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)

Recent evidence suggests that neural transmitters, including neuropeptides, may modulate the release of mast cell mediators. Because neuropeptide Y (NPY) has recently been recognized as a putative cotransmitter in noradrenergic neurons, we studied the effect of NPY on purified rat peritoneal mast cells. NPY induced mast cell degranulation, as assessed by a dose-dependent increase in net release of beta-hexosaminidase. The concentration that produced 50% of the maximal effect, approximately 10 mumol/L, evoked a 40% +/- 3% release. As previously reported for other neuropeptides, release was fast with maximal release already achieved at 60 seconds. Release was at 4 degrees C. In contrast to its effects on mast cell degranulation, NPY had no effect on the generation of prostaglandin D2, the major mast cell cyclooxygenase product. By comparison, the calcium ionophore A23187, at doses (4 mumol/L) that evoked comparable release of beta-hexosaminidase, stimulated a net release of 37 +/- 9 ng of PGD2 per 10(6) mast cells. These results raise the possibility that NPY may act as a modulator between the autonomic nervous system and mast cells. The results also imply that with neuropeptide stimulation, the release of preformed and newly formed mast cell mediators are mediated through independent pathways.
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PMID:Neuropeptide Y, a putative cotransmitter in noradrenergic neurons, induces mast cell degranulation but not prostaglandin D2 release. 182 2

Recent studies have identified a major contribution of the nervous system to inflammation and to inflammatory disease. In particular, substances released from the peripheral terminals of small diameter primary afferent fibers and from sympathetic postganglionic nerve (SPGN) terminals have been implicated in several of the major components of acute inflammation (e.g., vasodilatation and plasma extravasation) as well as in the regulation of tissue injury in an inflammatory disease model, experimental arthritis in the rat. Although the release of peptides from primary afferent terminals has received the most attention, our studies have established an important contribution of mast cells and the SPGN terminals to acute inflammation. We describe studies which indicate that plasma extravasation provoked by activation of small diameter primary afferents in the knee joint of the rat involves a cascade of events in which the mast cell and then the sympathetic terminal are sequentially activated. Our studies indicate that release of prostaglandins, but neither norepinephrine nor neuropeptide Y, from the SPGN terminal contributes to increased plasma extravasation. Although activation of the SPGN terminal (via the mast cell) or more directly, via injection of bradykinin, increased plasma extravasation, surgical or pharmacological sympathectomy decreased the severity of experimental arthritis. In related studies we demonstrated that adrenal medullary-derived epinephrine can exacerbate arthritis through a beta-receptor-mediated regulation of the release of an as yet unidentified substance(s) from the SPGN terminal. Our results raise important questions as to whether acute inflammation contributes to tissue repair or to further injury in the setting of disease.
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PMID:The contribution of the nervous system to inflammation and inflammatory disease. 186 15

The nasal mucosa is innervated by the sensory, parasympathetic, and sympathetic nervous systems. Nociceptive sensory nerves are stimulated by mucosal injury, inhalation of irritants, or mast cell degranulation and release of the calcitonin gene-related peptide, the tachykinins substance P and neurokinin A, and other peptides by the axon response mechanism. Sensory nerve stimulation initiates systemic reflexes, such as the sneeze, and central parasympathetic reflexes which release acetylcholine, vasoactive intestinal peptide, and other peptides and lead to glandular secretion. In concert, these proinflammatory neural responses lead to vasodilation, vascular permeability, and glandular secretion. Sympathetic nerves release neuropeptide Y and norepinephrine, potent vasoconstrictors which act to decompress the nasal mucosa and produce nasal patency. The balance between the effects of parasympathetic and sympathetic neurotransmitters may regulate nasal homeostasis, whereas the nociceptive sensory system may be held in reserve as a defense mechanism. Dysfunction of these systems may lead to pathological nasal syndromes. In the future, specific neuropeptide agonists and antagonists may be useful for the treatment of human rhinitic diseases.
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PMID:Neuropeptides and nasal secretion. 192 55

Recent research has disclosed that neurotransmitters and neuropeptides released within the autonomic nervous system exert homeostatic control of nasal secretion. Although cholinergic and adrenergic influences have long been thought to be the predominant mechanisms, the nonadrenergic, noncholinergic responses may have more suitable, longer-lasting effects. Peptides from sensory nerves, such as calcitonin gene related peptide, substance P, and neurokinin A, may participate in axon response-mediated vasodilation and plasma extravasation. Substance P and gastrin releasing peptide may induce glandular secretion. Defensive responses to local mucosal injury may be amplified by axon response, which initiates these vascular and glandular reactions. Cholinergic effects are primarily responsible for mediating parasympathetic reflexes, but vasoactive intestinal peptide may regulate acetylcholine release, augment glandular secretory responses, and have a vasodilatory effect. In the sympathetic nervous system, neuropeptide Y probably functions as a long-acting vasoconstrictor. Integration of sympathetic and parasympathetic influence may regulate the normal nasal cycle, and sensory and parasympathetic defensive reflexes may respond to epithelial and mast cell stimulation. It is possible, then, that the pathophysiology of vasomotor rhinitis involves an exaggeration of these neural influences.
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PMID:Neuropeptides and nasal secretion. 222 24

