Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to search for microbial modulators of the activity of neuropeptide, we established a screen based on substance P (SP)-induced myeloperoxidase (MPO) release from human polymorphonuclear leukocytes (PMN). SP induced MPO release in a dose-dependent manner at concentrations ranging from 1 approximately 10 x 10(-4) M. In comparison at 1 x 10(-4) M, induction was also observed with SP derivatives but not with other neuropeptides such as neurokinin and enkephalin. Based on this, we searched for microbial inhibitors against SP-induced MPO release. An actinomycete metabolite designated HS3, which turned out to be identical with dioxapyrrolomycin or A1-R2081, and structurally related pyrrolomycins were found to inhibit SP-induced MPO release. In addition, these compounds inhibited the f-Met-Leu-Phe (FMLP)-induced MPO release from PMN. Pyrrolomycin derivatives with an N-methylated pyrrole ring showed, however, a selective inhibition of the SP-induced MPO release. This was in contrast to results with aseanostatin P5 which selectively inhibited FMLP-induced MPO release.
 ...
PMID:Pyrrolomycin group antibiotics inhibit substance P-induced release of myeloperoxidase from human polymorphonuclear leukocytes. 171 7

Bilateral injection of endogenous tachykinins (substance P (SP), neurokinin A (NKA)) and selective neurokinin receptor ligands (senktide, [Sar9,Met(O2)11]SP, [MePhe7]NKB) into the substantia nigra reticulata increased striatal dopamine and serotonin metabolism. The increase in dopamine metabolism in the dorsal striatum at a low dose of the substances may be a direct effect on dopamine neurons in the substantia nigra reticulata via NK1 and NK3 receptors. The lack of effect at intermediate doses may be due to inhibitory mechanisms or desensitization. The changes after high doses in the dorsal and ventral striatum may be due to actions on dopaminergic neurons in the substantia nigra as well as in the ventral tegmental area, since there was considerable diffusion from the site of injection. An apparent rapid degradation of injected SP or NKA indicates that N-terminal SP fragments may participate in the SP response. The increased serotonin metabolism that occurs only at a high dose may involve all three neurokinin receptors.
 ...
PMID:Injection of tachykinins and selective neurokinin receptor ligands into the substantia nigra reticulata increases striatal dopamine and 5-hydroxytryptamine metabolism. 171 5

1 Plasma extravasation in the rat knee joint was induced by intra-articular injection of neurokinins and specific neurokinin receptor agonists. 2 Pronounced plasma extravasation was produced by substance P (SP, 4-185 microM) and to a lesser extent by neurokinin-B (NKB, 83-413 microM), whereas neurokinin-A (NKA, 88-440 microM) and calcitonin gene-related peptide (CGRP, 26-130 microM) had no significant effect. 3 The specific neurokinin1 receptor agonist [Sar9, Met(O2)11]-substance P (NK1 agonist) in doses of 0.4-70 microM appeared to be more potent than SP in eliciting plasma extravasation. The neurokinin2 receptor agonist [Nle10]-neurokinin A4-10 (NK2 agonist) was not effective at 70 microM but produced a small and significant effect at 330 microM, whereas the neurokinin3 receptor agonist [MePhe7]-neurokinin B (NK3 agonist) was without effect at 40 microM or 400 microM. 4 Injections of SP or NKA into the synovial cavity of the rat knee were equally effective in producing marked plasma extravasation in remote sites such as the forelimb and hindlimb paws. 5 Co-administration experiments showed that the effects of SP were synergistic with NKA or the NK1 receptor agonist, but not with CGRP or the NK2 receptor agonist. 6 The rank order of potency was NK1 agonist greater than or equal to SP greater than NKB greater than NK2 agonist suggesting that NK1 receptors mediate plasma extravasation in the rat knee joint.
 ...
PMID:Specific neurokinin receptors mediate plasma extravasation in the rat knee joint. 171 29

