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 nature of the interaction between spinally administered opioid and alpha-2 agonists was investigated using the substance P behavioral test in mice. Morphine and agonists which more selectively activate mu or delta opioid receptors were co-administered intrathecally with direct and indirect acting adrenergic agonists norepinephrine, cocaine or clonidine and the behavioral responses to intrathecally coadministered substance P were evaluated. The ED50 values for agonists administered separately and concurrently were computed and drug interactions were evaluated using isobolographic analyses. After separate administration, all the opioid and adrenergic agonists inhibited the substance P-induced behavioral responses. Upon coadministration of opioid and adrenergic agonists, a multiplicative interaction was observed between morphine or the delta agonist D-Pen2-D-Pen-5-enkephalin and the adrenergic agonists. Additive or antagonistic interactions were found between the mu agonist Tyr-D-Ala-NMe-Phe-Gly(ol) and the same adrenergic agonists. The opioid antagonist naloxone and the alpha-2 adrenergic antagonist idazoxan were given as intrathecal pretreatments at doses chosen to shift the dose-response curves of their corresponding agonist (given alone) 4- to 10-fold to the right; this always resulted in a smaller, but significant (2- to 4-fold) shift in the dose-response curve of the other agonist given alone. Intrathecal pretreatment with naloxone or idazoxan altered some interactions between the opioids and clonidine. Although naloxone blocked completely the multiplicative interaction between morphine and clonidine, idazoxan did not. Both naloxone and idazoxan changed the antagonistic interaction between Tyr-D-Ala-NMe-Phe-Gly(ol) and clonidine to a multiplicative interaction. Neither antagonist blocked the multiplicative interaction between D-Pen2-D-Pen5-enkephalin and clonidine. These results suggest that: 1) interactions between opioid and adrenergic agonists in mouse spinal cord are mediated by delta and alpha-2 receptor subtypes; 2) the synergistic interaction between morphine and alpha-2 adrenergic agonists may involve action at delta opioid receptors; and 3) antagonist action on these drug interactions is complex.
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PMID:Spinal interactions between opioid and noradrenergic agonists in mice: multiplicativity involves delta and alpha-2 receptors. 137 95

The structure of the gene encoding the bovine type B endothelin receptor (ETB) has been established and compared with those of other heptahelical receptors. The gene is present as a single copy in the bovine genome, as demonstrated by Southern blot analysis, and spans at least 36 kb. The coding region is divided into 7 exons separated by 6 introns, one of which is more than 23 kb in length. The exons correspond well to the structural domains of the receptor: the first exon encodes the first and second transmembrane domains, and each of the following transmembrane domains is encoded by a separate exon. The portion of the ETB protein sequence encoded by exon 3 is quite different from the corresponding ETA sequence, suggesting that this region is responsible for the distinct ligand specificities of the two receptor subtypes. The second intron interrupts the canonical Asp-Arg-Tyr sequence, which is located at the end of the third transmembrane domain of the heptahelical receptors, as with the substance P, substance K, dopamine D2 and dopamine D3 receptor genes. To map the 5' region of the gene and determine the start of transcription, primer-extended cDNAs were cloned and sequenced: multiple start sites were deduced with no apparent TATA box in the expected upstream region. Similar results were obtained by ribonuclease protection analysis.
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PMID:Structure of the bovine ETB endothelin receptor gene. 141 82

Enteroendocrine cells represent the most heterogeneous population of terminally differentiated cells in the mouse intestinal epithelium. Each of the approximately 15 different enteroendocrine cell subpopulations shows characteristic distributions along both the cephalocaudal and crypt-to-villus (in the small intestine) or crypt-to-surface epithelial cuff (in the colon) axes of the gut. These cells provide a sensitive model for studying how the continuously renewing gut epithelium is able to establish and maintain its spatial differentiation. Enteroendocrine cells are derived from the same multipotent stem cell that gives rise to enterocytes and goblet and Paneth cells. Regional differences in enteroendocrine cell number and type reflect positional differences in the differentiation programs of this lineage. To better understand the nature of these programs, we used multilabel immunocytochemical methods to examine the accumulation of endogenous neuroendocrine products as well as the product of a liver fatty acid binding protein/human growth hormone transgene in enteroendocrine cells located in proximal colonic glands. The results suggest that serotonin, substance P-, glucagon-like peptide-1 (GLP-1)-, peptide tyrosine tyrosine (PYY)-, neurotensin-, and cholecystokinin (CCK)-producing cells can all arise from a single stem cell located within a given gland. Based on pairwise comparison of the coexpression of each of these six products in individual cells as well as their ability to support transgene expression, it appears that the enteroendocrine lineage has two branches; one branch produces substance P and serotonin cells while the other yields GLP-1, PYY, neurotensin, and CCK cells.
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PMID:Immunocytochemical studies suggest two pathways for enteroendocrine cell differentiation in the colon. 151 28

