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)

Glycosylated analogues of the C-terminal heptapeptide of substance P either free or blocked on the N-terminal glutamine were synthesized in order to develop a metabolically stable peptide that would have an increased specificity for one type of receptor. Of the analogue described, (N-alpha-Boc-beta-D-Glc-p (1----5) Gln) -Gln-Phe-Phe-Gly-Leu-Met-NH2 is highly resistant to degradation on exposure to rat hypothalamic slices. This glycosylated peptide is about one third as potent as substance P in eliciting contractions of the guinea-pig ileum and is almost devoided of affinity for the 125I-Bolton Hunter-SP specific binding sites on rat brain synaptosomes.
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PMID:A peptidases-resistant glycosylated analogue of substance P-(5-11). Specificity towards substance P receptors. 620 5

beta-Amyloid protein (beta AP) has been frequently associated with the neuropathology of Alzheimer's disease (AD), although the mechanisms by which it can induce neurodegeneration are still unknown. Some studies in hippocampal cultured neurons suggest that beta AP, particularly its fragment 25-35, may induce neural growth or render neurons more vulnerable to excitotoxic insults by a mechanism involving intracellular Ca2+ dyshomeostasis. We have studied the effect of fragment 25-35 on the release of endogenous amino acids from hippocampal slices of young adult (3-3.5-month-old) and aged (23-25-month-old) rats, under basal, K(+)-depolarization, and post-depolarization conditions, in the presence and absence of Ca2+. In both young and aged tissue, the basal release of amino acids was not affected by the peptide. By contrast, 1-hr preincubation of slices from young animals with 10 microM 25-35 fragment resulted in a 140% increase of glutamate and aspartate release stimulated by K+ depolarization, compared with the control-stimulated release. These effects were strictly dependent on external Ca2+. Neither the K(+)-stimulated release of gamma-amino butyric acid (GABA) nor the release of glycine, glutamine, taurine, or alanine, which was not stimulated by high K+, were affected. Substance P and a scrambled sequence of the 25-35 fragment were without any effect per se, but substance P blocked the stimulatory effect of fragment 25-35 on glutamate and aspartate release. In slices from aged rats the basal release of glutamate was significantly higher (260%) than that in young tissue, and the K(+)-induced release of both aspartate and glutamate was also higher.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:beta-Amyloid peptide fragment 25-35 potentiates the calcium-dependent release of excitatory amino acids from depolarized hippocampal slices. 747 88

Residue number 17 in transmembrane segment VI has been shown to be crucial for the binding of agonists in G-protein-coupled receptors for the monoamines. In many peptide receptors a histidyl residue has been conserved at this position. We find that replacement of HisVI-17 in the NK-1 receptor with either glutamine, phenylalanine, or alanine has no apparent effect on the binding of the natural peptide ligand substance P or on the agonist induced increase in inositolphosphate turnover. However, the binding of certain non-peptide antagonists was impaired; for example, replacement of HisVI-17 with alanine decreased the affinity for FK888 and RP67,580 5- to 12-fold, respectively. A glutamine side chain was a good substitute for the imidazole in the binding of all non-peptide antagonists. It is concluded that the conserved HisVI-17 in the NK-1 receptor is involved in the binding of certain non-peptide antagonists, but is not important for the action of the natural peptide agonist, substance P.
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PMID:Conserved HisVI-17 of the NK-1 receptor is involved in binding of non-peptide antagonists but not substance P. 750 76

Substance P (SP) is a neuropeptide endowed with several important biological activities both in the central and peripheral nervous system. Taking advantage of the presence of glutamine residues in SP, the peptide was labelled with the fluorescent probe monodansylcadaverine using the transglutaminase (TGase)-reaction in order to study interactions between SP and model or natural membranes. Although it was verified that both adjacent glutamines of the peptide can act as substrate for TGase in a consecutive reaction, conditions were optimized to selectively label Gln5. This fluorescent SP analogue was found to adopt environment-dependent conformations similar to those of the natural peptide and proved to be functionally active on guinea pig trachea. Fluorescence spectroscopy was used to demonstrate the potential use of dansylated SP in studies involving interactions with membranes.
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PMID:Gln5 selectively monodansylated substance P as a sensitive tool for interaction studies with membranes. 752 Nov 62

