Disease relevance of TACR1

• NK1- and NK2-receptor mRNA expression was increased twofold in smokers without airflow obstruction compared with nonsmokers, whereas NK1-receptor mRNA expression was significantly lower in patients with chronic obstructive pulmonary disease compared with smoking controls [1].
• RNA blot hybridization and solution hybridization demonstrated that SPR mRNA was about 4.5 Kb in size, and was expressed in IM-9 lymphoblast and U373-MG astrocytoma cells, as well as in spinal cord and lung but not in liver [2].
• Substance P and substance P receptor histochemistry in human neurodegenerative diseases [3].
• In colon tissue obtained from ulcerative colitis and Crohn disease patients, however, very high concentrations of SP receptor binding sites are expressed by arterioles and venules located in the submucosa, muscularis mucosa, external circular muscle, external longitudinal muscle, and serosa [4].
• Taken together, these observations may have important physiological and pathophysiological implications, and provide the rationale for the use of NK-1R and NK-2R antagonists in the treatment of inflammatory bowel disease [5].

Psychiatry related information on TACR1

• Fine mapping of the 2p11 dyslexia locus and exclusion of TACR1 as a candidate gene [6].
• An NK1 receptor antagonist affects the circadian regulation of locomotor activity in golden hamsters [7].
• Although these studies point to the NK1 receptor as a promising target for the pharmacotherapy of anxiety disorders, high affinity antagonists for the human receptors could not be studied in rats or mice due to species differences in the antagonist binding sites [8].
• This study compared the effects of an NK1 receptor antagonist, citalopram, and placebo on brain activity and anxiety symptoms in social phobia [9].
• The neuropeptide substance P (SP) has been supposed to be involved in the etiopathology of affective disorders, mainly because of the finding of increased levels of SP in the cerebrospinal fluid of depressed patients and the preliminary evidence of antidepressant effects of SP-receptor antagonists in depressed patients [10].

High impact information on TACR1

• Susceptibility to the non-peptide antagonists can be conveyed to the previously unresponsive NK3 receptor by mutational transfer of this discontinuous epitope from the NK1 receptor [11].
• Different binding epitopes on the NK1 receptor for substance P and non-peptide antagonist [11].
• Here we identify epitopes on the NK1 receptor responsible for the specific binding of CP 96345 by systematic exchange of corresponding segments between the NK1 receptor and the homologous NK3 (neurokinin B) receptor, which does not bind the non-peptide ligand [11].
• Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenase inhibition [12].
• The protection of cells expressing class I HLA molecules from NK lysis is mediated by natural killer cell inhibitory receptors (NKIR) [13].

Chemical compound and disease context of TACR1

• NK1 receptor antagonists were also found to be effective antiemetics, and aprepitant has recently become available for the treatment of chemotherapy induced emesis [14].
• Use of an NK1 receptor antagonist to prevent delayed emesis after cisplatin [15].
• The substance P receptor antagonist CP-99,994 reduces acute postoperative pain [16].
• Morphine and L-baclofen partially reversed established STZ-induced mechanical hyperalgesia, whilst the NK-1 receptor-antagonist RP-67580, the NMDA-antagonists MK801 and ketamine, and the nitric oxide synthase inhibitor L-NAME were without significant effect [17].
• The effects of a novel nonpeptide NK1 tachykinin receptor antagonist, SR 140333, on the functional consequences of NK1 receptor activation in a human astrocytoma cell line, U373MG, were investigated [18].

Biological context of TACR1

• Regulation of the NK-1 receptor gene expression in human macrophage cells via an NF-kappa B site on its promoter [19].
• An earlier report noted that the promoter region of the human NK-1R gene contains a putative binding site for NF-kappa B [Takahashi, K., Tanaka, A., Hara, M. & Nakanishi, S. (1992) Eur. J. Biochem. 204, 1025-1033] [19].
• Analysis of restriction digests of genomic DNA from mouse/human cell hybrids indicates the NK-1 receptor is a single-copy gene located on human chromosome 2 [20].
• Human substance P receptor undergoes agonist-dependent phosphorylation by G protein-coupled receptor kinase 5 in vitro [21].
• The gene organization and amino acid sequences of human substance P and neuromedin K receptors (SPR and NKR, respectively) are reported on the basis of molecular cloning and sequence determination of genomic DNA containing the respective receptor gene [22].

Anatomical context of TACR1

• The NK1 receptor was transiently expressed in HEK293 and HepG2 cell lines and its localization in membrane microdomains investigated using biochemical methods and immunofluorescent labeling [23].
• Neurokinin 1 receptor (NK1R) is expressed in central and peripheral nervous system as well as in endothelial and smooth muscle cells and involved in mediation of pain, inflammation, exocrine secretion, and smooth muscle contraction [23].
• The NK1 receptor localizes to the plasma membrane microdomains, and its activation is dependent on lipid raft integrity [23].
• We show that the NK1 receptor, similar to the earlier described beta(2)-adrenergic receptor and G proteins, localizes to lipid rafts and caveolae [23].
• When transfected into COS-7 cells, the NK-1 receptor binds 125I-BHSP with a Kd of 0.35 +/- 0.07 nM and mediates substance P induced phosphatidylinositol metabolism [20].

