Disease relevance of TACR2

• For pharmacological comparison, we also transfected the human NK-2R into mouse erythroleukemia cells [1].
• These data suggest that infection of Sf-21 cells with baculovirus expression vector harboring the cDNA of hNK-2R resulted in expression of high affinity, G protein-coupled hNK-2R, with pharmacological selectivity compatible with the NK-2A receptor subtype [2].
• 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 [3].
• 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 [4].
• The NK-2 receptor antagonist SR 48968C does not improve adenosine hyperresponsiveness and airway obstruction in allergic asthma [5].

Psychiatry related information on TACR2

• In the same preparation MEN 11420 (0.1 microM) blocked (apparent pK(B) = 8.2) the potentiation of spontaneous motor activity produced by the NK2 receptor-selective agonist [betaAla8]NKA(4-10) [6].

High impact information on TACR2

• CONCLUSIONS: IL-1 beta-induced colonic hypersecretion in vivo involves NK1- and NK2-receptor activation in cascade, suggesting a release of substance P and neurokinin A acting through NO release [7].
• The strips were contracted by substance P and neurokinin A as well as by selective NK-2-receptor ligands, [beta Ala8]neurokinin A(4-10), and MDL 28,564, the latter peptide being capable of discriminating between NK-2-receptor subtypes [8].
• Here we show that two distinct phospholipase C-coupled receptors (those for neurokinin A and endothelin) share the same, homogeneously distributed PIP2 pool at the plasma membrane, even though the neurokinin A receptor is localized to microdomains and is cholesterol dependent in its PIP2 signaling whereas the endothelin receptor is not [9].
• The binding affinities of the natural peptide ligands, substance P and neurokinin A, were not affected by exchanging almost the entire C-terminal half of the NK1 receptor with the corresponding segment of the NK2 receptor [10].
• Although SP and NK-A can bind to either NK-1, NK-2, or NK-3 receptors (R), they have preferences for NK-1R and NK-2R, respectively [11].

Biological context of TACR2

• The results suggest that intramembranous residues, as well as residues which lie close to the extracellular side of transmembrane helices 3, 5, and 6, form part of the NK2 receptor binding site [12].
• The NK2 receptor mediates circular muscle contraction, whereas the role of the NK1 receptor in circular muscle is unclear [13].
• The selective tachykinin NK2 receptor antagonist, MEN 10627 (0.01-1 microM), likewise produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. (IC50 = 0.07 microM) and contraction (IC50 = 0.03 microM) [14].
• Tachykinins enhanced the expression of this cytokine in both control and rheumatoid monocytes and NK2 receptor stimulation was shown to trigger an enhanced respiratory burst in monocytes from rheumatoid patients [15].
• Analysis of EcoRI digests of genomic DNA from human-mouse cell hybrids indicates a single gene for the human NK-2 receptor localized to chromosome 10 [16].

Anatomical context of TACR2

• Its release within the bone marrow (BM) can mediate bidirectional neurohematopoietic communication via specific receptors: neurokinin-1R (NK-1R), NK-2R, or NK-3R [17].
• [3H]NKA bound in a protein-dependent, saturable (Bmax = 820 +/- 167 fmol/mg of protein), and highly specific (88 +/- 5%) manner to hNK-2R, but not to membranes from cells infected with wild-type virus (14 +/- 8%, 7 +/- 10 fmol/mg of protein) [2].
• The data from ligand binding assays in cloned receptors combined with functional receptor assays in airway smooth muscles, demonstrate that the nonpeptide antagonist ZM253,270 is selective for the NK2 receptor species that are prevalent in hamster, compared with those found in human tissues [18].
• These data 1) show for the first time that hHK-1 is a uterine stimulant in the human, 2) confirm that the NK2 receptor is predominant in mediating tachykinin actions on the human myometrium, and 3) indicate that mammalian tachykinin effects are tightly regulated during pregnancy in a manner that would negate an inappropriate uterotonic effect [19].
• Tachykinin NK1 and NK2 receptor selective antagonists and agonists were used to study excitatory non-adrenergic non-cholinergic (NANC) transmission in circular muscle strips from human ileum by the sucrose-gap method [14].

