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

A novel photoreactive substance P (SP) analogue has been synthesized by solid-phase peptide synthesis methodology to incorporate the amino acid p-benzoyl-L-phenylalanine [L-Phe(pBz)] in place of the Phe8 residue of SP. [Phe8(pBz)]SP was equipotent with SP in competing for SP binding sites on rat submaxillary gland membranes and had potent sialagogic activity in vivo. In the absence of light, the 125I-labeled Bolton-Hunter conjugate of [Phe8(pBz)]SP bound in a saturable and reversible manner to an apparently homogeneous class of binding sites (Bmax = 0.2 pmol/mg of membrane protein) with an affinity KD = 0.4 nM. The binding of 125I-[Phe8(pBz)]SP was inhibited competitively by various tachykinin peptides and analogues with the appropriate specificity for SP/NK-1 receptors. Upon photolysis, up to 70% of the specifically bound 125I-[Phe8(pBz)]SP underwent covalent linkage to two polypeptides of Mr = 53,000 and 46,000, identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Quantitative analysis of the inhibitory effects of SP and related peptides on 125I-[Phe8(pBz)]SP photoincorporation indicated that the binding sites of the two photolabeled polypeptides have the same peptide specificity, namely, that typical of NK-1-type SP receptors. In addition, the labeling of the two polypeptides was equally sensitive to inhibition by guanyl-5'-yl imidodiphosphate, a nonhydrolyzable analogue of GTP. Further information on the relationship between the two labeled SP binding sites was provided by enzymatic digestion studies: the Mr = 46,000 polypeptide contains N-linked carbohydrates and is derived most likely from the higher molecular weight species by proteolytic nicking.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Photoaffinity labeling the substance P receptor using a derivative of substance P containing p-benzoylphenylalanine. 170 17

The IgA producing murine B lymphoma, CH12.LX.C4.4F10 (4F10) and the IgM producing murine lymphoma, CH12.LX.C4.5F5 (5F5) were found to express substantial numbers of substance P (SP) receptors having dissociation constants equal to 0.69 nM. Binding of SP by these B lymphoma cells was via the tachykinin-specific C-terminus sequence, Phe-X-Gly-Leu-Met-NH2, because SP, SP antagonist (D-Pro2-D-Phe7-D-Trp9-SP), eledoisin, and substance K could effectively inhibit radiolabeled SP binding, whereas the SP N-terminus fragment, SP (1-4), could not. The functionality of these receptors could be demonstrated by the ability of subnanomolar concentrations of SP to induce Ig secretion in a dose-dependent fashion. However, the presence of a second stimulus in these cultures was required to obtain maximal increases. IgA secretion by 4F10 cells was elevated only 25 to 37%, and IgM secretion by 5F5 cells was not significantly increased in cultures in which nanomolar concentrations of SP were present. Conversely, coculturing 5F5 cells with a suboptimal concentration of LPS (50 ng/ml) and 10(-10)M SP resulted in an approximate threefold increase in supernatant IgM when compared to control cultures stimulated with LPS alone. While not as dramatic, 10(-10) M SP also enhanced IgA secretion of LPS-stimulated 4F10 cells by approximately 45%. This enhancement of Ig secretion was SP-specific, as evidenced by the ability of 1000-fold excess of SP antagonist to block SP-induced, but not LPS-induced, Ig production. Clearly, SP could act synergistically with LPS to enhance Ig secretion; therefore, we questioned whether this augmentation was also reflected at the level of H chain mRNA expression. 10(-9)M SP induced modest increases (50 to 60%) in mu-chain mRNA expression by LPS-stimulated 5F5 cells when compared with cells stimulated with LPS alone. The 4F10 cells did not display this magnitude of difference for alpha-chain mRNA expression. Thus, although SP-induced increases of mu-chain mRNA by 5F5 cells may contribute to the increased Ig secretion observed by these LPS-activated lymphocytes, it is unlikely that increased mRNA expression can totally account for the threefold increases in secretion that were observed.
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PMID:Substance P acts directly upon cloned B lymphoma cells to enhance IgA and IgM production. 170 87

