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)

The extracellular signal-regulated kinase (Erk) cascades are suggested to contribute to excitatory synaptic plasticity in the CNS, including the spinal cord dorsal horn. However, many of their upstream signaling pathways remain to be investigated. Here, we demonstrate that glutamate and substance P (SP), two principal mediators of sensory information between primary afferent fibers and the spinal cord, activate Erk in dorsal horn neurons of both adult rat and mouse spinal cord. In genetic knock-out mice of calcium calmodulin-stimulated adenylyl cyclase subtypes 1 (AC1) and 8 (AC8), activation of Erk in dorsal horn neurons were significantly reduced or blocked, either after peripheral tissue inflammation or by glutamate or SP in spinal cord slices. Our studies suggest that AC1 and AC8 act upstream from Erk activation in spinal dorsal horn neurons and the calcium-AC1/AC8-dependent Erk signaling pathways may contribute to spinal sensitization, an underlying mechanism for the development of persistent pain after injury.
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PMID:Calcium calmodulin-stimulated adenylyl cyclases contribute to activation of extracellular signal-regulated kinase in spinal dorsal horn neurons in adult rats and mice. 1642 5

Human colonic circular muscle produces spontaneous phasic contractions that are reduced in ulcerative colitis. How the spontaneous phasic contractions develop and why they decrease in ulcerative colitis are not known. We found that spontaneous phasic contractions of normal sigmoid circular muscle strips were significantly reduced by 90-min incubation with tetrodotoxin (10(-5) M), which blocked neurokinin A release in basal conditions and in response to electrical stimulation. In addition, spontaneous contraction of human sigmoid colon was significantly decreased by the NK2 receptor antagonists MEN10376 (Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Lys-NH2) and NK2ra (Bz-Ala-Ala-D-Trp-Phe-D-pro-Pro-Nle-NH2) but not by atropine or by the NK1 antagonist FK888 (N2-[(4R)-4-hydroxyl-1-(1-methyl-1H-indol-3-yl)carbonyl-l-prolyl]-N-methyl-N-phenylmethyl-3-(2-naphthyl)-l-alaninamide), suggesting that NK2 receptors are involved in their development. The spontaneous phasic contractions were abolished by thapsigargin and cyclopiazonic acid and significantly decreased by the protein kinase C inhibitor chelerythrine and by the calmodulin inhibitor CGS9343B (1,3-dihydro-1-[1-[(4-methyl-4H,6H-pyrrolo[1,2-a]-[4,1]-benzoxazepin-4-yl)methyl]-4-piperidinyl]-2H-benzimidazol-2-one (1:1) maleate), suggesting that spontaneous phasic contractions may be mediated by Ca2+ release from intracellular stores and by a protein kinase C- and calmodulin-dependent pathway. In strips from patients with ulcerative colitis, spontaneous contractions were significantly reduced, and this reduction was partially restored by the hydrogen peroxide scavenger catalase. Neurokinin A release, however, was not affected. We conclude that spontaneous phasic contractions of human sigmoid circular smooth muscle may be mediated by activation of NK2 receptors, calcium release from intracellular stores, and activation of calmodulin and protein kinase C. In ulcerative colitis patients, spontaneous phasic contractions are decreased, and this decrease may be in part due to overproduction of hydrogen peroxide affecting sigmoid circular muscle.
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PMID:NK2 receptor-mediated spontaneous phasic contractions in normal and ulcerative colitis human sigmoid colon. 1655 57

Acute diarrhea is a major cause of morbidity and mortality worldwide. Infants and pre-school children are the most vulnerable in whom there are 2-3 million deaths each year as a result of the associated dehydration and acidosis. Although oral rehydration therapy has reduced mortality during the past 30 years ago, the search for agents that will directly inhibit intestinal secretory mechanisms and thereby reduce faecal losses in patients with high-volume watery diarrhea has continued for more than 20 years. A variety of potential targets for antisecretory agents have been explored which include loci within the enterocyte (the chloride channel, calcium-calmodulin) and other sites such as enteric nerves and endogenous mediators (such as 5-HT, prostaglandins). Although the potential of calcium-calmodulin inhibition has as yet not been realised, preliminary studies suggest that there are chloride channel blockers under development that will find a place in the management of secretory diarrheas. Recent work has highlighted the importance of neurohumoral mechanisms in the pathogenesis of acute diarrhea. Potentiation of the effects of endogenous enkephalin activity by enkephalinase inhibition has already produced a safe, effective anti-secretory drug, racecadotril. Speculative early work indicates that there may be a role for antagonists of 5-HT, substance P, and VIP receptors. There now seems to be a real possibility that antisecretory therapy will become more widely available in the future.
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PMID:Antisecretory drugs for diarrheal disease. 1669 63