A novel ligand, [4,5-3H-Leu10]substance P ([3H]SP), with high specific activity (137 Ci/mmole) was utilized to investigate the properties of NK (neurokinin)-1 receptors on guinea pig lung membranes (GPLM) and compared them to NK-1 receptors on rat submaxillary glands (RSGM). In the presence of a neutral endopeptidase inhibitor, thiorphan (100 microM), [3H]SP bound with high specificity (greater than 95%), rapidly (k1 = 0.116 nM-1 x min-1) and in a reversible (k-1 = 0.012 min-1) manner to a single class of high-affinity (Kd = 0.16 nM) and saturable (Bmax = 256 fmol/mg protein) receptors. High specific binding with higher density (5-fold) was also detected in RSGM, albeit with a lower affinity (Kd = 1.36 nM). Guanyl-5'-yl-imidodiphosphate and guanosine-5'-O-3-thiotriphosphate inhibited binding to GPLM (and RSGM) in a concentration-related manner. In GPLM, this effect was mediated by a reduction in affinity, mainly via enhancement of ligand dissociation rates and appearance of a lower affinity state (Kd = 3.4 nM). Preincubation of GPLM with sulfhydryl modifying agents (p-chloromercuriphenyl sulfonic acid and N-ethylmaleimide) reduced receptor density and affinity in a time- and concentration-dependent manner. Competition experiments with tachykinins and analogs illustrated a rank order of potency of: SP greater than or equal to [Sar9,Met(O2)11]SP greater than SP-methyl ester greater than or equal to physalaemin greater than SP(6-11) much greater than kassinin greater than neurokinin A = eledoisin much greater than neurokinin B greater than Nle10-NKA(4-10), clearly demonstrating that these receptors are of NK-1 type. Moreover, analysis of over 30 peptide and non-peptide hormones and antagonists demonstrated exquisite selectivity (greater than 10,000-fold) towards NK-1-selective agonists (vs. other ligands. A highly significant (P less than .005) linear correlation (r = 0.924) exists between agonist affinities in GPLM and RSGM. Combined, the data suggest that [3H]SP labels a nearly homogeneous population of high-affinity, G-protein coupled NK-1 receptors on GPLM and RSGM, with very high degree of selectivity.
 ...
PMID:Binding of the novel ligand [4,5-3H-Leu10]substance P to high-affinity NK-1 receptors on guinea pig lung membranes: modulation by GTP analogs and sulfhydryl modifying agents. 171 78

A method of quantitatively measuring tachykinin-induced salivation in conscious, male, Sprague-Dawley rats is described. Salivation is quantified by determining the weight of a preweighed, absorbant foam cube after it has been used to swab the oral cavity of a tachykinin challenged rat. Salivation is induced by intravenous (i.v.) injection of sialogogues (microgram/kg) via the lateral tail vein. Measurements are made immediately after injection. Substance P (Sub.P), Sar9, Met (O2) 11Substance P (Sar9 Sub.P), a selective neurokinin (NK) 1 receptor agonist, Physalaemin and Eledoisin are equipotent sialogogues as determined by this method. Neurokinin A (NKA), the endogenous NK2 receptor agonist, is 0.27 (0.14-0.46) times as potent as Sub. P, while (Suc-[Asp6, MePhe8]Substance P(6-11), (senktide), a selective NK3 receptor agonist, only induced salivation at 300 microgram/kg. Acetylcholine (Ach) is only 0.006 (0.002-0.012) times as potent as Sub.P. Treatment with the neurokinin antagonist [D-Arg1, D-Trp7,9 Leu11]-Substance P (spantide) dose-dependently inhibits Sub. P stimulated salivation. Atropine dose-dependently inhibits Ach induced salivation but is inactive against Sub.P-induced salivation. These data are consistent with literature values and indicate that this method provides a simple, quantitative model, free of any possible anesthetic side effects, for the measurement of neurokinin stimulated salivation and the assessment of potential neurokinin antagonists in vivo.
 ...
PMID:Measurement of tachykinin-induced salivation in conscious rats. 171 93

The D-enantiomer of residues 2, 4, 5, 6, 7, 8, 10 and 11 was introduced in the sequence of Substance P: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH1. The achiral glycine was replaced by a D-Ala residue. The conformations of the D-substituted analogues were analysed by NMR and molecular energy calculations. Introduction of a D-amino acid in the address sequence of SP (1 to 5) distorted the helical structure of [D-Pro2]SP and [D-Pro4]SP. A D-glutamine in position 5 hampered the formation of an helix, the core of [D-Gln5]SP was stabilized by the presence of two beta-turns. The exact fitting of both Phe7 and Phe8 in the binding pocket can be achieved by either an alpha- or a 3(10) helix or two beta-turns types I and II'. Replacement of an amino acid in the message sequence, 6 to 11, drastically decreased the potencies of the corresponding analogues, different conformational modifications were observed. [D-Gln6]SP presented two beta-turns, however, the types of beta-turns should orientate the side-chains in such a way that [D-Gln6]SP did not fit in the binding site. The conformations of [D-Phe7]SP and [D-Phe8]SP were completely changed, a more or less extended structure being observed. Modifications in the Gly-Leu-Met-NH2 sequence did not affect the helical structure of the core of [D-Ala9]SP, [D-Leu10]SP and [D-Met11]SP, but decreased the percentage of extended structure of the C-terminal tripeptide.
 ...
PMID:Influence of the replacement of amino acid by its D-enantiomer in the sequence of substance P. 2. Conformational analysis by NMR and energy calculations. 171 77

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.
 ...
PMID:Pharmacology of neurokinin receptors. 171 74

