomes to drive prolonged nociceptive excitation (PMID:1657150, PMID:8384323, PMID:15590676, PMID:28566424). Alternative splicing produces a full-length isoform that predominates in the brain and supports high-affinity binding, Ca²⁺ mobilization, and receptor internalization, and a truncated isoform lacking 96 C-terminal residues that predominates in peripheral tissues and monocytes and signals through ERK2 and CCR5 crosstalk rather than canonical Ca²⁺ pathways (PMID:1310144, PMID:18835883, PMID:12752772). Genetic ablation or pharmacological blockade of NK1R abolishes central sensitization and wind-up in spinal pain circuits, suppresses emesis, reduces alcohol reward, and produces antidepressant-like effects by elevating prefrontal noradrenergic and dopaminergic tone, while defined Tacr1-expressing spinoparabrachial and RVM circuits selectively mediate sustained pain and suppress itch (PMID:9537323, PMID:9733503, PMID:19204064, PMID:33591273, PMID:35972457).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1991 High

    Molecular cloning of TACR1 established it as a Gq/PLC-coupled GPCR that binds substance P with sub-nanomolar affinity and triggers IP3 production, resolving the molecular identity of the pharmacologically defined NK-1 receptor.

    Evidence cDNA cloning and heterologous expression in COS-7 cells with radioligand binding and IP3 assays, independently in two laboratories

    PMID:1657150 PMID:1718267

    Open questions at the time
    • Downstream signaling beyond IP3 not characterized
    • No structural information on ligand-receptor interaction
    • Receptor trafficking after activation unknown
  2. 1992 High

    Identification of two alternatively spliced isoforms (full-length and truncated) and systematic mutagenesis of extracellular domains defined the structural basis for peptide agonist binding and revealed that the C-terminal tail is required for high-affinity coupling and full signaling efficacy.

    Evidence Gene structure determination (5 exons), chimeric receptor/mutagenesis approaches, heterologous expression in COS cells and Xenopus oocytes with binding and electrophysiology

    PMID:1280161 PMID:1281469 PMID:1310144 PMID:1312928

    Open questions at the time
    • Physiological relevance of the truncated isoform unknown
    • Antagonist binding site not yet mapped
    • No in vivo isoform-specific data
  3. 1993 High

    Identification of His197 in TM5 as essential for non-peptide antagonist binding demonstrated that agonist and antagonist binding pockets are spatially distinct, opening a structural framework for drug design.

    Evidence Site-directed mutagenesis with structure-activity analysis of CP 96345 analogues

    PMID:8384323

    Open questions at the time
    • No three-dimensional structure available
    • Whether other TM residues contribute to the antagonist pocket not fully mapped
    • Mechanism of antagonist-induced conformational change unknown
  4. 1998 High

    NK1R knockout mice and a placebo-controlled clinical trial of MK-869 established that NK1R mediates central sensitization (wind-up) in pain and participates in mood regulation through a monoamine-independent mechanism, broadening the receptor's role beyond nociception.

    Evidence Targeted gene knockout with behavioral and electrophysiological phenotyping; randomized placebo-controlled clinical trial for depression; preclinical vocalization assays

    PMID:9537323 PMID:9733503

    Open questions at the time
    • Monoamine-independent mechanism of antidepressant action not molecularly defined
    • Whether NK1R signaling in mood uses the same PLC/PKC cascade as in pain unknown
    • Circuit-level locus of NK1R's antidepressant action not identified
  5. 2003 High

    Mapping of isoform-specific expression in human brain (full-length dominant in locus coeruleus, ventral striatum) and identification of endokinins A/B as additional high-affinity endogenous agonists expanded the ligand-receptor framework and linked regional isoform distribution to mood and stress functions.

    Evidence TaqMan PCR and in situ hybridization in human brain; radioligand competition binding and hemodynamic assays for endokinins

    PMID:12716968 PMID:12752772

    Open questions at the time
    • Whether endokinins and SP activate distinct downstream pathways via NK1R unknown
    • Isoform-specific signaling in native brain tissue not demonstrated
    • NK1R role in emesis (brainstem) characterized pharmacologically but not genetically
  6. 2004 High

    Demonstration that NK1R resides in lipid rafts/caveolae and that raft integrity is required for PKC translocation, together with identification of SNX1/GASP as C-terminal tail interactors directing post-endocytic lysosomal sorting, defined the membrane-microdomain and trafficking framework for NK1R signaling.

    Evidence Sucrose gradient fractionation, cholesterol depletion/rescue, PKC translocation assays; systematic GST pull-down and SPR kinetics for C-tail interactors

    PMID:15452121 PMID:15590676

    Open questions at the time
    • Whether raft localization is required in neurons (not just HEK293/HepG2) unknown
    • Relative contribution of SNX1 vs GASP to degradation vs recycling not resolved
    • Relationship between raft-dependent signaling and endosomal signaling not established
  7. 2007 High

    NK1R knockout mice revealed that tonic NK1R signaling maintains noradrenergic and dopaminergic tone by sustaining α2a-autoreceptor sensitivity in locus coeruleus and dopamine efflux in prefrontal cortex, providing a mechanistic basis for the antidepressant and ADHD-like phenotypes of NK1R loss.

    Evidence In vivo microdialysis for noradrenaline and dopamine in freely moving NK1R−/− mice; [³⁵S]GTPγS autoradiography for α2a coupling; psychostimulant challenge

    PMID:17331215 PMID:19204064

    Open questions at the time
    • Direct synaptic mechanism by which NK1R regulates α2a-autoreceptor sensitivity not defined
    • Whether dopaminergic and noradrenergic phenotypes share a common upstream mechanism unknown
    • Translation to human neurochemistry not demonstrated
  8. 2008 High

    Discovery that monocytes express exclusively the truncated NK1R isoform, which signals through ERK2 and CCR5 crosstalk rather than Ca²⁺ mobilization, established isoform-specific signaling as a general principle with immunological relevance.