Somatostatin-14 (SS-14) and somatostatin-28 (SS-28) produce concentration dependent reductions in short-circuit current in rat colonic mucosa. EC50 values of 15.0 and 13.3 nM were obtained for SS-14 and SS-28 respectively while the N-terminal fragments of SS-28, namely somatostatin-(1-12) (SS1-12) and somatostatin-(1-14) (SS1-14) were inactive. Cyclo(Pro-Phe-D-Trp-Lys-Thr-Phe) and cyclo(Pro-Tyr-D-Trp-Lys-Thr-Phe) were potent antisecretory peptides, like SS-14 and SS-28; while the putative somatostatin antagonist, cyclo(7-aminoheptanoyl-Phe-D-Trp-Lys-Thr[Bzl]) exhibited neither agonist nor antagonist effects. Responses to SS-14 could be regulated by agents which affected the secretory state of the epithelium. Antisecretory effects of SS-14 were markedly attenuated by piroxicam and were restored following piroxicam plus either forskolin or vasoactive intestinal polypeptide (VIP). SS-14 also attenuated secretory responses produced by carbachol, substance P (SP), VIP and alpha- and beta-calcitonin gene related peptide (alpha-, beta-CGRP). Therefore, SS-14 exhibits broad spectrum antisecretory effects in rat descending colon mucosa.
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PMID:The antisecretory effects of somatostatin and analogues in rat descending colon mucosa. 170 67

We compared histamine release induced by substance P with those obtained with classical secretagogues on human basophils, lung and skin fragments. We also tested the capacity of nedocromil sodium and theophylline to inhibit histamine release in these 3 experimental models. Substance P (10(-4) M) caused a noncytotoxic histamine release (about 10% of total) from basophils, lung and skin fragments. Substance P-induced histamine release was always smaller than that obtained with optimal doses of anti-IgE, formyl-methionine phenylalanine or compound 48/80. Nedocromil sodium did not prevent secretagogue-induced histamine release from basophils or sliced skin. In contrast, it significantly inhibited anti-IgE- or substance P-induced histamine release from human lung. Theophylline caused a dose-related inhibition on these 3 models. We conclude that substance P is a modest secretagogue for human basophils and mast cells, and that skin and lung mast cells are heterogeneous with respect to their response to nedocromil sodium.
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PMID:Substance P-induced histamine release from human basophils, skin and lung fragments: effect of nedocromil sodium and theophylline. 170

The catabolism of substance P and bradykinin, two peptides involved in inflammation, by human neutrophils was investigated. Substance P was cleaved by unstimulated neutrophils, but the rate of hydrolysis increased greatly (about 4-fold) when the cells were lysed by freezing and thawing or stimulated to release with fMet-Leu-Phe and cytochalasin B. The enzyme responsible for cleaving substance P was cathepsin G, hydrolyzing the Phe7-Phe8 bond. Neutral endopeptidase 24.11 (enkephalinase) became the main inactivating enzyme only when neutrophil cytoplasts (containing plasma membrane but no subcellular particles) or washed plasma membrane enriched high speed sediments were tested. Subcellular fractionation showed the highest substance P degrading activity to be in the granules. Purified cathepsin G readily cleaved substance P with a Km of 1.13 MK, a kcat of 6.35 sec-1 and a kcat/Km of 5639 M-1 sec-1, similar to kinetic constants previously reported for the best peptide substrates of cathepsin G. Despite the high Km, purified cathepsin G did hydrolyze SP at a much lower substrate concentration (down to 1 nM) as determined by radioimmunoassay. Bradykinin was also hydrolyzed by intact neutrophils but, in contrast, was not inactivated by cathepsin G, but by neutral endopeptidase at the Pro7-Phe8 bond. The inactivation of bradykinin by intact neutrophils was decreased by phorbol 12-myristate 13-acetate, probably due to down-regulation by endocytosis of the neutral endopeptidase on the plasma membrane. Thus, both bradykinin and substance P are inactivated by human neutrophils, although by different enzymes. In spite of the less favorable kinetics in vitro than with neutral endopeptidase, cathepsin G is the main inactivator of substance P in neutrophils. This may be due to the estimated 300 to 3600-fold higher concentration of cathepsin G in neutrophils than that of the neutral endopeptidase.
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PMID:Metabolism of substance P and bradykinin by human neutrophils. 170 55

A new hexapeptide analog of Substance P, containing a C-terminal thioamide group in the molecule [( Glp6, Mett11]SP6-11) was synthesized: Glp-Phe-Phe-Gly-Leu-Mett-NH2. Conversion to thioamide was accomplished from tert-butoxycarbonyl-L-methionine amide (Boc-Met-NH2) using Lawesson's Reagent. Its contracting activity on isolated guinea-pig ileum was considerably lower than that of [Glp6]SP6-11.
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PMID:Synthesis and some biological properties of the hexapeptide analog of substance P with a C-terminal thioamide group. 171 85

