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)

The potent vasodilator calcitonin gene-related peptide (CGRP, human synthetic), when mixed with histamine and injected intradermally in the rabbit, induced a marked potentiation of local oedema. CGRP also potentiated oedema induced by other mediators of increased microvascular permeability in the rabbit; bradykinin, platelet-activating factor (Paf), C5a des Arg, N-formylmethionyl-leucyl-phenylalanine (FMLP) and leukotriene B4 (LTB4). Substance P alone, or mixtures of substance P and CGRP, failed to induce oedema in rabbit skin. In rat skin, however, substance P induced oedema and this was potentiated by CGRP. CGRP had a protracted potentiating action following intradermal injection in the rabbit. The time for half loss of activity for CGRP was 40.1 +/- 7.5 min compared to 18 +/- 1 min for prostaglandin E2 (PGE2). No loss of potentiating activity was detected after incubation of CGRP in rabbit plasma or blood for 60 min. We postulate that endogenous CGRP, if released locally from nerve endings, could have a marked enhancing effect on oedema induced by other mediators in an inflammatory reaction.
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PMID:Inflammatory oedema induced by synergism between calcitonin gene-related peptide (CGRP) and mediators of increased vascular permeability. 241 78

The undecapeptide substance P (SP) was tested for its ability to promote human monocyte chemotaxis in a modified Boyden chamber assay. Substance P was found to be active in this assay system with an ED50 for chemotactic effect of approximately 10(-13) M. This response was shown to be chemotactic in nature since a concentration gradient of attractant was required for maximal effect. Other substance P analogs tested showed a rank order of potency of substance P greater than or equal to SP(3-11) greater than SP(8-11) approximately equal to SP(9-11) much greater than SP(1-9), SP, free acid. These results suggest that chemotactic responsiveness is largely encoded in the C-terminus of the molecule. The relative potency order for SP and its analogs in promoting monocyte chemotaxis correlates well with their potencies in displacing labeled SP when binding sites are directly measured in other tissues, such as rat brain or human lymphocytes. Additionally, the chemotactic effects of SP could be partially reversed by the weak antagonist [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-SP. The N-formyl peptide receptor antagonist, t-Boc-Phe-Leu-Phe-Leu-Phe, did not block SP-mediated chemotaxis, further indicating the specificity of these effects. These results suggest the existence of a specific substance P receptor on human monocytes which directs this chemotactic response. The ability of monocytes to respond chemotactically to SP may be relevant to the enhancing effects of SP in arthritis or other inflammatory diseases.
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PMID:Substance P receptor-mediated chemotaxis of human monocytes. 241 6

Angiotensin I converting enzyme (ACE) and neutral endopeptidase ("enkephalinase"; NEP), were purified to homogeneity from human renal membranes. NEP hydrolyzed substance P (SP) at Gln6-Phe7, Phe7-Phe8, and Gly9-Leu10 and neurotensin (NT) at Pro10-Tyr11 and Tyr11-Ile12. ACE cleaved SP at Phe8-Gly9 and Gly9-Leu10 to release C-terminal tri- and dipeptide (ratio = 4:1). The hydrolysis was dependent on chloride ion and inhibited by captopril. Modification of arginine residues in ACE with cylcohexanedione or butanedione inhibited hydrolysis of SP, bradykinin and Bz-Gly-Phe-Arg (80-93%) indicating an active site arginine is required for hydrolysis of SP. ACE cleaved NT at Tyr11-Ile12 to release Ile12-Leu13. These studies indicate that ACE and NEP, two enzymes which are widely distributed in the body, may be involved in the metabolism of SP and NT.
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PMID:Characterization of the metabolism of substance P and neurotensin by human angiotensin I converting enzyme and "enkephalinase". 241 54

The authors describe the synthesis of Gln-Phe-Phe-Gly-Leu-Met by cyclization of H-Leu-Met-Gln-Phe-Phe-Gly using three different methods. The linear sequence was obtained by a (2+4)-segment condensation. The resulting cyclopeptide showed only a small kinin activity on isolated guinea pig ileum compared to substance P, but it is a full agonist.
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PMID:[Synthesis of cyclic and non-cyclic tachykinin partial sequences. 2. Synthesis of the homocyclic substance P(6-11) hexapeptide]. 241 64

We have prepared a series of conformationally constrained hexapeptide analogs of substance P which are 500-1500-fold more potent as inhibitors of 125I-labeled Bolton Hunter-conjugated eledoisin binding to rat brain cortex membranes than as inhibitors of 125I-labeled Bolton Hunter-conjugated substance P binding. These analogs stimulate guinea pig ileum contraction (ED50 1-16 nM) and stimulate rat vas deferens contraction (ED50 2-4 microM). However, these peptides are poor stimulators of rat salivation (greater than 40 nmol/100 g body weight). Thus, based on both their receptor potency and pharmacological potency, these peptides are potent and selective tachykinin analogs. These data indicate that a specific carboxyl-terminal conformation is recognized by the 125I-labeled Bolton Hunter-conjugated eledoisin binding site and that this conformation is different from the conformation recognized by the 125I-labeled Bolton Hunter-conjugated substance P binding site. Hexapeptides containing phenylalanine, isoleucine, and valine identical with the carboxyl-terminal sequences of substance P, eledoisin, and neurokinin B, respectively, were nearly equipotent as inhibitors of 125I-labeled Bolton Hunter-conjugated eledoisin binding. The valine analog was only approximately 5-fold less potent than the isoleucine and phenylalanine analogs as an inhibitor of 125I-labeled Bolton Hunter-conjugated substance P binding. Thus, unknown determinants in the amino-terminal sequences of substance P must strongly contribute to the carboxyl-terminal peptide selectivity and conformation. The contraction of guinea pig ileum induced by one of the conformationally constrained analogs is attenuated by pretreatment of the tissue with atropine (2 microM), while that induced by substance P methyl ester, a selective inhibitor of 125I-labeled Bolton Hunter-conjugated substance P binding, is not. Thus, the constrained analog has a higher affinity for the tachykinin receptors in the guinea pig myenteric plexus which are responsible for acetylcholine release than for the tachykinin receptors present on the smooth muscle cells.
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PMID:Conformationally constrained tachykinin analogs which are selective ligands for the eledoisin binding site. 241 47