    Evidence Flow cytometry, RT-PCR, Ca²⁺ imaging, chemotaxis, and ERK1/2 phosphorylation in human monocytes; rescue by full-length transfection

    PMID:18835883

    Open questions at the time
    • Structural basis for truncated isoform's selective ERK2 activation unknown
    • Whether CCR5 and NK1R-T physically heterodimerize not determined
    • In vivo immune consequences of isoform-specific signaling not tested
  9. 2017 High

    Demonstration that NK1R signals from endosomes (not only the plasma membrane) to produce sustained PKC/ERK activation and prolonged pain established endosomal signaling as the pharmacologically relevant compartment and inspired endosome-targeted antagonist design.

    Evidence Pharmacological/genetic disruption of clathrin, dynamin, β-arrestin in spinal cord slices and in vivo pain models; cholestanol-conjugated antagonists targeting endosomal membranes

    PMID:28566424

    Open questions at the time
    • Whether endosomal signaling also underlies NK1R's roles in emesis and mood not tested
    • Endosomal signaling pathway components beyond PKC/ERK not characterized
    • Truncated isoform's endosomal signaling capacity unknown
  10. 2021 High

    Circuit-level studies using Tacr1-Cre genetics identified a spinoparabrachial Tacr1+ projection essential for sustained (but not acute) pain and RVM Tacr1+ ON cells that suppress itch, dissociating NK1R-defined circuits for pain and itch modulation.

    Evidence Chemogenetics, optogenetics, optotagging in Tacr1-Cre mice; behavioral nociception and itch assays

    PMID:33591273 PMID:35972457

    Open questions at the time
    • Molecular signaling within Tacr1+ parabrachial neurons not characterized
    • Whether the same or different SP sources drive the pain and itch circuits unknown
    • Human translational evidence for these circuits lacking
  11. 2021 Medium

    NK1R was placed upstream of PKCδ→NLRC4 inflammasome-driven neuronal pyroptosis after intracerebral hemorrhage, extending its neuroinflammatory role to a defined cell-death pathway.

    Evidence Mouse ICH model with aprepitant, NK1R agonist reversal, PKCδ agonist reversal, NLRC4 siRNA epistasis; Western blot for pyroptosis markers

    PMID:34244927 PMID:35922848

    Open questions at the time
    • Single-lab findings not independently replicated
    • Whether this pyroptosis pathway operates in non-hemorrhagic neuroinflammation unknown
    • Direct physical interaction between NK1R signaling components and NLRC4 not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis for isoform-specific signaling, the contribution of endosomal versus plasma membrane signaling to non-nociceptive NK1R functions (mood, emesis, immune), and whether endokinin versus substance P agonism activates distinct downstream programs.
  • No high-resolution structure of agonist-bound full-length NK1R in a lipid bilayer
  • Endosomal signaling paradigm untested outside pain
  • Isoform-selective pharmacology not developed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 3 R-HSA-9709957 Sensory Perception 2 R-HSA-5357801 Programmed Cell Death 1
Partners
ARRB1CCR5GASP1NSFSNX1TAC1TAC4