The sea urchin hatching enzyme (HEz) is a protease capable of dissolving the fertilization envelope that surrounds the embryo as a protective coat during early development. We have now purified a 37-kDa active enzyme from the supernatant fluid of hatched blastula medium of the species Hemicentrotus pulcherrimus. The purified enzyme was completely inhibited by alpha 2-macroglobulin and the chelating agents EDTA, EGTA, and 1,10-phenanthroline and was slightly inhibited by chymostatin and pepstatin, but was not inhibited by various other serine and thiol protease inhibitors. These results suggest that HEz is a metalloproteinase. Quantitative analyses of the products of HEz's action on various peptides revealed that the enzyme preferentially cleaved the peptide bonds on the amino side of bulky hydrophobic residues, -Leu, -Ile, and -Phe as well as -Tyr, in a similar but more limited fashion than thermolysin. Furthermore, although substance P was a good substrate of HEz, snake venom alpha-protease, and thermolysin, the analogue [Sar9]substance P was a poor substrate for HEz. This analogue was a good substrate for thermolysin and alpha-protease, but the scissile bonds were altered from those of substance P. The failure of HEz and alpha-protease to cleave the P1-P1 bond that meets the primary specificity is ascribed to the presence of an imino acid residue (proline or sarcosine) or the absence of any amino acid at the P2h or P3' position, in contrast to the simple P2' restriction of thermolysin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The specificity of sea urchin hatching enzyme (envelysin) places it in the mammalian matrix metalloproteinase family. 171 95

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.
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PMID:Pyrrolomycin group antibiotics inhibit substance P-induced release of myeloperoxidase from human polymorphonuclear leukocytes. 171 7

Various peptide immunoreactivities in the respiratory system have been reported, indicating complex physiological mechanisms. There is only little information on the upper respiratory system of man. The present study was carried out to demonstrate regulatory peptides in the nasal mucosa, larynx (vocal cords and ventricular folds) and soft palate of man using highly efficient immunocytochemical methods. In addition, some peptide immunoreactivities were measured by use of radioimmunoassay (RIA). Using indirect immunofluorescence and immunogold-silver staining (IGSS) with silver acetate autometallography, a series of peptides could be detected, including vasoactive intestinal polypeptide (VIP), peptide histidine methionine (PHM), galanin, calcitonin gene-related peptide (CGRP), substance P, neuropeptide tyrosine (NPY), C-flanking peptide of NPY (CPON) and somatostatin. In addition, antibodies to protein gene-product (PGP) 9.5, neuron-specific enolase (NSE), S-100, PHE-5 and neurofilament proteins gave positive reactions in tissue sections. Using RIA, CGRP, substance P, and neurokinin A were measured. Our results demonstrate a complex network of regulatory peptide-containing nerve fibers and the possible existence of endocrine cells regulating various functions of the upper respiratory system, which need to be further investigated.
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PMID:Regulatory peptides and general neuroendocrine markers in human nasal mucosa, soft palate and larynx. 171 32

Since the growth hormone-releasing peptide (GHRP), His-D-Trp-Ala-Trp-D-Phe-Lys-NH2, was found to specifically release growth hormone by a complementary but yet not clearly defined action on the pituitary as well as the hypothalamus, in vitro studies have been performed to demonstrate and characterized GHRP binding sites on peripheral membranes of both the rat anterior pituitary and hypothalamus. Optimum binding assay conditions were established using [125I]Tyr-Ala-GHRP as the radioligand. The membrane binding sites were specific, reversible, saturable and time, temperature, pH and concentration dependent. Computerized analyses of competition experiments suggested two classes of binding sites in both pituitary and hypothalamic membranes. The maximum specific binding was observed at pH 5.0 than the physiological pH in both tissues. Pretreatment of the membranes with trypsin prevented specific binding. The increase in Bmax was statistically significant and showed a 2.0- to 8.9-fold and 5.8- to 11.2-fold in pituitary and hypothalamus, respectively, whereas the affinity constants (Kds) were not significant. Of the synthetic and natural neuropeptides that influence the release of GH from somatotrophs, only (D-Lys3)GHRP, substance P antagonists and growth hormone-releasing factor analog were potent inhibitors of GHRP binding in both tissues.
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PMID:Demonstration and characterization of the specific binding of growth hormone-releasing peptide to rat anterior pituitary and hypothalamic membranes. 171 88


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