Changes in vascular tone brought about by electrical field stimulation were studied in isolated guinea-pig and monkey pial arteries, using stimulus intensities similar to, or weaker than, those usually utilized by other investigators. In the guinea-pig, excitation of the smooth muscle cells was easily induced, even at low intensity stimulus parameters. This contraction faded upon repeated stimulation. Certain characteristics indicated that the response was neurogenic with excitation of perivascular sympathetic nerve terminals, despite the fact that it persisted after treatment with guanethidine and phentolamine and was only little reduced by tetrodotoxin; surgical sympathectomy or pretreatment with reserpine abolished the response, whereas removal of endothelium or mast cell degranulation was without effect. Attempts were made to further characterize the substance released. It was probably not noradrenaline, neuropeptide Y, adenosine triphosphate, serotonin, histamine or acetylcholine. In the monkey, similar low intensity stimulus parameters induced a fully tetrodotoxin-sensitive contractile response, attributable to the release of noradrenaline alone. By a minor increase in stimulus intensity, tetrodotoxin-resistant contractions, probably due to direct smooth muscle activation, could easily be obtained in pial arteries from both species. Tests were also performed to elucidate whether a dilatation, caused by a neurogenic transmitter release, could be obtained in these vessels. In both species, however, only a tetrodotoxin-resistant response was found, even at weak stimulus intensities, in agreement with previous observations in vessels from several other species. The present data illustrate the need for a careful choice of stimulus parameters when vascular tonic responses upon electrical field stimulation are used as an index for neurogenic release. They also demonstrate that such a response may, indeed, be neurogenic despite marked resistance to tetrodotoxin.
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PMID:Characterization of the contractile and dilatory responses to electrical field stimulation in guinea-pig and monkey isolated pial arteries. 261 29

The common pathway of heterogenous mast cell activation as mediated by antigens is through the cross-linking of IgE bound to Fc epsilon RI receptors. The peptidergic pathway of mast cell activation, achieved by cationic secretagogues, is restricted to "serosal" mast cells, the experimental models being rat peritoneal and human skin mast cells. Cationic secretagogues include positively charged peptides but also various amines such as compound 48/80 and natural polyamines. An early intracellular event of this pathway is the activation of pertussis toxin-sensitive G proteins. The correlation observed between the ability of basic compounds to trigger mast cell exocytosis and their potency to activate purified G proteins strongly suggests that cationic compounds activate mast cell G proteins via a receptor-independent but membrane-assisted process. In this paper, alternative mechanisms are discussed. The consequence of G protein stimulation is the activation of phospholipase C with an increase in inositol triphosphates. Natural polyamines are relatively poor triggers of mast cells (10(-4) to 10(-2) M). Neuropeptides such as substance P, neuropeptide Y or vasoactive intestinal peptide, peptidic hormones such as kinins, and venoms such as mastoparan and mast cell degranulating peptide, are all active in a concentration range from 10(-7) to 10(-4) M. The cationic anaphylatoxin C3a also stimulates mast cells at concentrations below precursor complement C3 blood levels. The component C3 of the complement system is one of only a few plasma proteins having activation fragments (i.e. C3a) that can be generated at micromolar levels. The effects of basic secretagogues defines a peptidergic pathway of mast cell activation, which represents a potentially toxic process considering the tissue effects caused by exogenous basic compounds such as venom peptides and certain amine containing drugs. Peptidergic activation of mast cells may also be a pathophysiological process having an important role in neurogenic inflammation and in diseases involving extensive activation of the blood complement cascade.
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PMID:Peptidergic pathway in human skin and rat peritoneal mast cell activation. 751 63

Recent evidence suggests that peptides induce the release of mediators from rat peritoneal mast cell by means of a receptor-independent mechanism, possibly involving an interaction with sialic acid residues at the cell surface followed by the activation of a guanine nucleotide binding protein (G protein). We have now examined the potential involvement of sialic acid residues and of G protein stimulation in the activation of both human and rat cutaneous mast cells by neuropeptide Y, its C-terminal fragments and the wasp venom peptide, mastoparan. Neuropeptide Y-(18-36) was the most effective histamine releaser of the fragments tested, the order of potency being neuropeptide Y-(18-36) > neuropeptide Y-(22-36) > neuropeptide Y-(1-36). This order of potency suggests that the effects of the peptides are not mediated through classical NPY receptors. The hydrolysis of sialic acid residues by neuraminidase and the inhibition of G proteins by benzalkonium chloride or pertussis toxin significantly inhibited the secretory response of cutaneous mast cells to neuropeptide Y-(18-36) and mastoparan. These results demonstrate that the peptidergic pathway described for the activation of peritoneal rat mast cells is also involved in the response of cutaneous human and rat mast cells to peptides.
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PMID:Human and rat cutaneous mast cells: involvement of a G protein in the response to peptidergic stimuli. 753 61