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 The human substance P receptor (NK-1/TACR1) was cloned as a 407-amino-acid G-protein-coupled receptor; when expressed in COS-7 cells it binds substance P with Kd ~0.24–0.35 nM and its stimulation triggers rapid, transient inositol 1,4,5-trisphosphate production, establishing Gq/phospholipase C as its primary intracellular effector. The gene resides on human chromosome 2 as a single-copy locus. cDNA cloning, heterologous expression in COS-7 cells, radioligand binding, IP3 assay, chromosome mapping with mouse/human hybrids Biochemistry / Biochemical and biophysical research communications High 1657150 1718267
1992 The human TACR1 gene contains five exons with intron positions conserved with the NK-2 (neuromedin K) receptor gene, consistent with evolution from a common ancestral GPCR gene. The gene spans ~60 kb. Genomic DNA cloning and sequencing, Southern blot, restriction mapping European journal of biochemistry High 1312928
1992 Two isoforms of the human NK-1 receptor (long and short/truncated) arise from alternative pre-mRNA splicing. The long form binds substance P with high affinity and activates oscillating Cl⁻ currents in Xenopus oocytes. The short form binds substance P with ≥10-fold lower affinity and elicits only weak electrophysiological responses, indicating the C-terminal cytoplasmic tail is required for full agonist coupling and signaling efficacy. cDNA cloning, heterologous expression in COS cells and Xenopus oocytes, radioligand binding, electrophysiology Molecular pharmacology High 1310144
1992 The N-terminal extracellular domain of NK-1R is required for high-affinity peptide binding: mutagenesis of residues in the N-terminus reduced affinity for substance P, substance K, and a C-terminal SP analog, but not for a non-peptide antagonist. Val-97 in the second extracellular segment selectively influences neurokinin B affinity, implicating distinct extracellular determinants for peptide selectivity. Site-directed mutagenesis, heterologous expression in COS cells, radioligand competition binding Biochemistry High 1280161
1992 Systematic extracellular domain substitutions revealed that three residues in the first extracellular segment and two in the second are required for optimal binding of all three natural tachykinin peptide agonists; the third and fourth extracellular segments partially determine NK-1R subtype selectivity of the non-peptide antagonist L-703,606, showing that agonist and antagonist binding domains are spatially distinct. Chimeric receptor construction, mutagenesis, heterologous expression, radioligand competition binding The Journal of biological chemistry High 1281469
1993 Histidine 197 in the fifth transmembrane helix of the human NK-1R forms an amino-aromatic interaction specifically with the benzhydryl moiety of the non-peptide antagonist CP 96345 but not with peptide agonists, defining a transmembrane antagonist-binding pocket distinct from the extracellular peptide-binding site. Site-directed mutagenesis, heterologous expression, radioligand binding, structure-activity analysis of antagonist analogues Nature High 8384323
1996 An antibody targeting the third extracellular region (ECR-3) of rat brain NK1R blocked >95% of [¹²⁵I]-SP binding to intact C6 astrocytes and CHO cells expressing NK1R, confirming the third extracellular loop is surface-exposed and participates in ligand access. Immunoaffinity purification from rat brain yielded bands of ~54 kDa and ~44 kDa on SDS-PAGE. Peptide-immunized antibody generation, radioligand binding inhibition, Western blot, affinity purification from rat brain membranes Journal of neuroimmunology Medium 8707930
1998 Genetic ablation of the NK-1 receptor (TACR1) in mice abolished wind-up amplification of nociceptive reflexes and intensity coding in the dorsal horn, demonstrating that NK-1R–mediated substance P signaling is required for the full development of central sensitization. NK-1R was also essential for stress-induced analgesia and aggression, but not for acute pain or hyperalgesia. Targeted gene knockout in mice, behavioral nociception assays (wind-up, tail-flick, hot-plate), electrophysiology of spinal dorsal horn neurons Nature High 9537323
1998 Blockade of central NK-1 receptors by the non-peptide antagonist MK-869 produced antidepressant effects in a placebo-controlled clinical trial, and in preclinical studies NK-1R antagonists suppressed isolation-induced vocalizations without interacting with monoamine systems in the manner of established antidepressants, establishing a monoamine-independent mechanism for NK-1R in mood regulation. Randomized placebo-controlled clinical trial; preclinical vocalization suppression assay; receptor binding and monoamine interaction studies Science High 9733503
2001 NK1R-/- mice phenocopied the behavioral effects of NK1R antagonists in antidepressant-relevant assays (forced swim, resident-intruder), and both genetic and pharmacological inactivation of NK1R did not produce sedation or motor impairment, validating that the antidepressant-like phenotype requires absence of functional NK1R signaling rather than developmental compensation. NK1R knockout mice vs. NK1R antagonists (L-760735, GR205171) in behavioral assays; central receptor occupancy confirmed by agonist-challenge test Behavioural pharmacology High 11742144
2003 The long NK-1R isoform is the dominant form in human brain (quantified by TaqMan PCR), with highest levels in locus coeruleus and ventral striatum, whereas the truncated isoform predominates in peripheral tissues; ³H-SP autoradiography correlated with mRNA distribution, linking isoform-specific expression to region-specific functions in mood and stress circuits. Riboprobe in situ hybridization, quantitative TaqMan PCR, in vitro autoradiography with ³H-SP The European journal of neuroscience High 12752772
2003 Substance P and the NK-1R in nucleus tractus solitarius and area postrema brainstem nuclei are critical mediators of the emetic reflex; NK-1R antagonists block emesis triggered by diverse stimuli (chemotherapy, motion, apomorphine) in animal models, placing NK-1R downstream of multiple emetic pathways converging on brainstem integrative nuclei. NK-1R antagonist pharmacology in ferret/cat emesis models; lesion and microinjection studies targeting brainstem nuclei Journal of pharmacological sciences Medium 12686752