Airway hyperresponsiveness (AHR) is present in almost all patients with symptomatic asthma, yet its mechanism is not well understood. Airway inflammation is thought to be an important underlying mechanism involved in causing AHR. Recent studies indicate release of neuropeptides from C-fiber endings plays a pivotal role in airway inflammation. Substance P (SP) is a critical neurotransmitter of sensory C-fiber and a well-known effector of inflammatory response. However, roles of other neuropeptides and interaction among these neuropeptides in airway inflammation and AHR were largely unknown. Calcitonin gene-related peptide (CGRP), another intrapulmonary neuropeptide that functions as a potent vasodilator and neutrophils activator, is released from the same C-fiber ending as SP is released. By using an ozone-stressing animal model, previously we had demonstrated that CGRP might be involved in the development of AHR in rabbits. To extend the functional roles of SP, and to explore the possible interactive roles of SP and CGRP in airway inflammation, we examined expressions of SP, SP receptor (neurokinin 1, or NK-1R) and CGRP in vivo and ex vivo. We exposed guinea pigs at intervals to inhalation of ozone to induce airway inflammation. Animals were sacrificed at different time points; SP, SP receptor and CGRP expression were determined during the onset and progression of airway inflammation by radioimmunoassay, immunohistochemistry and in situ hybridization. Our data showed that after exposure to ozone, the concentration of SP in lung homogenate and the number of SP-immunoreactive cell bodies in lung slides increased within 24h, peaked on day 2, and then decreased slowly. Interestingly, CGRP expressions exhibited a similar temporal and spatial pattern, and there was a strong correlation between SP expression and CGRP expression, indicating a possible cooperative action of these two neuropeptides. We also noted an increased expression of SP receptor NK-1R in the development of airway inflammation. In order to test the hypothesis that CGRP as a coexisting neurotransmitter with SP can regulate the expression of NK-1R in the lung, and contribute to the SP-mediated inflammatory response, we used in vitro lung tissue culture to determine the effect of CGRP on NK-1R expression. We found that NK-1R expression was induced by CGRP incubation at both mRNA and protein levels, and the induction was attenuated by additions of the inhibitors of Protein Kinase A (PKA) pathway, Calmodulin-dependent Kinase pathway, and Tyrosine Protein Kinase pathway. In conclusion, our data provide compelling evidence that SP and CGRP are involved in the development of airway inflammation. The interaction between SP and CGRP is likely to contribute to the pathogenesis of AHR and other lung inflammatory diseases.
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PMID:Upregulation of substance P receptor expression by calcitonin gene-related peptide, a possible cooperative action of two neuropeptides involved in airway inflammation. 1677 50

In this work we have examined the appearance and distribution of nitric oxide synthase (NOS), with histochemical, immunohistochemical and biochemical methods, during development of the sea bass (Dicentrarchus labrax) gut. The data showed that both the calcium-calmodulin dependent neuronal isoform (nNOS) and calcium-independent inducible isoform (iNOS) are present in the larval gut of sea bass. The nNOS-immunoreactivity was present in the epithelial cells and enteric nerve cells of gut both in the 8-day-old specimens and in the 24-day-old-larvae. In the adult nNOS-immunoreactivity disappeared from epithelial cells, remaining in the wall intramural neurons and fibers. The iNOS-immunoreactivity was present in the epithelial cells of 24-day-old-larvae and was not detectable in the adult gut. Western blot analysis and determination of NOS activity also demonstrated the presence of the two NOS isoforms, nNOS and iNOS, in the gut of 24-day-old specimens. The presumably different roles played by the two isoforms of enzyme are discussed. The presence of nNOS isoform in the gut enteric neurons of the same larval stages of D. labrax in which we previously demonstrated the presence of substance P and Vasoactive Intestinal Polypeptide (VIP), may suggest that all these three components of the motility control system are already present in the larval phase. Nitric oxide (NO) may be also involved in the early immune response. The present results on the occurrence of iNOS isoform in epithelial gut cells of the same regions in which the gut-associated lymphoid tissue (GALT) will differentiate, may suggest for NO a role in early defence mechanisms, before the establishment of immune responses in GALT. Finally, the developmental and regional differences in nNOS and iNOS expression also suggest a regulatory role in development and differentiation of the sea bass gut.
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PMID:Occurrence of two NOS isoforms in the developing gut of sea bass Dicentrarchus labrax (L.). 1761 32

Desensitization is induced by the repeated administration of high doses of substance P (SP) or hemokinin-1 (HK-1). However, little information is available about the mechanisms involved in the induction of desensitization by these peptides. Thus, to characterize this desensitization, we examined the dose-dependent effect of these peptides, the effect of pretreatment with neurokinin 1(NK1) receptor antagonists, and the effect of pretreatment with inhibitors of protein kinases such as protein kinase A (PKA), protein kinase C (PKC), calcium/calmodulin kinase II (CaMKII) and mitogen-activated protein kinase kinase (MEK). The number of scratchings induced by 10(-3)M SP or HK-1 decreased following pretreatment with 10(-11)-10(-3)M SP or HK-1 with a marked reduction at 10(-3) and 10(-6)M SP or HK-1. The effect of NK1 receptor antagonists on desensitization induced by pretreatment with 10(-6)M SP was marked, whereas there was little effect of pretreatment with these antagonists on 10(-6)M HK-1-induced desensitization. Additionally, 10(-6)M SP- and HK-1-induced desensitization was attenuated by pretreatment with PKA, PKC and MEK inhibitors, except a CaMKII inhibitor that inhibited SP-induced desensitization. These results indicate that the receptor and kinases involved in HK-1-induced desensitization are partially different from those of SP.
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PMID:Pharmacological characterization of desensitization in scratching behavior induced by intrathecal administration of hemokinin-1 in the rat. 1805 10

