Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neurokinins are a group of naturally occurring peptides with the common C-terminal sequence Phe-X-Gly-Leu-Met.NH2. They include substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). SP and NKA are coded on the same gene, the PPT-A, while NKB is coded on a separate gene, the PPT-B. Neurokinins are present in the central nervous system and in peripheral organs where they exert various actions. They act on three receptors--NK-1, NK-2, and NK-3--characterized through pharmacological, biochemical, and histochemical studies. Selective agonists for each neurokinin receptor were developed and evaluated on isolated smooth muscle preparations containing only one neurokinin receptor type. All three neurokinin receptors were cloned and expressed in Xenopus oocytes. Relative affinities of those receptors to neurokinins are the same as in their respective smooth muscle preparation. Finally, the mechanism of action of SP on histamine release from rat peritoneal mast cell has been studied and a direct activation of G proteins by peptides with basic amino acids is proposed as a working hypothesis.
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PMID:Pharmacology of neurokinin receptors. 171 74

1. Human skin mast cells, unlike other human mast cells so far studied, released histamine in a concentration-related manner in response to substance P, vasoactive intestinal peptide (VIP) and somatostatin (1 microM to 30 microM). In contrast, eledoisin, physalaemin, neurokinin A, neurokinin B, calcitonin gene-related peptide (CGRP), neurotensin, bradykinin and Lys-bradykinin induced negligible histamine release. 2. The low histamine releasing activity of physalaemin, eledoisin, neurokinin A and neurokinin B relative to substance P suggests that the human skin mast cell activation site is distinct from the tachykinin NK-1, NK-2 or NK-3 receptors described in smooth muscle. 3. The relative potencies of substance P and its fragments SP2-11, SP3-11, SP4-11 and SP1-4 in releasing histamine from human skin mast cells suggests that both the basic N-terminal amino acids and the lipophilic C-terminal portion of substance P are essential for activity. 4. Peptide-induced histamine release, like that induced by compound 48/80, morphine and poly-L-lysine, is rapid, reaching completion in 10-20 s, is largely independent of extracellular calcium but requires intact glycolysis and oxidative phosphorylation. 5. The substance P analogue, [D-Pro4,D-Trp7,9,10] SP4-11 (SPA), not only reduced substance P-induced histamine release in a concentration-related manner but also inhibited that induced by VIP, somatostatin, compound 48/80, poly-L-lysine and morphine but not anti-IgE. 6. The similar characteristics of histamine release induced by substance P, VIP, somatostatin, compound 48/80, poly-L-lysine and morphine suggest that they share a common pathway of activation-secretion coupling distinct from that of IgE-dependent activation. Furthermore, the ability of human skin mast cells to respond to basic non-immunological stimuli including neuropeptides may reflect a specialised function for these cells.
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PMID:Characterization of neuropeptide-induced histamine release from human dispersed skin mast cells. 246 82

Mast cells of human skin, but not lung, adenoids, tonsils, or intestine, release histamine in response to substance P, vasoactive intestinal polypeptide, and somatostatin. The substance P receptor of skin mast cells is not of the NK-1, NK-2 or NK-3 subtypes of smooth muscle. Time course and calcium dependency of release by peptides differed from anti-IgE. With anti-IgE, the molar ratios of histamine:PGD2:LTC4 generated by skin mast cells was 1,000:25:2, whereas with substance P these ratios were 1,000:1:0.1. Similar results were obtained with the other neuropeptides. The ability of peptides to stimulate skin mast cell histamine release suggests a mechanism whereby their release from dermal nerve endings is coupled to changes in microvasculature.
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PMID:Interaction of neuropeptides with human mast cells. 246 22

A series of substance P (SP)- and bradykinin (BK)-related peptides have been compared for their histamine-releasing activities on rat peritoneal mast cells. Some of these peptides only differed in the N-acetylation of the N-terminal arginine residue or by the removal of charged residue at the N-terminal. The aim was to examine the role of the N-terminal positive charges in the histamine-releasing activity of compounds that are selective for the SP receptor (named NK-1) or for the B2 type bradykinin receptor. Only compounds with positive charges at the N-terminal caused non-cytotoxic histamine release from rat mast cells. It is suggested that SP- and BK-related peptides caused histamine release by a mechanism which appeared to be non-specific and not related to the activation of mast cell NK-1 or B2 receptors, respectively. Our results show that NK-1 agonists or B2 antagonists devoid of histamine-releasing activity, which could be of potential use in the clinic, can be obtained by removing the positively charged N-terminal aminoacids or by N-acetylation of the N-terminal arginine.
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PMID:Role of the N-terminal arginine in the histamine-releasing activity of substance P, bradykinin and related peptides. 247 72