2003 Endokinins A and B (EKA/B), encoded by the tachykinin precursor 4 gene, display equivalent affinity for the NK-1 receptor as substance P and produce identical hemodynamic effects in rats, identifying them as additional endogenous agonists for TACR1 at peripheral SP receptors. Radioligand competition binding at NK-1R, in vivo hemodynamic measurements in rats Proceedings of the National Academy of Sciences of the United States of America High 12716968
2004 NK-1R localizes to lipid rafts and caveolae at the plasma membrane; cholesterol depletion with methyl-β-cyclodextrin abolishes NK1R-mediated signaling. Upon substance P stimulation, activated PKC translocates from cytoplasm specifically to lipid rafts, demonstrating that raft integrity is required for productive NK1R–PKC coupling. Sucrose gradient fractionation, immunofluorescence, cholesterol depletion/replenishment assay, PKC translocation assay in HEK293 and HepG2 cells The Journal of biological chemistry High 15590676
2004 The C-terminal tail of NK-1R (truncated by 50 residues) retains interaction with both SNX1 (sorting nexin 1) and GASP (G protein-coupled receptor-associated sorting protein) as well as NSF, identifying an extended C-terminal binding epitope that directs post-endocytic trafficking of the receptor toward lysosomal degradation versus recycling pathways. GST pull-down library screen of 59 receptor C-terminal tails; SPR kinetics confirmation for selected hits; NK-1R truncation mapping The Journal of biological chemistry High 15452121
2004 IL-1β upregulates NK-1R expression in human astroglioma cells and primary rat astrocytes at both mRNA and protein levels via NF-κB activation; the induced NK-1R is functional (SP triggers Ca²⁺ mobilization), and NF-κB inhibitor CAPE blocks both the promoter activation and the induction of NK-1R gene expression. Western blot, RT-PCR, Ca²⁺ imaging, NF-κB reporter assay, pharmacological inhibition in human astroglioma (U87 MG) and primary rat astrocytes Glia High 15390113
2007 NK1R-/- mice display elevated basal extracellular noradrenaline in frontal cortex (2–4× higher than wildtype) associated with desensitization/reduced GTPγS coupling of somatodendritic α2a-adrenoceptors in locus coeruleus, demonstrating that tonic NK1R signaling normally suppresses noradrenergic tone through α2a-autoreceptor regulation. In vivo microdialysis (anaesthetized and freely moving mice), [³⁵S]GTPγS autoradiography of locus coeruleus, Western blot for noradrenaline transporter, α2-antagonist pharmacology The European journal of neuroscience High 17331215
2008 Human peripheral blood monocytes express exclusively the truncated NK-1R isoform (NK1R-T), which lacks the C-terminal 96-aa cytoplasmic domain. NK1R-T does not mobilize Ca²⁺ alone but enhances CCL5/CCR5-mediated Ca²⁺ mobilization and chemotaxis through ERK1/2 (selectively activating ERK2 alone), and induces serine phosphorylation of CCR5, revealing cross-receptor crosstalk at the receptor level. Flow cytometry, RT-PCR, Ca²⁺ imaging, chemotaxis assay, Western blot for ERK1/2 phosphorylation, CCR5 serine phosphorylation assay; NK1R-F transfection comparator Journal of leukocyte biology High 18835883
2008 Chronic stress-induced upregulation of spinal NK1R expression depends on microglial p38 MAPK activation; minocycline (microglia inhibitor) blocked both NK1R upregulation and visceral hyperalgesia, while the p38 inhibitor SB203580 blocked hyperalgesia without blocking NK1R upregulation, placing microglial activation upstream of spinal NK1R increase and dissociating the two downstream effects. Water-avoidance stress rat model, Western blot and immunostaining for NK1R/OX42/P-p38, intrathecal drug delivery, colorectal distension visceromotor response Gastroenterology High 19249394
2009 NK1R-/- mice exhibit hyperactivity that is reversed by psychostimulants (d-amphetamine, methylphenidate), mirroring ADHD. In vivo microdialysis revealed >50% reduction in spontaneous dopamine efflux in prefrontal cortex and abolished striatal dopamine response to d-amphetamine in NK1R-/- mice, demonstrating that NK1R signaling tonically maintains dopaminergic tone in frontocortical and striatal circuits. Locomotor activity measurement, in vivo microdialysis (prefrontal cortex and striatum), NK1R antagonist (L-760735) pharmacology, psychostimulant challenge Journal of psychopharmacology High 19204064
2009 NK1R-/- mice survive hyperoxia (90% O₂) significantly worse than wildtype (median survival 84 h vs. 120 h), with increased lung inflammation, edema, and apoptosis (TUNEL), demonstrating a paradoxical protective role for NK1R in hyperoxic lung injury. In cultured lung epithelial cells, exogenous SP promoted cell death under hyperoxia, revealing distinct tissue-level versus cell-autonomous signaling by the SP/NK1R axis. NK1R-/- and TRPV1-/- mouse hyperoxia model, BAL fluid analysis, TUNEL staining, metallothionein/Na-K-ATPase Western blot, cell culture SP treatment under hyperoxia American journal of physiology. Lung cellular and molecular physiology Medium 19633070
2009 Prolonged exposure of NK1R to substance P decreases NK1R mRNA in bladder urothelium and upregulates specific miRNAs (miR-449b, miR-500, miR-328, miR-320) that directly correlate with NK1R mRNA/protein downregulation, identifying a miRNA-mediated negative feedback loop regulating NK1R expression. RT-PCR, Western blot, miRNA expression profiling, correlation analysis in cell models and human bladder biopsy specimens from BPS patients The American journal of pathology Medium 20008142
2010 NK1R deletion or antagonism with L-703,606 reduces voluntary alcohol consumption and alcohol-conditioned place preference in a gene-dose-dependent manner; escalation of intake after repeated deprivation cycles occurs in wildtype but not NK1R-/- mice, identifying NK1R as a direct (non-developmental) regulator of alcohol reward and motivational escalation. Two-bottle free-choice intake, conditioned place preference, deprivation-escalation model in C57BL/6 NK1R-/- mice; NK1R antagonist receptor-specificity confirmed in KO Psychopharmacology High 20112009