The neurokinin-1 tachykinin receptor is a member of the G protein-coupled receptor superfamily. An unusual feature of the neurokinin-1 receptor is the presence of glutamic acid (residue 78) in the second putative transmembrane domain, at the location of a highly conserved aspartate residue in the G protein-coupled receptor superfamily. The rat neurokinin-1 receptor cDNA was mutated to lysine, aspartate, and glutamine at this site and functionally expressed in Chinese hamster ovary cells, and clonal cell lines were isolated and characterized. Radioligand binding demonstrated that the Asp78 and Lys78 receptors have substance P binding affinities indistinguishable from those of the wild-type receptor and are expressed at roughly the same number of receptors per cell. The Gln78 receptor variant, on the other hand, exhibited no detectable agonist binding. Although wild-type and Asp78 receptors have essentially the same ability to stimulate inositol phospholipid turnover, cAMP production, and arachidonic acid release, the Lys78 variant is markedly attenuated in its ability to activate any of these pathways. These data indicate that residue 78 plays a role in the coupling of the rat neurokinin-1 receptor to cellular effectors. In addition, both Asp78 and Lys78 receptors show a greater percentage of high affinity binding that is resistant to guanosine-5'-O-(3-thio)triphosphate than does the wild-type receptor, indicating a potential difference in G protein coupling between wild-type and mutated receptors.
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PMID:Residue 78 in the second transmembrane domain of the neurokinin-1 receptor is important in coupling high affinity agonist binding to multiple second messenger responses. 753 94

Amino acids are potential components of oral rehydration solutions for infants, which could combine with glucose to further stimulate intestinal Na+ and water absorption. L-Glutamine, the principal fuel of the intestine, stimulates neutral NaCl absorption and enhances enterocyte DNA synthesis, but is unstable in solution. L-Asparagine (ASN), a more stable amino acid with similar structure to L-glutamine, also stimulates enterocyte proliferation. We determined the effects of ASN on electrolyte transport across piglet jejunum in Ussing chambers. Mucosal but not serosal ASN produced electrogenic Cl- secretion (delta JClnet = -1.8 +/- 0.3 microEq/cm2.hr-1). ASN, when added at 0.1 to 30 mM, increased short-circuit current in a dose-dependent manner with a K1/2 of approximately 5 mM and maximal effect at approximately 10 mM. The stimulation of Cl- secretion by ASN was blocked by pretreatment with serosal tetrodotoxin and bumetanide and was inhibited by preincubation with capsaicin (8-methyl-N-vanillyl-6-nonenamide) or substance P. Inhibition of nitric oxide synthesis with the structural analog of L-arginine, NG-monomethyl-L-arginine, reduced ASN-stimulated secretion by > 70%. Additionally, serosal 6-cyanonitro-quinoxaline 2-3-dione, which is a nonspecific blocker of neural non-N-methyl D-aspartate (NMDA) glutamate receptors, fully inhibited the ASN response (IC50 = 10(-6) M). Inhibition was specific for neurally mediated secretion. We found no inhibition of ASN-stimulated secretion by atropine, ketanserin, indomethacin or L-2-amino-5-phosphonovalerate (specific for NMDA receptors). When compared to ASN, L-glutamate was a weaker stimulator of jejunal Cl- secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Asparagine stimulates piglet intestinal Cl- secretion by a mechanism requiring a submucosal glutamate receptor and nitric oxide. 754 37

The analogues [Glp6,Glu(OBzl)11]SP(6-11) and [Glp5,Glu(OBzl)11]SP(5-11) of the C-terminal hexapeptide and heptapeptide of Substance P have been synthesized by conventional solution methods. In each analogue the N-terminal glutamine has been replaced by pyroglutamic acid, while the COOCH2C6H5 ester group has replaced the SCH3 group of the Met11 side chain. The in vitro activity of both analogues has been determined on three biological preparations: guinea pig ileum (GPI), rat vas deferens (RVD) and rat portal vein (RPV). The results showed that both analogues are highly potent and selective agonists on GPI through the NK-1 receptor. They are more potent than SP itself, with 1.54 and 1.25 respective values of relative potency on GPI. Their selectivity has been studied by utilizing atropine-treated guinea pig ileum (GPI+At). The analogues showed low activity on RVD and RPV tissues, which represent NK-2 and NK-3 monoreceptor assay, respectively.
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PMID:Synthesis of potent agonists of substance P by replacement of Met11 with Glu(OBzl) and N-terminal glutamine with Glp of the C-terminal hexapeptide and heptapeptide of substance P. 755 80