Inflammation, trauma or nerve injury trigger low-level activity in C-fibres and may cause long-lasting hyperalgesia. Long-term potentiation (LTP) at synapses of primary afferent C-fibres is considered to underlie some forms of hyperalgesia. In previous studies, high- but not low-frequency conditioning stimulation of C-fibres has, however, been used to induce LTP in pain pathways. Recently we could show that also conditioning low-frequency stimulation (LFS) at C-fibre intensity induces LTP in vitro as well as in the intact animal, i.e. with tonic descending inhibition fully active. In the slice preparation, this form of LTP requires a rise in postsynaptic Ca2+-concentration and activation of Ca2+-dependent signalling pathways. Here, we investigated the signalling mechanisms underlying this novel form of LTP in vivo. We found that the signal transduction pathways causing LFS-induced LTP in vivo include activation of neurokinin 1 and N-methyl-D-aspartate receptors, rise of [Ca2+]i from intracellular stores and via T-type voltage-dependent Ca2+ channels, activation of phospholipase C, protein kinase C and Ca2+-calmodulin dependent kinase II. These pathways match those leading to hyperalgesia in behaving animals and humans. We thus propose that LTP induced by low-level activity in C-fibres may underlie some forms of hyperalgesia.
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PMID:Long-term potentiation at C-fibre synapses by low-level presynaptic activity in vivo. 1850 18

In this report, matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) was used to study the binding interactions between calmodulin and two target peptides (melittin and substance P). Various matrix conditions were tested and the less acidic matrix DHAP and THAP were found to favor the survival of the intact calcium-calmodulin as well as the calmodulin-peptide complexes. However, the application of direct MALDI-MS to detect the intact complexes turned out to be very difficult due to the dissociation of the complexes and the formation of nonspecific aggregates. In contrast, the specific binding of the target peptides to calmodulin could be easily deduced using intensity-fading (IF) MALDI-MS. Compared with the nonbinding control, clear reduction in the ion abundances of the target peptides was observed with the addition of calmodulin. Relative binding affinities of different peptides towards the protein could also be estimated using IF-MALDI-MS. This study may extend the application of IF-MALDI-MS in the analysis of noncovalent complexes and offer a perspective into the utility of MALDI-MS as an alternative approach to study the peptides binding to calmodulin.
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PMID:Investigation of calmodulin-Peptide interactions using matrix-assisted laser desorption/ionization mass spectrometry. 1911 Apr 43

The effects of the sensory neurotransmitter substance P on the expression of tight junction proteins and on barrier function in human corneal epithelial cells were investigated. The expression of ZO-1, but not that of occludin or claudin-1, was increased by substance P in a concentration- and time-dependent manner. This effect was inhibited by the NK-1 receptor antagonist GR82334 and by KN62, an inhibitor of Ca(2+)- and calmodulin-dependent protein kinase II. Substance P also increased the transepithelial electrical resistance of a cell monolayer in a manner sensitive to GR82334. Substance P may therefore play a role in maintenance of tight junctions in the corneal epithelium.
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PMID:Up-regulation of ZO-1 expression and barrier function in cultured human corneal epithelial cells by substance P. 1944 55

In vitro, prolyl oligopeptidase (POP) cleaves proline-containing bioactive peptides such as substance P, gonadotropin-releasing hormone, thyrotropin-releasing hormone, arginine-vasopressin, and neurotensin. Based on specific in vivo inhibition, POP has been suggested to be involved in cognitive and psychiatric processes but the identity of its physiological substrates has remained inconclusive. We have combined (a) sample snap-freezing and boiling buffer extraction, to limit protein degradation and reduce sample complexity; (b) pH two-dimensional liquid reverse-phase chromatography to enhance resolution; and (c) iTRAQ isobaric labeling to identify the rat brain peptides whose levels were differentially changed due to in vivo POP inhibition. In the hypothalamus, all the substrates found were part of precursors of secreted peptides such as copeptin, PACAP-related peptide, somatostatin, and proSAAS derived peptides, while in the cerebellum the peptides were derived from carcinoma-amplified sequence 1 homolog and calmodulin. In the striatum, somatostatin precursor derived peptide, fragments from E3-SUMO protein ligase RanBP2, and the subunit 5A of cytochrome c oxidase were increased. When analyzing the peptides that were significantly reduced by POP inhibition we found fragments from large protein complexes but, exclusively in the cerebellum, bioactive peptides such as cerebellin and fibrinopeptides A and B were detected.
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PMID:Combination of snap freezing, differential pH two-dimensional reverse-phase high-performance liquid chromatography, and iTRAQ technology for the peptidomic analysis of the effect of prolyl oligopeptidase inhibition in the rat brain. 1953 95


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