2011 Substance P activates both contractile (MLC₂₀ phosphorylation) and pro-inflammatory (p38-MAPK, ERK1/2) pathways in lymphatic muscle cells via NK1R and NK3R. ERK1/2 inhibition reduces p-MLC₂₀ in a PKC-dependent manner, demonstrating crosstalk between the inflammatory and contractile cascades downstream of SP receptor activation in lymphatics. Rat mesenteric lymphatic muscle cell culture, pharmacological inhibitors, Western blot for p-MLC₂₀, p-p38, p-ERK1/2, NK1R/NK3R expression confirmed by RT-PCR Microcirculation Medium 21166923
2013 Elevated Tacr1 expression in prefrontal cortex and central amygdala of alcohol-preferring (P) rats, driven in part by a -1372C allele that increases GATA-2/E2F-1 transcription factor binding and promoter activity, confers heightened sensitivity to NK1R antagonist (L822429) effects on alcohol self-administration; central amygdala infusion of L822429 replicates systemic effects, localizing NK1R's role in alcohol intake to this region. Operant self-administration, microinfusion, Tacr1 qPCR, NK1R autoradiography, Tacr1 promoter sequencing, EMSA, luciferase reporter assay Biological psychiatry High 23419547
2014 NK-1R full-length and truncated isoforms are differentially expressed across glioblastoma cell lines; only cell lines with high full-length NK1R (e.g., LN319) show significant SP conjugate binding, receptor internalization, and targeted cell killing by saporin-SP toxin, establishing that full-length NK1R isoform expression is required for SP-mediated receptor internalization and targeted cytotoxicity. RT-PCR for isoform quantification, radioligand binding (¹⁷⁷Lu-SP), fluorescence-labeled SP internalization, saporin-SP cytotoxicity assay in 4 GBM cell lines Cancer biotherapy & radiopharmaceuticals Medium 24552486
2017 NK1R signals from endosomes (not only the plasma membrane) to produce sustained neuronal excitation and pain: after SP stimulation, NK1R undergoes clathrin/dynamin/β-arrestin–dependent endocytosis required for activation of cytosolic PKC and nuclear ERK as well as transcription. Endocytosis inhibitors block sustained spinal neuron excitation in vitro and nociception in vivo. Cholestanol-conjugated NK1R antagonists that target endosomal membranes provide more effective and prolonged antinociception than conventional antagonists. Pharmacological/genetic disruption of clathrin, dynamin, β-arrestin in spinal cord slice electrophysiology and in vivo pain models; cholestanol-conjugated antagonist synthesis and testing; PKC/ERK activation assays; mouse nociception models Science translational medicine High 28566424
2018 In pancreatic cancer, MMP1 secreted by cancer cells activates PAR1 on dorsal root ganglion neurons, which then release substance P; SP activates NK1R on pancreatic cancer cells to enhance migration, invasion, and perineural invasion via SP/NK1R/ERK signaling. Silencing MMP1 or blocking NK1R or PAR1 inhibited perineural invasion in vitro and in vivo. Matrigel/DRG co-culture PNI model, sciatic nerve invasion mouse model, shRNA knockdown, NK1R/PAR1 antagonists, Western blot for p-ERK, MRI with iron oxide nanoparticles Theranostics High 29896303
2021 A spinoparabrachial circuit defined by Tacr1 expression drives ongoing pain: Tacr1-expressing spinal projection neurons (NK1R+) target a small cluster of neurons in the superior lateral parabrachial nucleus (PBN-SL) that also express Tacr1; chemogenetic silencing of PBN-SLTacr1 neurons causes mice to ignore long-lasting noxious stimuli, while activation heightens nocifensive behavior and suppresses itch, establishing this circuit as essential for sustained (but not acute) pain processing. Chemogenetics (DREADD), optogenetics, optotagging to identify ON cells, Tacr1-Cre mouse intersectional genetics, behavioral nociception and itch assays eLife High 33591273
2021 NK1R inhibition with aprepitant after intracerebral hemorrhage promotes M2 microglial polarization and hematoma clearance by downregulating the PKC/p38MAPK/NFκB signaling pathway; NK1R agonist or PKC agonist reversed these effects, placing NK1R upstream of PKC/p38MAPK/NFκB in post-hemorrhagic neuroinflammation. Thrombin injection increased substance P, identifying thrombin as an upstream activator of the NK1R axis after ICH. Mouse ICH model (autologous blood injection), Western blot, immunofluorescence, intracerebroventricular NK1R agonist/PKC agonist reversal experiments, neurobehavioral testing Neurotherapeutics Medium 34244927
2022 After intracerebral hemorrhage, NK1R activation drives NLRC4-dependent neuronal pyroptosis via a PKCδ-dependent pathway; aprepitant (NK1R antagonist) reduced NLRC4, cleaved-caspase-1, GSDMD, IL-1β and IL-18, and these neuroprotective effects were abolished by NK1R agonist GR73632 or PKCδ agonist PMA, while NLRC4 siRNA recapitulated aprepitant's effects, placing NK1R→PKCδ→NLRC4 as a sequential pyroptosis pathway. Mouse ICH model, Western blot, immunofluorescence, intracerebroventricular siRNA knockdown, agonist reversal experiments, neurobehavioral assays Journal of neuroinflammation Medium 35922848
2022 Tacr1-expressing ON cells in the rostral ventromedial medulla (RVM) exert inhibitory control over spinal pruriceptive transmission: intramedullary substance P potentiated RVM ON-cell firing and reduced pruritogen-evoked scratching while producing mild mechanical sensitization; chemogenetic activation of RVM Tacr1+ neurons reduced acute itch; optotagging confirmed Tacr1+ neurons are ON cells. Intramedullary microinjection of SP, chemogenetics (DREADD), optotagging electrophysiology in Tacr1-Cre mice, behavioral pruritogen scratching assay eLife High 35972457
2023 Activation of the SP/NK1R axis in breast cancer MCF-7 cells drives ROS accumulation and NF-κB-mediated upregulation of pro-inflammatory cytokines (TNF-α, IL-6) while downregulating p21; aprepitant (NK1R antagonist) reverses these effects and induces p53-mediated p21 upregulation, placing NK1R upstream of the ROS/NF-κB/p53 axis controlling cancer cell proliferation. ROS assay (H2DCFDA), qRT-PCR, resazurin viability assay, SP and aprepitant dose-response in MCF-7 cells Cell biochemistry and biophysics Low 37740877

