Disease relevance of TAC3

• 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 [1].
• By contrast, staining for NKB was only observed in ganglion cells and in the nerve fiber layer [2].
• In human pregnancy, the expression of NKB was confined to the outer syncytiotrophoblast of the placenta, significant concentrations of NKB could be detected in plasma as early as week 9, and plasma concentrations of NKB were grossly elevated in pregnancy-induced hypertension and pre-eclampsia [3].
• We conclude that elevated levels of NKB in early pregnancy may be an indicator of hypertension and pre-eclampsia, and that treatment with certain neurokinin receptor antagonists may be useful in alleviating the symptoms [3].
• We describe here the establishment and characterization of a novel human ovarian cancer cell line, TAC3, which has high anchorage-independent growth ability [4].

Psychiatry related information on TAC3

• Neurokinin B (NKB), a decapeptide of mammalian origin exhibits a variety of biological activities such as regulatory functions in reproduction, pre-eclampsia and neuroprotection in Alzheimer's disease [5].

High impact information on TAC3

• Here we have cloned a complementary DNA from human placental messenger RNA encoding a precursor protein of 121 amino acids which gives rise to a mature peptide identical to the neuropeptide neurokinin B (NKB) of other mammalian species [3].
• Individuals homozygous for the NKB complementation groups have fewer circulating NK cells than individuals heterozygous for these alleles and alleles of other complementation groups, possibly explaining the low activity of cells in these subjects [6].
• RESULTS: Tachykinins produced concentration-dependent increases in tension in circular and longitudinal muscle strips, with the following order of potency: beta-Ala(8)-neurokinin (NK) A (4-10) > NKB > substance P, suggesting NK(2) receptor involvement [7].
• In contrast, specific NK binding sites were not observed in any area of the human colon [1].
• A methylation interference assay revealed the critical G residues (from -167 to -151) for the DNA-protein complex formation specific to the cytokine response, and within this region the novel kappaB sequence, the promoter distal kappaB (pdkappaB) element (5'-GGGGAAG TAC-3'), was identified [8].

Chemical compound and disease context of TAC3

• Placental neurokinin B (NKB) was recently identified as the causative agent in preeclampsia, a condition characterized by increased maternal and feto-placental vascular resistance [9].
• We investigated the contractility of isolated human neurogenic bladders taken from patients with myelomeningocele or sacral agenesis, and tested the response to neurokinin A (NKA), neuromedin K (NKB), and substance P (SP) [10].

Biological context of TAC3

• Using selective receptor antagonists, we found that NKB-induced vasodilation is through the NK(1) receptor subtype [11].
• We hypothesized that NKB is a paracrine modulator of tone in the fetal placental circulation [11].
• Tachykinins (TKs), substance P (SP), neurokinin A (NKA) and B (NKB) are important peptide modulators of intestinal motility in animal species studied so far, including humans [12].
• These data demonstrate that human menopause is associated with marked increases in hypothalamic NKB and SP gene expression [13].
• Excessive secretion of placental NKB into the maternal circulation during the third trimester of pregnancy has been found in women suffering from PE [14].

Anatomical context of TAC3

• We found, for the first time, that TAC3 and TACR3 mRNAs are expressed in human airways and pulmonary arteries and veins, providing further evidence for the involvement of this system in lung physiopathology [15].
• There is recent evidence that NKB is expressed by the syncytiotrophoblast of the human placenta, an organ that is not innervated [11].
• The mammalian tachykinins [substance P and neurokinin (NK) A and NKB] elicited concentration-dependent contractions of human esophageal smooth muscle [16].
• Binding sites for NK were not detected in any part of the human GI tract [17].
• METHODS: Comparison of the time-activity curve (TAC) of the left hemiscrotum with those of the femoral artery and femoral muscle identified three types of scrotal TAC:TAC-1 peaked as rapidly as in the femoral artery; TAC-3, as slowly as in femoral muscle, and TAC-2, intermediate between these [18].

Associations of TAC3 with chemical compounds

• A reverse transcription-polymerase chain reaction (RT-PCR) assay was used to analyse the expression of TAC1 and TAC3, the genes that encode substance P/neurokinin A and neurokinin B, respectively, and the genes encoding the tachykinin NK(1), NK(2) and NK(3) receptors in different human tissues [15].
• We have also identified a residue (Leu292) which appears to play a minor role in the binding of substance P (SP) and neurokinin B (NKB) to the NK2 receptor [19].
• NKB and [Lys5,methyl-Leu9,Nle10]NKA(4-10) displaced [3H]ALIE-124 binding but with lower potency, whereas senktide had no affinity [20].
• Our data show that NKB is a dilator of the fetal vasculature, causing a maximal 25.1 +/- 4.5% (mean +/- SEM; n = 5) decrease in fetal-side arterial hydrostatic pressure (5- microM NKB bolus; effective concentration in the circulation, 1.89 nM) after preconstriction with U-46619 [11].
• When experiments were repeated in the presence of SR140333 (0.1 microM), the curve for SP became monophasic and showed a significant shift to the right, whereas curves to NKA and NKB were unaffected [21].

Physical interactions of TAC3

• The order of potency of the three neurokinins substance P, neurokinin A and neuromedin K was consistent with published data and results from ligand binding studies performed with the same NK2 test cell line [22].

Regulatory relationships of TAC3

• All three spantides failed to antagonize NKB-induced calcium responses at the NK3 receptor [23].

Other interactions of TAC3

• The mutant receptor Leu292-->Ser binds NKB and SP with approximately a 5-fold greater affinity in comparison with the wild type receptor while the affinity of NKA remains unaffected [19].
• SP, NKA, NKB and FK888 exhibited similar affinities for [125I]-BH-SP binding sites in both guinea pig arteries and bronchi.(ABSTRACT TRUNCATED AT 250 WORDS)[24]
• The potent and selective NK1 and NK3-receptor antagonists, SR 140333 and SR 142801 (both 0.1 microM), failed to inhibit contractions induced by SP or NKB [25].
• Tachykinin receptor subtypes were initially defined using agonist potency rations for the endogenous ligands substance P (SP), neurokinin (NK) A, and NKB [26].
• We propose that neurons containing estrogen receptor, SP, and NKB mRNAs participate in the hypothalamic circuitry regulating estrogen negative feedback in the human [13].

Analytical, diagnostic and therapeutic context of TAC3

• Semen analysis showed improved total motile sperm counts in 58.8, 69.2 and 26.7% of TAC-1, TAC-2, and TAC-3 patients, respectively [18].
• To understand the molecular regulation, we have compared the differences in gene expression of the tachykinins and their receptors in control and pre-eclamptic placentae and the responses of the TAC3 gene encoding NKB to proposed physiological triggers of pre-eclampsia including hypoxia and oxidative stress using real-time quantitative PCR [27].
• In situ hybridization histochemistry was used to map the distribution of neurons expressing the substance P (SP) or neurokinin B (NKB) genes in the human hypothalamus and basal forebrain [28].
• The contractile response to substance P (SP), neurokinin A (NKA) and arginin-neurokinin B (Arg-NKB) (a water soluble analogue of NKB) was investigated in detrusor muscle strips from the dome of the urinary bladder obtained from patients undergoing total cystectomy for carcinoma of the bladder base [29].
• Using immunocytochemistry, we describe here for the first time in adult rats, a conspicuous sex-difference in its axonal wiring by intrinsic glutamatergic neurons containing the neuropeptides neurokinin B (NKB) and dynorphin [30].

References