Highly purified populations of lymphocytes were obtained from the murine intestinal mucosa using EDTA-collagenase isolation procedures in combination with discontinuous density centrifugation. Intraepithelial lymphocytes (IEL) were separated from lamina propria lymphocytes (LPL) and, within these two populations, fractions enriched or depleted in gut granular lymphocytes (gGL) were obtained. Using these cells in cytotoxic assays, it was shown that both IEL and LPL possess natural killer (NK) activity, and this was associated with gGL. The major effector cells of gut NK activity appeared to be Thy-1.2+, Lyt-1.1-, and Lyt-2.1-. The susceptibility of gut NK cells to anti-Thy-1.2 plus complement (C) was significantly higher than that of splenic NK cells. In contrast, anti-asialo GM1 and anti-NK-1.2 plus C only slightly affected the gut NK activity. Thus, the phenotype of the gut NK cells appears to be different from the splenic one and provides further evidence for NK heterogeneity and establishes the compartmentalization of one NK subpopulation. Beige mice, deficient in splenic NK activity, also had very low gut NK activity. W/Wv mice, which lack mast cell precursors, had normal numbers of gGL and diminished, but still present, gut and splenic NK activity. This deficiency did not segregate with the genes responsible for the basic hemopoietic stem cell defect, and these results argue against a close ontogenetic relationship between IEL, gGL, and intestinal mucosal mast cells. The relevance of these observations to the cell lineage of the effector cell of gut NK activity is discussed.
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PMID:Characteristics of natural killer cells in the murine intestinal epithelium and lamina propria. 707 24

We examined the effect of a novel tachykinin NK-2-receptor antagonist, N alpha-(tert-Butylcarbamoyl)-L-glutaminyl-L-tryptophyl-alpha-aza- phenylalanine 2-benzyloxyethylamide (TAC-363), on hyperventilation- and citric acid-induced bronchoconstriction and neurokinin A (NKA)-, capsaicin- and antigen-induced airway hyperresponsiveness in guinea pigs. The i.v. administration of TAC-363 at doses of 0.01-1 mg/kg inhibited hyperventilation- and citric acid-induced bronchoconstriction in a dose-dependent manner, while FK-888, a tachykinin NK-1-receptor antagonist, did not inhibit hyperventilation-induced bronchoconstriction. NKA-induced airway hyperresponsiveness to acetylcholine was attenuated by i.v. injection of TAC-363, but not by the thromboxane A2 synthetase inhibitor ozagrel and the mast cell stabilizer DSCG. Furthermore, TAC-363 prevented the occurrence of capsaicin- and antigen-induced airway hyperresponsiveness to acetylcholine, while FK-888 did not prevent occurrence of capsaicin-induced airway hyperresponsiveness. In summary, TAC-363 inhibits bronchoconstriction and airway hyperresponsiveness induced by various stimuli. These results suggest that NKA mediates bronchoconstriction and airway hyperresponsiveness. Thus, TAC-363 is expected to be useful in the treatment of airway diseases such as asthma.
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PMID:[Effect of a novel tachykinin NK-2-receptor antagonist, TAC-363, on bronchoconstriction and airway hyperresponsiveness in guinea pigs]. 906 96

Communication between nerves and mast cells is a prototypic demonstration of neuroimmune interaction. However, whether mast cell activation occurs as a direct response to neuronal activation or requires an intermediary cell is unclear. Addressing this issue, we used an in vitro coculture approach comprising cultured murine superior cervical ganglia and rat leukemia basophilic cells (RBLs; possesses properties of mucosal-type mast cells). Following loading with the calcium fluorophore, Fluo-3, neurite-RBL units (separated by <50 nm) were examined by confocal laser scanning microscopy. Addition of bradykinin, or scorpion venom, dose-dependently elicited neurite activation (i.e., Ca2+ mobilization) and, after a lag period, RBL Ca2+ mobilization. Neither bradykinin nor scorpion venom had any direct effect on the RBLs in the absence of neurites. Addition of a neutralizing substance P Ab or a neurokinin (NK)-1 receptor antagonist, but not an NK-2 receptor antagonist, dose-dependently prevented the RBL activation that resulted as a consequence of neural activation by either bradykinin or scorpion venom. These data illustrate that nerve-mast cell cross-talk can occur in the absence of an intermediary transducing cell and that the neuropeptide substance P, operating via NK-1 receptors, is an important mediator of this communication. Our findings have implications for the neuroimmune signaling cascades that are likely to occur during airways inflammation, intestinal hypersensitivity, and other conditions in which mast cells feature.
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PMID:Direct neurite-mast cell communication in vitro occurs via the neuropeptide substance P. 1045 75