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1998 Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science (New York, N.Y.) 837 9733503
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1998 Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 615 9537323
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2013 Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. PLoS genetics 339 23754948
1992 Differential activation of intracellular effector by two isoforms of human neurokinin-1 receptor. Molecular pharmacology 239 1310144
2007 SPR microscopy and its applications to high-throughput analyses of biomolecular binding events and their kinetics. Biomaterials 220 17337300
1993 Amino-aromatic interaction between histidine 197 of the neurokinin-1 receptor and CP 96345. Nature 192 8384323
1991 Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones. Biochemistry 175 1657150
2017 Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief. Science translational medicine 174 28566424
1991 Molecular cloning, structural characterization and functional expression of the human substance P receptor. Biochemical and biophysical research communications 169 1718267
2010 Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation. Annals of the New York Academy of Sciences 148 21091716
2004 A library of 7TM receptor C-terminal tails. Interactions with the proposed post-endocytic sorting proteins ERM-binding phosphoprotein 50 (EBP50), N-ethylmaleimide-sensitive factor (NSF), sorting nexin 1 (SNX1), and G protein-coupled receptor-associated sorting protein (GASP). The Journal of biological chemistry 139 15452121
2007 SPR-based fragment screening: advantages and applications. Current topics in medicinal chemistry 134 17979772
2004 Direct detection of genomic DNA by enzymatically amplified SPR imaging measurements of RNA microarrays. Journal of the American Chemical Society 132 15053580
1992 The extracellular domain of the neurokinin-1 receptor is required for high-affinity binding of peptides. Biochemistry 132 1280161
2001 Comparison of the phenotype of NK1R-/- mice with pharmacological blockade of the substance P (NK1 ) receptor in assays for antidepressant and anxiolytic drugs. Behavioural pharmacology 129 11742144
2003 Neurokinin 1 receptor and relative abundance of the short and long isoforms in the human brain. The European journal of neuroscience 128 12752772
1992 Localization of agonist and antagonist binding domains of the human neurokinin-1 receptor. The Journal of biological chemistry 126 1281469
2003 Characterization of the endokinins: human tachykinins with cardiovascular activity. Proceedings of the National Academy of Sciences of the United States of America 121 12716968
2013 Involvement of substance P and the NK-1 receptor in cancer progression. Peptides 119 23933301
2013 Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity. Proceedings of the National Academy of Sciences of the United States of America 116 23471985
2013 Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties. Cancer cell 113 23597562
1992 The primary structure and gene organization of human substance P and neuromedin K receptors. European journal of biochemistry 113 1312928
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
1999 Interaction of the Ras-related protein associated with diabetes rad and the putative tumor metastasis suppressor NM23 provides a novel mechanism of GTPase regulation. Proceedings of the National Academy of Sciences of the United States of America 108 10611312
2009 MicroRNAs may mediate the down-regulation of neurokinin-1 receptor in chronic bladder pain syndrome. The American journal of pathology 93 20008142
2004 The NK1 receptor localizes to the plasma membrane microdomains, and its activation is dependent on lipid raft integrity. The Journal of biological chemistry 91 15590676
2003 Roles of substance P and NK(1) receptor in the brainstem in the development of emesis. Journal of pharmacological sciences 91 12686752
2008 High-throughput SPR sensor for food safety. Biosensors & bioelectronics 87 18809310
2018 MMP1/PAR1/SP/NK1R paracrine loop modulates early perineural invasion of pancreatic cancer cells. Theranostics 80 29896303
2018 Ultra-sensitive detection by metal nanoparticles-mediated enhanced SPR biosensors. Talanta 77 30348366
1999 Expression, regulation, and function of the SPR family of proteins. A review. Cell biochemistry and biophysics 74 10356644
2023 Surface Plasmon Resonance (SPR) Sensor for Cancer Biomarker Detection. Biosensors 73 36979608
2000 The integration of SPR biosensors with mass spectrometry: possible applications for proteome analysis. Trends in biotechnology 68 10652507
2008 Role of spinal microglia in visceral hyperalgesia and NK1R up-regulation in a rat model of chronic stress. Gastroenterology 67 19249394
2009 NK1 (TACR1) receptor gene 'knockout' mouse phenotype predicts genetic association with ADHD. Journal of psychopharmacology (Oxford, England) 64 19204064
2021 A spinoparabrachial circuit defined by Tacr1 expression drives pain. eLife 63 33591273
2013 Recent advances in the development of graphene-based surface plasmon resonance (SPR) interfaces. Analytical and bioanalytical chemistry 60 23314618
2008 Substance P (SP) enhances CCL5-induced chemotaxis and intracellular signaling in human monocytes, which express the truncated neurokinin-1 receptor (NK1R). Journal of leukocyte biology 60 18835883
2004 Interleukin-1beta upregulates functional expression of neurokinin-1 receptor (NK-1R) via NF-kappaB in astrocytes. Glia 59 15390113
2010 Neurokinin-1 receptors (NK1R:s), alcohol consumption, and alcohol reward in mice. Psychopharmacology 56 20112009
2003 IL-18 and IL-12 signal through the NF-kappa B pathway to induce NK-1R expression on T cells. Journal of immunology (Baltimore, Md. : 1950) 50 12734344
2014 Fragment screening by SPR and advanced application to GPCRs. Progress in biophysics and molecular biology 49 25301577
2022 Optical fiber SPR biosensor based on gold nanoparticle amplification for DNA hybridization detection. Talanta 44 35653863