An experimental arthritis, induced by injection of the knee joint with kaolin and carrageenan, results in guarding of and decreased weight bearing on the limb. At the time of injection, a transient increased release of all amino acids examined is measurable in samples collected by microdialysis. A second and prolonged increase of aspartate (ASP), glutamate (GLU), and glutamine (GLN) concentrations follows after 3 h. The increased release at time of injection is blocked by microdialysis application of a non-N-methyl-D-aspartate (non-NMDA) or an NMDA receptor antagonist, and the release of ASP, GLU, and GLN in the late phase is blocked by pretreatment with a non-NMDA (CNQX), an NMDA (AP7) or a neurokinin 1 (NK1; CP-96,345) antagonist. Dorsal horn immunoreactive staining of GLU, substance P (SP), and calcitonin gene-related peptide (CGRP) is reflective of the events occurring in the late phase of amino acid release since GLU release is positively correlated with GLU staining density. Increased immunoreactivity for GLU, SP, and CGRP at 8 hr in the arthritic animals is differentially altered by pretreatment of the spinal cord dorsal horn with non-NMDA, NMDA, or NK1 receptor antagonists. The differential staining pattern for GLU, SP, and CGRP, the differential release of ASP and GLU, and the differential activation of the EAA and NK1 receptors implies that ASP, GLU, SP, and CGRP are each involved in the processing of sensory information and that their roles in the central sensitization occurring with the inflammatory process, are unique.
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PMID:Spinal cord amino acid release and content in an arthritis model: the effects of pretreatment with non-NMDA, NMDA, and NK1 receptor antagonists. 790 87

Substance P binds to and activates the neurokinin-1 receptor with high affinity, thereby modulating several neuronal pathways including pain transmission and neurogenic inflammation. Several high affinity non-peptide antagonists have recently been described. To elucidate the molecular interactions specific for binding to the neurokinin-1 receptor, site-directed mutagenesis has been utilized to identify amino acid residues that interact directly with antagonists. Glutamine 165 in the fourth transmembrane segment was shown to be critical for the binding of CP-96,345 but not SR140333. Analysis of quinuclidine analogs suggests that glutamine 165 interacts with the C-3 heteroatom in this class of antagonists, probably through a hydrogen bond. Glutamine 165 also plays a minor role in the binding of peptides and RP67580. In contrast, serine 169 was determined to be critical for the binding of RP67580. These data indicate that residues 165 and 169 in the fourth transmembrane segment, along with residues in the fifth, sixth, and seventh transmembrane segments as demonstrated previously, form the non-peptide antagonist binding site in the neurokinin-1 receptor. Furthermore, the antagonist binding site overlaps with the binding site for peptide agonists in the fourth and seventh transmembrane segments.
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PMID:Interaction of glutamine 165 in the fourth transmembrane segment of the human neurokinin-1 receptor with quinuclidine antagonists. 819 29

A neutral endopeptidase (NEP) from Lactococcus lactis has recently been cloned and shown to contain high sequence homology with the human neutral endopeptidase, endopeptidase 24.11 (I. Mierau et al., J. Bacteriol. 175, 2087-2096, 1993). The gene for the neutral endopeptidase from L. lactis was cloned into the pQE expression vector, resulting in the fusion of a hexahistidine at the N-terminus. The recombinant enzyme was expressed to high levels in Escherichia coli (approximately 10 mg/liter of culture) and purified to homogeneity in a two-step procedure. A number of peptides were studied as substrates for the enzyme. The enzyme cleaves the following peptides at the Gly3-Phe4 bond: enkephalins, dynorphins A-6, A-8, A-9, A-10, A-13, and A-17, and alpha-neo-endorphin. In addition the enzyme hydrolyzes bradykinin, substance P, beta-endorphin, ACTH, and VIP. Although the cleavage patterns observed are similar to that seen with mammalian neutral endopeptidase, the lactococcal enzyme more efficiently cleaves larger peptide substrates. As observed with the mammalian neutral endopeptidase, the lactococcal enzyme exhibits higher kcat/K(m) values for the enkephalins than for their corresponding amides, indicating the functionality of an active-site arginine. Inactivation of the lactococcal endopeptidase by diethyl pyrocarbonate and protection afforded by the substrate dynorphin A-6 indicate the functionality of a positionally conserved active-site histidine. This was confirmed by demonstrating that conversion of this histidine, histidine 587, to glutamine generated inactive enzyme. Similarly, conversion of the putative zinc ligand glutamate 535 to glutamine led to inactive enzyme. These studies indicate a conservation of critical catalytic residues between the two enzymes and suggest that the lactococcal endopeptidase is a better model than thermolysin for the mammalian enzyme.
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PMID:Heterologous expression and characterization of recombinant Lactococcus lactis neutral endopeptidase (neprilysin). 880 62


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