A vector system has been designed for obtaining high yields of polypeptides synthesized in Escherichia coli. Multiple copies of a synthetic gene encoding the neuropeptide substance P (SP) (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2) have been linked and fused to the lacZ gene. Each copy of the SP gene was flanked by codons for methionine to create sites for cleavage by cyanogen bromide (CNBr). The isolated multimeric SP fusion protein was converted to monomers of SP analog, each containing a carboxyl-terminal homoserine lactone (Hse-lactone) residue (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Hse-lactone), upon treatment with CNBr in formic acid. The Hse-lactone moiety was subjected to chemical modifications to produce an SP Hse amide. This method permits synthesis of peptide amide analogs and other peptide derivatives by combining recombinant DNA techniques and chemical methods.
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PMID:Multiple-copy genes: production and modification of monomeric peptides from large multimeric fusion proteins. 241 4

Two pseudopeptide analogues [Bz-(RS)Phe8 psi (COCH2)Gly9]SP8-11 (I) and [pGlu6,(RS)Phe8 psi (COCH2)Gly9]SP6-11 (II) of the substance P related C-terminal hexapeptide [pGlu6]SP6-11 were prepared as follows. The pseudodipeptidic unit H(RS)Phe psi (COCH2)GlyOH was synthesized by using a modified Dakin-West reaction between Bz-Phe-OH and monomethyl succinoyl chloride. The N alpha-protected pseudopeptidic unit was then incorporated into the appropriate peptide by using various coupling methods. The two pseudopeptide analogues were purified, characterized, and tested for their biological activity and inhibitory effect on SP degrading enzymes. Analogue II was a full agonist contracting the isolated guinea pig ileum with a potency of 70% compared to the parent hexapeptide [pGlu6]SP6-11. It was also a potent inhibitor of SP degrading activity in rat diencephalon membranes with a Ki of 20 microM whereas analogue I was a weak inhibitor.
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PMID:Ketomethylene pseudopeptide analogues of substance P: synthesis and biological activity. 241 59

Two peptides with tachykinin-like ability to contract longitudinal muscle from the guinea pig ileum were isolated from the intestine of the common dogfish, Scyliorhinus caniculus. The amino acid sequence of scyliorhinin I was established as Ala-Lys-Phe-Asp-Lys-Phe-Tyr-Gly-Leu-Met-NH2 and this peptide cross-reacted with antisera directed against the C-terminal region fo substance P. The amino acid sequence of scyliorhinin II was established as Ser-Pro-Ser-Asn-Ser-Lys-Cys-Pro-Asp-Gly-Pro-Asp-Cys-Phe-Val-Gly-Leu-Met- NH2 and this peptide cross-reacted with antisera directed against the C-terminal region of neurokinin A. The mammalian peptides substance P and neurokinin A were absent from the dogfish intestinal tissue.
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PMID:Scyliorhinin I and II: two novel tachykinins from dogfish gut. 242 58

Substance P analogues have been synthesized, by solid-phase methodology, in order to get a better knowledge of the structural requirements for the 125I-BHSP binding on rat brain synaptosomes. Assuming that the core of SP exists in an alpha-helicoidal structure three major points should be underlined: the SP receptor recognizes probably the side of the helix bearing the two side chains of Phe and Phe; the arginine guanidinium interacts with either a carboxylate or a phosphate function of the binding site; the C-terminal tripeptide undergoes a conformational change allowing the interactions of the C-terminal amide with a carboxylate and that of the sulfur atom with an electrophile of the binding site. The specificity of these peptides have been further estimated by comparing their binding potencies to those observed for the 125I-BHE specific binding on rat cortical synaptosomes and their bioactivities on guinea-pig ileum.
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PMID:Influence of the amino acids of substance P in the recognition of its receptor: affinities of synthesized SP analogues for the specific 125I-BHSP binding site on rat brain synaptosomes. 242 81

We have investigated certain aspects of the mechanism whereby substance P triggers secretion of 5-hydroxytryptamine (5-HT) from rat peritoneal mast cells in vitro. Substance P-induced release of 5-HT was inhibited following pretreatment of rat peritoneal cells with 0.01-1.0 units/ml neuraminidase; secretion induced by anti-IgE antibody was inhibited by pretreatment with 1.0 units/ml but not by lower concentrations of enzyme. Addition of the sialic acid-rich substances N-acetyl-neuraminlactose (up to 1.0 mM) and mucin (up to 1.0 mg/ml) to substance P in free solution failed to block the activity of the neuropeptide. Limulin, a sialic acid-specific lectin, failed to block substance P-induced secretion of 5-HT, but was found to possess intrinsic non-lytic secretory activity (at 5-20 micrograms/ml). Release of 5-HT induced by limulin was independent of that induced by substance P. A range of octapeptides incorporating the C-terminal sequence Gly-Ser-Phe-Phe, but differing in degree of cationicity and positioning of cationic residues in the four N-terminal positions, were tested for their capacity to antagonise the mast cell-triggering activity of substance P. A peptide incorporating two lysine residues at the N-terminus was found to have partial substance P antagonist activity; no effects on IgE-mediated secretion were observed.
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PMID:The mast cell response to substance P: effects of neuraminidase, limulin, and some novel synthetic peptide antagonists. 242 85


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