Associations of TACR1 with chemical compounds

• 4. The NK1 receptor selective agonist, [Sar9]SP sulphone (10 nM) evoked a maximal facilitatory action on cholinergic responses of 334.9 +/- 63% (P < 0.01) (pD2 = 8.5 +/- 0.06) an effect which was blocked by the selective NK1-receptor antagonist, CP 96,345 (100 nM) (P < 0.05) but not by the NK2 receptor antagonist, MEN 10,376 (100 nM) [24].
• The human NK-1 receptor transfected in Chinese hamster ovary (CHO) cells was studied with use of different tachykinin analogs: Substance P, [Pro9]SP, [Sar9, Met(O2)11]SP, [Gly9 psi (CH2CH2) Leu10]SP, Ac-Arg-septide, septide, [Gly9 psi (CH2CH2) Gly10]SP, NKA, [pGlu6]SP(6-11) and [Lys5]NKA(4-10) [25].
• All these data indicated that SR 140333 blocked SP-induced cytokine production in U373MG astrocytic cells via a specific NK1 receptor-mediated process [26].
• The effects of NKA and eledoisin were blocked by the NK2 receptor antagonist SR 48968 but not by the NK1 receptor antagonist SR 140333 in tissues from both groups of women [27].
• Nonpeptide tachykinin receptor antagonists: I. Pharmacological and pharmacokinetic characterization of SB 223412, a novel, potent and selective neurokinin-3 receptor antagonist [28].

Physical interactions of TACR1

• The NK-2 receptor-selective compound SR 48,968 was found to bind with low affinity to the human NK-1 receptor but with 15-fold even lower affinity to the rat receptor [29].
• These results suggest that the tachykinin-induced inward current is mediated through the NK1 receptor which mainly couples to PTX-insensitive G-protein in bullfrog primary afferent neurons [30].
• Finally, we show here that the amyloid-beta peptide competes for binding to the SEC receptor but does not bind to the substance P receptor, therein raising the possibility that the SEC receptor is involved in certain biological activities, including the recently described neurotrophic and neurotoxic effects ascribed to the amyloid-beta peptide [31].
• These data suggest that the pharmacological properties of [125I]L-703606 binding to the human NK1 receptor are similar to those of antagonists of nonpeptide guanine nucleotide-binding protein-coupled receptors and that this ligand will be useful for the biochemical and pharmacological characterization of the human NK1 receptor [32].

Regulatory relationships of TACR1

• The stimulatory effects on BM progenitors mediated by NK-1R can be partly inhibited by NK-2R activation [33].
• Highly selective non-peptide (CP96,345) or peptide (GR82,334) NK1 receptor antagonists were more effective in antagonizing septide-(IC50's 0.2 +/- 0.06 nM and 70 +/- 18 nM) than SP-(IC50's 6.7 +/- 1.3 nM and 1.95 +/- 0.4 microM) induced IL-6 secretion [34].
• These data support the existence, also in human U373 MG cells, of a septide-sensitive NK1 receptor subtype(s) and/or epitope(s) blocked with high affinity by NK1 antagonist [34].
• These results suggest that IL 2 stimulates B cells via a low-affinity interaction with a receptor different from the Tac receptor identified on T cells, and that the active site on the IL 2 molecule for B cells differs from that for T cell targets [35].
• However, the signalling mechanisms by which SP-NK-1R interaction induces NF-kappaB activation and IL-8 expression are still not clear [36].

Other interactions of TACR1

• Binding experiments with [3H][Pro9]SP discriminated two classes of peptides with either high affinity (K iota in the nanomolar range) for the human NK-1 receptor or with low affinity (K iota in the micromolar range); this second group of peptides included NKA and [pGlu6]SP(6-11) [25].
• Agonist treatment induced a stronger intracellular calcium ([Ca2+]i) increase after activation of NK-1R compared to NK-3R, a result that we verified by calcium imaging [37].
• The contractile response to capsaicin obtained in the presence of the three tachykinin receptor antagonists could be due to the co-released CGRP and/or to other unknown neurotransmitters [38].
• SU5402 and TGF-beta1 had no effect on the basal level of short NK1R mRNA [39].
• We report here that human monocytic/macrophage THP-1 cells express the neurokinin 1 receptor (NK-1R), and that exposure of these cells to the proinflammatory cytokine IL-1 beta increased the expression of the NK-1R gene at the mRNA and protein levels [19].

Analytical, diagnostic and therapeutic context of TACR1

• Human IM9 lymphoblast cells express relatively high levels of the NK-1 receptor, and Northern blot analysis indicates modulation of mRNA levels by glucocorticoids and growth factors, suggesting that this cell line may be useful as a model for studying the control of NK-1 receptor gene expression [20].
• In situ hybridization indicated NK1-receptor mRNA was expressed in submucosal glands and airway epithelial cells, whereas NK2-receptor and NK3-receptor mRNA were not detected [1].
• Functional cDNA clones for human NK-1 receptor were isolated from human lung RNA using the polymerase chain reaction (PCR) [40].
• Chemically unfixed and fixed specimens, TRITC and PAP stainings and a battery of NK-1 receptor antibodies, including antibodies against the C-terminus and the N-terminal region, were utilized [41].
• Consistent with this observation, immunohistochemistry revealed NK1 receptor immunoreactivity to be largely restricted to a subset of GABA interneurones [42].

References