Mast cell-neurite interaction serves as a model for neuroimmune interaction. We have shown that neurite-mast cell communication can occur via substance P interacting with neurokinin (NK)-1 receptors on the mucosal mast cell-like cell, the rat basophilic leukemia (RBL) cell. Neurite (murine superior cervical ganglia) and RBL cell [expressing the granule-associated antigen CD63-green fluorescent protein (GFP) conjugate] cocultures were established and stimulated with bradykinin (BK; 10 nM) or scorpion venom (SV; 10 pg/ml), both of which activate only neurites. Cell activation was assessed by confocal imaging of Ca2+ (cells preloaded with fluo 3), and analyses of RBL CD63-GFP+ granule movement were conducted. Neurite activation by BK or SV was followed by RBL Ca2+ mobilization, which was inhibited by an NK-1 receptor antagonist (NK-1 RA). Moreover, membrane ruffling was observed on RBL pseudopodial extensions in contact with the activated neurite, but not on noncontacting pseudopodia. RBL membrane ruffling was inhibited by NK-1 RA, but not NK-2 RA, and was accompanied by a significant increase in granule movement (0.13 +/- 0.04 vs. 0.05 +/- 0.01 microm/s) that was most evident at the point of neurite contact: many of the granules moved toward the plasmalemma. This is the first documentation of such precise (restricted to the membrane's contact site) transfer of information between nerves and mast cells that could allow for very subtle in vivo communication between these two cell types.
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PMID:Nerve-mast cell (RBL) interaction: RBL membrane ruffling occurs at the contact site with an activated neurite. 1238 97

Migraine headaches are often precipitated by stress and seem to involve neurogenic inflammation (NI) of the dura mater associated with the sensation of throbbing pain. Trigeminal nerve stimulation had been reported to activate rat dura mast cells and increase vascular permeability, effects inhibited by neonatal pretreatment with capsaicin implicating sensory neuropeptides, such as substance P (SP). The aim of the present study was to investigate NI, assessed by extravasation of 99-Technetium-gluceptate (99Tc-G), as well as the role of mast cells, SP and its receptor (NK-1R) in dura mater of mice in response to acute stress. Restraint stress for thirty min significantly increased 99Tc-G extravasation in the dura mater of C57BL mice. This effect was absent in W/W(v) mast cell-deficient mice and NK-1 receptor knockout mice (NK-1R-/-), but was unaltered in SP knockout mice (SP-/-). Acute restraint stress also resulted in increased dura mast cell activation in C57BL mice, but not in NK-1R-/- mice. These data demonstrate for the first time that acute stress triggers NI and mast cell activation in mouse dura mater through the activation of NK-1 receptors. The fact that SP-/- mice had intact vascular permeability response to stress indicates that some other NK-1 receptor agonist may substitute for SP. These results may help explain initial events in pathogenesis of stress-induced migraines.
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PMID:Stress-induced dura vascular permeability does not develop in mast cell-deficient and neurokinin-1 receptor knockout mice. 1286 61

Neuropeptides such as substance P (SP) and related peptides are supposed to act as mast cell agonists, and thus as mediators of neuroimmune interactions. The data supporting this hypothesis were obtained mostly from rodent experiments. Here, we studied for the first time the effect of SP and other peptides on mediator release in human intestinal mast cells, either unpurified or enriched to 85-99% purity. We found that SP at 0.1-100 micromol L(-1), or other peptides including neurokinin A and B, calcitonin gene-related peptide, vasoactive intestinal peptide and serotonin at 1 micromol L(-1) do not induce release of mediators such as histamine, sulphidoleukotrienes, and tumour necrosis factor alpha. The peptides also failed to cause mediator release in mast cells isolated from inflamed tissue derived from Crohn's disease. Using reverse transcriptase-polymerase chain reaction, flow cytometry and immunohistochemistry, we could show that human intestinal mast cells do not express the tachykinin receptors NK-1, NK-2, or NK-3 under basal conditions. However, upon stimulation by immunoglobulin E (IgE) receptor-crosslinking, which induces an extensive mediator release reaction, a subpopulation of mast cells clearly expressed NK-1, the SP receptor. In conclusion, our data show that SP and other neuropeptides do not act as secretagogues in human intestinal mast cells that have not been pre-activated by IgE receptor-crosslinking.
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PMID:Substance P and other neuropeptides do not induce mediator release in isolated human intestinal mast cells. 1508 72


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