2015 Development of SPR biosensor for simultaneous detection of multiplex respiratory viruses. Bio-medical materials and engineering 43 26406000
2005 Enhanced sensitivity of surface plasmon resonance (SPR) immunoassays using a peroxidase-catalyzed precipitation reaction and its application to a protein microarray. Journal of immunological methods 38 15777936
2018 Hybridization conditions of oligonucleotide-capped gold nanoparticles for SPR sensing of microRNA. Biosensors & bioelectronics 37 29567568
2013 Tacr1 gene variation and neurokinin 1 receptor expression is associated with antagonist efficacy in genetically selected alcohol-preferring rats. Biological psychiatry 37 23419547
2016 Developments in SPR Fragment Screening. Expert opinion on drug discovery 35 26948323
2011 Substance P activates both contractile and inflammatory pathways in lymphatics through the neurokinin receptors NK1R and NK3R. Microcirculation (New York, N.Y. : 1994) 35 21166923
2019 MicroRNA detection on microsensor arrays by SPR imaging measurements with enzymatic signal enhancement. Biosensors & bioelectronics 33 31404878
2019 lncRNA RMRP knockdown suppress hepatocellular carcinoma biological activities via regulation miRNA-206/TACR1. Journal of cellular biochemistry 32 31579977
2007 Disruption of noradrenergic transmission and the behavioural response to a novel environment in NK1R-/- mice. The European journal of neuroscience 32 17331215
2012 On-chip synthesis of RNA aptamer microarrays for multiplexed protein biosensing with SPR imaging measurements. Langmuir : the ACS journal of surfaces and colloids 31 22458258
2013 Protein-Ligand Interactions Using SPR Systems. Methods in molecular biology (Clifton, N.J.) 30 23729252
2005 SPR-MS in functional proteomics. Briefings in functional genomics & proteomics 30 15975263
2022 Aprepitant attenuates NLRC4-dependent neuronal pyroptosis via NK1R/PKCδ pathway in a mouse model of intracerebral hemorrhage. Journal of neuroinflammation 28 35922848
2017 Pain in knee osteoarthritis is associated with variation in the neurokinin 1/substance P receptor (TACR1) gene. European journal of pain (London, England) 28 28493529
2012 TACR1 genotypes predict fMRI response to alcohol cues and level of alcohol dependence. Alcoholism, clinical and experimental research 28 23078527
2014 SPR analysis of promoter binding of Synechocystis PCC6803 transcription factors NtcA and CRP suggests cross-talk and sheds light on regulation by effector molecules. FEBS letters 27 24846138
2014 Capture-stabilize approach for membrane protein SPR assays. Scientific reports 27 25484112
2017 SPR-based fragment screening with neurotensin receptor 1 generates novel small molecule ligands. PloS one 26 28510609
2015 Surface Enzyme Chemistries for Ultrasensitive Microarray Biosensing with SPR Imaging. Langmuir : the ACS journal of surfaces and colloids 26 25641598
2003 Spying on HIV with SPR. Trends in microbiology 26 12648944
2021 Adsorption and Conformation Behavior of Lysozyme on a Gold Surface Determined by QCM-D, MP-SPR, and FTIR. International journal of molecular sciences 23 33525751
2021 A multiplex and regenerable surface plasmon resonance (MR-SPR) biosensor for DNA detection of genetically modified organisms. Talanta 23 33965027
2021 Neurokinin Receptor 1 (NK1R) Antagonist Aprepitant Enhances Hematoma Clearance by Regulating Microglial Polarization via PKC/p38MAPK/NFκB Pathway After Experimental Intracerebral Hemorrhage in Mice. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 23 34244927
2015 TACR1 gene polymorphism and sex differences in postoperative nausea and vomiting. Anaesthesia 23 26012530
2014 Real-time ligation chain reaction for DNA quantification and identification on the FO-SPR. Biosensors & bioelectronics 22 25212376
2014 Unravelling nonspecific adsorption of complex protein mixture on surfaces with SPR and MS. Analytical chemistry 22 25287274
2006 lin-35/Rb and the CoREST ortholog spr-1 coordinately regulate vulval morphogenesis and gonad development in C. elegans. Developmental biology 22 17070797
2023 The SP/NK1R system promotes the proliferation of breast cancer cells through NF-κB-mediated inflammatory responses. Cell biochemistry and biophysics 21 37740877
2021 Potential in vitro therapeutic effects of targeting SP/NK1R system in cervical cancer. Molecular biology reports 21 34766230
2021 Construction of an enzyme-based all-fiber SPR biosensor for detection of enantiomers. Biosensors & bioelectronics 21 34847363
2018 Neurokinin-1 receptor (NK1R) inhibition sensitizes APL cells to anti-tumor effect of arsenic trioxide via restriction of NF-κB axis: Shedding new light on resistance to Aprepitant. The international journal of biochemistry & cell biology 21 30145367
2014 Salinity-dependent impacts of ProQ, Prc, and Spr deficiencies on Escherichia coli cell structure. Journal of bacteriology 21 24443528
2023 2D MOF-enhanced SPR sensing platform: Facile and ultrasensitive detection of Sulfamethazine via supramolecular probe. Journal of hazardous materials 20 37236101
2022 Neurokinin-1 Receptor (NK-1R) Antagonists as a New Strategy to Overcome Cancer Resistance. Cancers 20 35565383
2021 Chaiqin chengqi decoction ameliorates acute pancreatitis in mice via inhibition of neuron activation-mediated acinar cell SP/NK1R signaling pathways. Journal of ethnopharmacology 20 33731310
2015 A combinatorial biophysical approach; FTSA and SPR for identifying small molecule ligands and PAINs. Analytical biochemistry 20 25837771
2015 Urinary micro-RNA biomarker detection using capped gold nanoslit SPR in a microfluidic chip. The Analyst 20 25891475
2015 SPR Biosensor Probing the Interactions between TIMP-3 and Heparin/GAGs. Biosensors 20 26213979
2014 Applications of SPR for the characterization of molecules important in the pathogenesis and treatment of neurodegenerative diseases. Expert review of neurotherapeutics 20 24625008
2021 Pathogenic role of the SP/ NK1R system in GBM cells through inhibiting the thioredoxin system. Iranian journal of basic medical sciences 19 34094032