Associations of TACR2 with chemical compounds

• Site-directed mutagenesis was used to alter these residues in order to ascertain their importance in binding neurokinin A (NKA), the physiological peptide ligand for the NK2 receptor, and the non-peptide NK2 receptor selective antagonist SR48968 [12].
• 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 [19].
• The NK2 receptor selective agonist, [beta Ala8]NKA(4-10) (10 nM), produced a maximum enhancement of 278 +/- 83.5% (P < 0.01) (pD2 = 8.7 +/- 0.1) an effect which was blocked by MEN 10,376 (100 nM) (P < 0.05) and not by CP 96,345 [20].
• These inhibitory effects were reversed in the presence of the CB(1) receptor-selective antagonist N-(piperidine-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (10(-7) M).ACEA did not alter LM or CM contractile responses to acetylcholine or NK-2 receptor-evoked contraction [21].
• The effect of SP was antagonised by two selective antagonists of NK1 receptors, namely (+/-) CP 96,345 (10(-10)-10(-8) M) and FK 888 (10(-9)-10(-7) M), while the NK2 receptor antagonist MEN 10627 (10(-8)-10(-7) M) was not effective [22].

Physical interactions of TACR2

• These results suggest that some regions of the binding site for NKA in the NK2 receptor are not used for binding SP in the NK1 receptor [12].
• 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 [23].
• Analogues of [Leu10]NKA4-10 were synthesized in which each of the amide bonds was sequentially replaced with the reduced amide psi (CH2NH) bond to determine the effect of this structural modification on the antagonism of NKA binding to the HUB NK2 receptor [24].

Regulatory relationships of TACR2

• NK2 receptor stimulation also triggered an enhanced respiratory burst in monocytes isolated from rheumatoid arthritis (RA) patients [25].
• The stimulatory effects on BM progenitors mediated by NK-1R can be partly inhibited by NK-2R activation [26].
• A single mutation of the neurokinin-2 (NK2) receptor prevents agonist-induced desensitization. Divergent conformational requirements for NK2 receptor signaling and agonist-induced desensitization in Xenopus oocytes [27].
• The human ileum neurokinin NK2 receptor has been stably expressed in Chinese hamster ovary (CHO) cells using the dihydrofolate reductase (DHFR) expression system [28].
• In the present study, endothelin A receptor and neurokinin A receptor were coexpressed in Xenopus laevis oocytes in an effort to characterize heterologous desensitization of the receptors that activate phospholipase C-beta [29].

Other interactions of TACR2

• Using the novel ligand [4,5-3H-Leu9]neurokinin A ([4,5-3H-Leu9] NKA) in a receptor binding assay, we characterized the pharmacology of a cloned neurokinin NK-2 receptor from human lung (hNK-2R), expressed in baculovirus-infected Sf-21 insect cells [2].
• 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 [3].
• We have characterized the action of the novel, water-soluble, tachykinin NK2 receptor antagonist MEN 11420 ([Asn(2-AcNH-beta-D-Glc)-Asp-Trp-Phe-Dap-Leu] c(2 beta-5 beta)) on the circular muscle of the guinea-pig and human colon in vitro and on the guinea-pig colon in vivo [30].
• Sequence analysis of exons 1 and 5, where major differences occur between the human and animal species, provided information for polymerase chain reaction primers which allowed us to prepare full-length cDNA for the human NK-2 receptor [16].
• Secondly, NK-2 receptor-linked AA mobilization requires concomitant PKC activation and based upon limited subtype immunodetectability as well as toxin, identical pretreatment inhibits AA release partially and blocks PKC alpha translocation completely [31].

Analytical, diagnostic and therapeutic context of TACR2

• Functional cDNA clones for human NK-2 receptor were isolated from human lung RNA using a polymerase chain reaction (PCR) based method (RACE-PCR) [32].
• One such candidate is the neurokinin-2 receptor (NK2R), and clinical trials to assess the antidepressant effects of NK2R antagonists are currently underway [33].
• After oral administration of ZD6021, the time to peak activity was 150 min for the NK1 receptor and 60 min for the NK2 receptor with pharmacodynamic half-lives of 280 and 458 min, respectively [34].
• Dog urinary bladder contractility to a series of TK-receptor agonists also suggests a predominance of NK2-receptor activation by tachykinins and indicates the dog may provide a useful model for the development of pharmacotherapy for bladder hyperreflexia [35].
• Nuclear run-on assays revealed a 51% reduction in the rate of tachykinin NK2 receptor gene transcription after treatment with dexamethasone for 6 h [36].

References