Aminopeptidase P (EC 3.4.11.9) was purified from rat brain cytosol. A subunit Mr of 71,000 was determined for the reduced, denaturated protein whereas an Mr of 143,000 was determined for the native enzyme. The purified aminopeptidase P selectively liberated all unblocked, preferentially basic or hydrophobic ultimate amino acids from di-, tri- and oligopeptides with N-terminal Xaa-Pro- sequences. Corresponding peptides with penultimate Ala instead of Pro were cleaved with much lower rates; oligopeptides with residues other than Pro or Ala in the penultimate position appeared not to be substrates for the enzyme. Several bioactive peptides with Xaa-Pro sequences, especially bradykinin, substance P, corticortropin-like intermediate lobe peptide, casomorphin and [Tyr]melanostatin were shortened by the N-terminal amino acid by aminopeptidase P action. Rat brain aminopeptidase P was optimally active at pH 7.6-8.0 in the presence of Mn2+. Chelating agents and SH-reacting reagents inhibited the enzyme, but common inhibitors of aminopeptidases, like amastatin or bestatin, of prolidase or of dipeptidyl peptidases II and IV, like N-benzoyloxycarbonyl-proline or epsilon-benzyl-oxycarbonyl-lysyl-proline, as well as antibiotics like beta-lactam ones, bacitracin or puromycin, had little or no effect.
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PMID:Aminopeptidase P from rat brain. Purification and action on bioactive peptides. 164 59

Binding of [125I-Tyr8]bradykinin (BK) was measured in homogenates of epithelial and smooth muscle layers of the guinea pig ileum. Binding assays were performed at 4 degrees C for 40 min (smooth muscle) or 90 min (epithelium) in 25 mM PIPES buffer at pH 6.8 in the presence of 1 mM 1,10-phenanthroline, 140 micrograms/mL bacitracin, 1 mM captopril, 1 mM dithiothreitol, and 0.1% bovine serum albumin. Specific binding of [125I-Tyr8]BK (0.32 nM) to epithelial and smooth muscle cell membranes was linearly related to protein concentration between 0.05 and 0.5 mg/mL. Equilibrium experiments showed that specific binding of [125I-Tyr8]BK was saturable and Scatchard analysis indicated the presence of a high affinity site with a Kd value of 1.6 nM and a Bmax of 156 fmol/mg of protein in the epithelial cell membranes. In smooth muscle membranes, Kd was 1.8 nM and the maximum number of binding sites was 58 fmol/mg of protein. Unlabelled peptides, namely bradykinin, [Tyr8]BK, [Hyp3]BK, D-Arg[Hyp3]BK, [Hyp3,Tyr(Me8)]BK, and kallidin displaced [125I-Tyr8]BK binding while other peptides, angiotensin II and substance P, had no effect. A series of B2-receptor antagonists displaced [125I-Tyr8]BK from specific binding sites with IC50 values ranging from 16 to 152 nM on epithelial cell membranes; similar values were obtained from smooth muscle cell membranes. These findings suggest that the binding sites in both preparations are of the B2 type. B1-receptor agonists and antagonists were found to be inactive at concentrations up to 10(-4) M. Results obtained in the two preparations were compared and a positive highly significant correlation was demonstrated between the two sets of data.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of kinin binding sites: identity of B2 receptors in the epithelium and the smooth muscle of the guinea pig ileum. 165 82

An extract of the whole brain of the frog Rana ridibunda contained high concentrations of substance P-like immunoreactivity, measured with an antiserum directed against the COOH-terminal region of mammalian substance P and neurokinin B-like immunoreactivity, measured with an antiserum directed against the NH2-terminus of neurokinin B. The primary structure of the substance P-related peptide (ranakinin) was established as: Lys-Pro-Asn-Pro-Glu-Arg-Phe-Tyr-Gly-Leu-Met-NH2. Mammalian substance P was not present in the extract. The primary structure of the neurokinin B-related peptide was established as: Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2. This amino acid sequence is the same as that of mammalian neurokinin B. Ranakinin was equipotent with substance P and [Sar9,Met(O2)11]substance P in inhibiting the binding of 125I-Bolton-Hunter-[Sar9,Met(O2)11]substance P, a selective radioligand for the NK1 receptor, to binding sites in rat submandibular gland membranes (IC50 1.6 +/- 0.3 nM; n = 5). It is concluded that ranakinin is a preferred agonist for the mammalian NK1 tachykinin receptor subtype.
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PMID:Ranakinin: a novel NK1 tachykinin receptor agonist isolated with neurokinin B from the brain of the frog Rana ridibunda. 165 33