The distribution of nerves and mast cells was studied in the lacrimal glands of 3-5-, 14- and 24-month-old rats, using light microscopic histochemical and immunohistochemical techniques. In 14-month and, to a greater extent, in 24-month-old rats there were signs of chronic inflammation and patchy destruction of acinar, ductal and vascular tissue. The glands of the three different age groups contained acetylcholinesterase (AChE), vasoactive intestinal polypeptide (VIP)-, neuropeptide Y (NPY)-, calcitonin gene-related peptide (CGRP)-, tyrosine hydroxylase-, substance P- and the phosphoprotein B-50-immunoreactive nerves. B-50-immunoreactive nerves were distributed around acini, blood vessels and ducts, in a similar manner to VIP and AChE. Substance P- and CGRP-immunoreactive nerves were sparsely distributed in interlobular connective tissue and around ducts and blood vessels. Tyrosine hydroxylase- and NPY-containing nerves were found around blood vessels. The 3-5- and 14-month-old rats had a similar pattern of innervation, however, by 24 months there was a reduction in the number and intensity of immunoreactive nerves. The loss of nerves was particularly associated with damage to the gland. Mast cells were also found in the lacrimal, mostly associated with neurovascular tissue. These could be histochemically labelled with alcian blue/safranin or toluidine blue and were immunohistochemically labelled with histamine and serotonin. Substance P-, CGRP-, VIP- and NPY-immunoreactive nerves were found apposed to mast cells. A large increase in mast cells was observed in 24-month compared to 3-5-month-old rats and these were found throughout the acinar tissue. These results show that a decrease in innervation and also chronic inflammation, with mast cell infiltration, occurs in aged rats. These findings may be contributing factors to reduced tear output in aging.
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PMID:Innervation and mast cells of the rat exorbital lacrimal gland: the effects of age. 818 88

The proteolytic cleavage product of complement component 3, (C3a), is like C4a and C5a, is a potent anaphylatoxin and induces the production of inflammatory mediators in phagocytes. Notably, mast cells respond to C3a with the release of vasoactive substances, including histamine. We have examined the function and receptor binding of C3a in a human leukemic mast cell line, HMC-1. Similar to chemoattractant agonists in leukocytes, C3a induced rapid cytosolic free calcium concentration increases in HMC-1 cells. EGTA did not diminish this response, indicating that mobilizable Ca2+ was from intracellular stores. Receptors of C3a in HMC-1 cells couple in part to Bordetella pertussis toxin-sensitive G-proteins and, therefore, appear to belong to the family of serpentine receptors that require G-proteins for signal transduction. HMC-1 cells express two types of C3a receptors, C3aR1 and C3aR2, that were shown to bind 125I-C3a with high-(Kd1 = 2.1-4.8 nM) or low-affinity (Kd2 = 30-150 nM), and both receptors are expressed at high level: 3 x 10(5)-6 x 10(5) C3aR1/cell and 5 x 10(5)-2.3 x 10(6) C3aR2/cell. Results from cross-linking experiments with 125I-C3a fully agree with the presence of two different classes of C3a receptors in HMC-1 cells. Two membrane proteins with apparent molecular masses of 54-61 kDa (p57) and 86-107 kDa (p97) could be covalently modified with 125I-C3a, and this cross-linking was inhibited with an excess of unlabeled C3a. Many of the known agonists for leukocytes including 13 chemokines (IL-8, NAP-2, GRO alpha, ENA-78, IP10, PF4, MCP-1, 2 and 3, RANTES, MIP-1 alpha, MIP-1 beta and I309), three neuropeptides (neuropeptide Y, somatostatin and calcitonin), as well as C5a, did not activate HMC-1 cells, indicating that C3a is one of a few protein ligands for which this cell line expresses specific receptors. The apparent selectivity for C3a and the abundant expression of C3a receptors make the HMC-1 cell line an excellent choice for the cloning of the receptor genes.
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PMID:Expression of high- and low-affinity receptors for C3a on the human mast cell line, HMC-1. 862 64

Mast cell activation by polycationic substances is believed to result from a direct activation of G protein alpha subunits and it was suggested that the adaption of amphipathic, alpha-helical conformations would allow the peptide to reach the cytosolic compartment to interact with G proteins (Mousli et al., 194, Immunopharmacology 27, 1, for review). We investigated the histamine-releasing activity of model peptides as well as analogues of magainin 2 amide and neuropeptide Y with different amphipathicities and alpha-helix content on rat peritoneal mast cells. Amphipathic helicity is not a prerequisite for mast cell activation. Moreover, non-helical magainin peptides with high histamine-releasing activity were less active in the liberation of carboxyfluoresceine from negatively charged liposomes, indicating that peptide-induced mast cell activation and peptide-induced membrane perturbation do not correlate. In contrast to the negligible influence of the secondary structure, amino acid configuration may exert a striking influence on peptide-induced mast cell activation. Thus histamine-release by substance P was markedly impaired when the L-amino acids in the positively charged N-terminal region were replaced by D-amino acids, with [D-Arg1)substance P being the most inactive substance P diastreoisomer.
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PMID:Influence of alpha-helicity, amphipathicity and D-amino acid incorporation on the peptide-induced mast cell activation. 871 13


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