2020 Label-Free Analysis of Multivalent Protein Binding Using Bioresponsive Nanogels and Surface Plasmon Resonance (SPR). ACS applied materials & interfaces 19 31898885
2012 Antagonism of L-type Ca(v) channels with nifedipine differentially affects performance of wildtype and NK1R-/- mice in the 5-Choice Serial Reaction-Time Task. Neuropharmacology 19 22884624
2010 Alterations in dopamine and glutamate neurotransmission in tetrahydrobiopterin deficient spr-/- mice: relevance to schizophrenia. BMB reports 19 20846490
2021 Recent Advancements in Receptor Layer Engineering for Applications in SPR-Based Immunodiagnostics. Sensors (Basel, Switzerland) 18 34072572
2018 Tropisetron attenuates lipopolysaccharide induced neuroinflammation by inhibiting NF-κB and SP/NK1R signaling pathway. Journal of neuroimmunology 18 29759144
2016 Pharmacologic rationale for the NK1R antagonist, aprepitant as adjunctive therapy in HIV. Journal of translational medicine 18 27230663
2015 A lack of functional NK1 receptors explains most, but not all, abnormal behaviours of NK1R-/- mice(1). Genes, brain, and behavior 18 25558794
2004 Fine mapping of the 2p11 dyslexia locus and exclusion of TACR1 as a candidate gene. Human genetics 18 15007729
2022 Purification and Characterization of Novel Anti-MRSA Peptides Produced by Brevibacillus sp. SPR-20. Molecules (Basel, Switzerland) 17 36500545
2020 Radiochemical Synthesis and Evaluation of Novel Radioconjugates of Neurokinin 1 Receptor Antagonist Aprepitant Dedicated for NK1R-Positive Tumors. Molecules (Basel, Switzerland) 17 32824729
2019 SP promotes cell proliferation in esophageal squamous cell carcinoma through the NK1R/Hes1 axis. Biochemical and biophysical research communications 17 31109645
2012 Diminished pheromone-induced sexual behavior in neurokinin-1 receptor deficient (TACR1(-/-)) mice. Genes, brain, and behavior 17 22471406
2009 Association and linkage analysis of candidate genes GRP, GRPR, CRHR1, and TACR1 in panic disorder. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 17 18452185
1996 Recognition of neurokinin 1 receptor (NK1-R): an antibody to a peptide sequence from the third extracellular region binds to brain NK1-R. Journal of neuroimmunology 17 8707930
2023 Characterization of Small Molecule-Protein Interactions Using SPR Method. Methods in molecular biology (Clifton, N.J.) 16 37450146
2022 Dramatic Effect of Botulinum Toxin Type A on Hypertrophic Scar: A Promising Therapeutic Drug and Its Mechanism Through the SP-NK1R Pathway in Cutaneous Neurogenic Inflammation. Frontiers in medicine 16 35308522
2021 Carbohydrate-Based NK1R Antagonists with Broad-Spectrum Anticancer Activity. Journal of medicinal chemistry 16 34236855
2014 Expression of different neurokinin-1 receptor (NK1R) isoforms in glioblastoma multiforme: potential implications for targeted therapy. Cancer biotherapy & radiopharmaceuticals 16 24552486
2009 A paradoxical protective role for the proinflammatory peptide substance P receptor (NK1R) in acute hyperoxic lung injury. American journal of physiology. Lung cellular and molecular physiology 16 19633070
2023 Fiber SPR biosensor sensitized by MOFs for MUC1 protein detection. Talanta 15 36989617
2011 Antibody characterization and immunoassays for palytoxin using an SPR biosensor. Analytical and bioanalytical chemistry 15 21523328
2008 Automated SPR-LC-MS/MS system for protein interaction analysis. Journal of proteome research 15 18652503
2023 Machine learning for detecting DNA attachment on SPR biosensor. Scientific reports 14 36879019
2022 A Fiber-Based SPR Aptasensor for the In Vitro Detection of Inflammation Biomarkers. Micromachines 14 35888854
2022 The Potential In Vitro Inhibitory Effects of Neurokinin-1 Receptor (NK-1R) Antagonist, Aprepitant, in Osteosarcoma Cell Migration and Metastasis. BioMed research international 14 36177059
2022 The Current Status and Future Promise of SPR Biosensors. Biosensors 14 36354442
2020 Regenerable Biosensors for Small-Molecule Kinetic Characterization Using SPR. SLAS discovery : advancing life sciences R & D 14 33289457
2017 Up-regulated expression of substance P in CD8+ T cells and NK1R on monocytes of atopic dermatitis. Journal of translational medicine 14 28460633
2022 Inhibition of itch by neurokinin 1 receptor (Tacr1) -expressing ON cells in the rostral ventromedial medulla in mice. eLife 13 35972457
2022 Conformational transition in SPR experiments: impact of spacer length, immobilization mode and aptamer density on signal sign and amplitude. The Analyst 13 35983869
2020 Multiplexed Remote SPR Detection of Biological Interactions through Optical Fiber Bundles. Sensors (Basel, Switzerland) 13 31963277
2018 SPR Biosensors in Direct Molecular Fishing: Implications for Protein Interactomics. Sensors (Basel, Switzerland) 13 29783662
2009 A rapid method for detection of PrP by surface plasmon resonance (SPR). Archives of virology 13 19862471
2023 Multiplexed experimental strategies for fragment library screening against challenging drug targets using SPR biosensors. SLAS discovery : advancing life sciences R & D 12 37714432
2021 An SPR imaging immunosensor for leptin determination in blood plasma. Analytical methods : advancing methods and applications 12 33438698
2021 The SP/NK1R System-Mediated ROS Generation in GBM Cells through Inhibiting Glutaredoxin Protein. Neurology research international 12 34917417
2018 Trends in SPR Cytometry: Advances in Label-Free Detection of Cell Parameters. Biosensors 12 30380705
2016 Perseveration by NK1R-/- ('knockout') mice is blunted by doses of methylphenidate that affect neither other aspects of their cognitive performance nor the behaviour of wild-type mice in the 5-Choice Continuous Performance Test. Journal of psychopharmacology (Oxford, England) 12 27097734
2015 Differences in the performance of NK1R-/- ('knockout') and wildtype mice in the 5‑Choice Continuous Performance Test. Behavioural brain research 12 26522842
2008 Mining the oncoproteome and studying molecular interactions for biomarker development by 2DE, ChIP and SPR technologies. Expert review of proteomics 12 18532914