The role of the D-Trp residues in the sequence of the NK2-selective tachykinin antagonist, MEN 10207 (Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg-NH2). has been examined by replacement of each D-Trp with either the L-isomer or the residue naturally occurring in the same position of neurokinin A(4-10). The biological activity of the analogues thus obtained has been characterized, with special attention to the selectivity for the three tachykinin receptors and for the two subtypes of the NK2 receptor recently described. We conclude that the simultaneous presence of the three D-Trp residues of MEN 10207 is crucial both for affinity and for selectivity.
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PMID:Role of D-tryptophan for affinity of MEN 10207 tachykinin antagonist at NK2 receptors. 166 80

There are four main classes of membrane-bound receptors: receptors which are also enzymes (tyrosine protein-kinase or guanylate cyclase), receptor channels, receptors coupled to G proteins (GTP binding proteins) and receptors with unknown transduction mechanisms. Receptors coupled to G proteins which have been cloned, constitute a superfamily of proteins containing seven hydrophobic transmembrane helices. The binding site of the ligand is within the hydrophobic core of the protein and the domain of interaction of the G proteins is constituted by the N- and C-terminal parts of the third intracellular loop, plus the C-terminal tail, adjacent to the transmembrane VII. G proteins themselves are also members of another superfamily. These proteins have highly conserved domains constituting the GTP binding site and they interact with the receptors by their C-terminal parts. Compounds such as mastoparan, substance P and 48/80 directly stimulate G proteins, an action which probably mediates their exocytotic properties. A high degree of homologies between G protein-linked receptors explains the non-specificity of some antagonists (like beta-adrenergic blocking agents on 5-HT1 receptors). The discovery of new members of the G protein-linked receptors which have not yet been pharmacologically characterized, raises the problem of receptor classification.
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PMID:Coupling of receptors to G proteins, pharmacological implications. 166 41

High levels of substance-P are present in the plasma of patients with carcinoid tumours and some thyrotoxic conditions. The majority of the substance-P in the blood plasma was shown, by immunoassay, to be associated with high molecular-weight material in a complex that could be dissociated by repeated gel-filtration. Smaller amounts of an intermediate molecular-weight (about 65,000 Da) complex were also detected. Chemical crosslinking with glutaraldehyde was used to show that the radioactively-labelled derivative [125I]Tyr-8-substance-P was able to bind to the high-Mr fraction of human plasma and also to human serum albumin. Binding to serum albumin was also demonstrated by equilibrium gel-filtration. Substance-P added to human plasma from a thyrotoxic subject, which contained high endogenous levels of the tachykinin (980 pg/mL), was rapidly degraded during incubation at 37 degrees, whereas the endogenous substance-P was considerably more stable. These results suggest that the binding of substance-P to blood plasma components may play an important role in protecting it against degradation. Furthermore, immunoassay techniques involving prior extraction, which fail to detect the bound substance-P, will give inaccurate measurements of the levels of this peptide in plasma.
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PMID:The binding of endogenous and exogenous substance-P in human plasma. 169 Sep 97

In the present study characterization of phosphatidylinositol 4,5-bisphosphate-specific phospholipase C (PIP2-PLC) activity and receptor-mediated hydrolysis of PIP2 in rat anterior pituitary membranes were investigated. Incubation of the membrane fraction of anterior pituitary homogenate with [3H]inositol-labeled PIP2 in the presence of calcium increased the concentration of the water-soluble degradation product inositol trisphosphate (IP3) in a time-dependent manner. PIP2-PLC in the rat anterior pituitary had a pH optimum at 5.5 and a requirement for cations. Ca2+ and Mg2+ could activate the enzyme. Activity was maximal at a total magnesium concentration of 1 mM and at a free Ca2+ concentration of 100 microM. The addition of the detergent Triton X-100 (0.05% w/v) to the membrane fraction resulted in a 50% decrease of PIP2-PLC activity, whereas the presence of sodium deoxycholate (1 mg/ml) in the membrane fraction increased the PIP2-PLC activity by 100%. The tachykinins substance P, 8-Tyr-substance P, physalaemin, neurokinin A, eledoisin, kassinin and neurokinin B induced receptor-mediated breakdown of [3H]inositol-labeled PIP2 in the membrane fraction in a concentration-dependent manner, but with different potencies. The tachykinins displayed the following rank order of potencies: substance P greater than 8-Tyr-substance P greater than physalaemin greater than neurokinin A greater than eledoisin greater than kassinin greater than neurokinin B, which is consistent with the involvement of a NK-1 receptor. Combined treatment of anterior pituitary membranes by substance P and thyrotropin-releasing hormone (TRH) resulted in an additional increase in PIP2-PLC activity compared to stimulation with TRH alone.
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PMID:Substance P and related tachykinins induce receptor-mediated hydrolysis of polyphosphoinositides in the rat anterior pituitary. 169 Nov 15


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