During the formation of an inhibitory complex with neutrophil elastase, alpha 1 antitrypsin (alpha 1 AT) undergoes a structural rearrangement and the resulting alpha 1 AT-elastase complex becomes endowed with chemoattractant activities, mediates an increase in synthesis of alpha 1 AT, and is rapidly cleared from the circulation. In previous studies we have provided evidence that these biological activities involve the recognition of a conformation-specific domain in the alpha 1 AT molecule by a cell surface receptor on human hepatoma HepG2 cells and human monocytes. The receptor has been termed the serpin-enzyme complex (SEC) receptor because it also recognizes complex of serpins antithrombin III, alpha 1 anti-chymotrypsin, and C1 inhibitor with their cognate enzymes. Because a pentapeptide domain of alpha 1 AT (amino acids 370-374, Phe-Val-Phe-Leu-Met) is sufficient for binding to the SEC receptor and the sequence of this domain is remarkably similar to those of substance P, several other tachykinins, bombesin, and the amyloid-beta peptide, we have examined the possibility that these other ligands bind to the SEC receptor. The results indicate that substance P, several other tachykinins, and bombesin compete for binding to, and cross-linking of, the SEC receptor. The SEC receptor is distinct from the substance P receptor by several criteria. There is no substance P receptor mRNA in HepG2 cells; the SEC receptor is present in much higher density on receptor-bearing cells and binds its ligands at lower affinity than the substance P receptor; the SEC receptor is much less restricted in the specificity with which it recognizes ligand; ligands for the SEC receptor including peptide 105Y (based on alpha 1 AT sequence 359-374), alpha 1 AT-protease complexes, and bombesin do not compete for binding of substance P to a stable transfected cell line expressing the substance P receptor. 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.
 ...
PMID:Amyloid-beta peptide, substance P, and bombesin bind to the serpin-enzyme complex receptor. 171 86

Substance P (SP) is a neuropeptide that has recently been implicated in the pathogenesis of neurogenic inflammation. SP has been shown to activate polymorphonuclear leukocytes (PMN) as well as other inflammatory cells. The present study investigated the direct stimulatory and priming effects of SP on canine PMN aggregation and migration. Direct stimulation of cell migration by SP was present at an unphysiologically high concentration of the mediator. However, when micromolar concentrations of SP were added to PMN prior to stimulation with sub-optimal concentrations of leukotriene B4 (LTB4), the cells exhibited enhanced aggregation and migration, i.e. priming, when stimulated with the latter. Since SP has been reported to act via the formyl-Met-Leu-Phe (fMLP) chemotaxin receptor, this mediator was also studied and found not to possess any effects similar to SP. Thus, the results indicate that SP acts as a primer of canine PMN functions in vitro via a receptor different from that for fMLP. Before ascribing SP a mediator role in canine neurogenic inflammation, in vivo studies determining the concentrations of, and responses to SP in inflamed tissue should be performed.
 ...
PMID:Substance P: a neurogenic mediator of acute cellular inflammation in the dog? 172 Aug 20

[3H][Sar9,Met(O2)11]substance P (SP) with high specific activity (32 Ci/mmol) was used to study neurokinin-1 (NK-1) binding sites on rat brain and smooth muscle membranes of the guinea pig ileum. The specific binding of [3H][Sar9,Met(O2)11]SP was shown to be saturable, reversible and increased in parallel with the protein concentration. Scatchard analyses of equilibrium binding experiments revealed that [3H][Sar9,Met(O2)11]SP binds to a class of non-interacting binding sites in rat brain membranes (Kd = 2 nM, Bmax = 56 fmol/mg of protein) and ileum muscle membranes (Kd = 2 nM, Bmax = 194 fmol/mg of protein). Competition of [3H][Sar9,Met(O2)11]SP, 125I-BH[Sar9,Met(O2)11]SP and 125I-BH.SP with different tachykinin-related peptides gave the following rank order of potencies: SP greater than physalaemin greater than [Sar9,Met(O2)11]SP greater than N-Ac[Arg6,Sar9,Met(O2)11]SP(6-11) greater than neurokinin A (NKA) greater than or equal to eledoisin greater than or equal to neurokinin B (NKB) greater than [MePhe7]NKB (4-10) greater than [beta-Ala8]NKA(4-10). A very similar pattern was observed on ileum muscle membranes. [3H][Sar9,Met(O2)11]SP was found to be highly selective for NK-1 binding sites in rat brain and in the intestinal tissue. Binding showed good correlation with the biological activity of tachykinins and related peptides. From these data it can be suggested that (a) the NK-1 receptor characterized in the central nervous system is identical to the one in the periphery, (b) the NK-1 binding site of the muscle membranes appears to be similar to the contractile receptor of the guinea pig ileum and (c) the functional site mediating relaxation of the dog carotid artery is similar to the contractile receptor of the guinea pig ileum.
 ...
PMID:Binding sites for [3H][Sar9, Met(O2)11]substance P in rat brain and guinea pig ileum. 172 29


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>