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 cAMP response element (CRE) plays an important role in the cAMP-mediated gene regulation. Several factors that recognize a CRE have been characterized, and it has been shown that they need either covalent modification by protein kinase A or a cofactor such as the adenovirus Ela to function as an activator. In this study we show that the substance P precursor gene expression is regulated by protein kinase A and identify the CRE sequence in its promoter region. We find that a novel factor and ATF2 bind to the region containing the CRE of the substance P precursor gene. The sequence analysis indicates that the novel protein, designated CELF, has a significant homology to C/EBP gene family proteins in the carboxyl-terminal part containing the basic region and the leucine zipper motif. Ubiquitous expression of CELF suggests that this factor is utilized by various genes. Cell-free transcription analyses indicate that CELF is a constitutive transcriptional activator without apparent phosphorylation by protein kinase A. These results demonstrate that multiple factors are responsible for transcriptional control of the substance P precursor gene through the CRE region.
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PMID:Molecular characterization of transcription factors that bind to the cAMP responsive region of the substance P precursor gene. cDNA cloning of a novel C/EBP-related factor. 171 59

Effects of centrally (intracerebro-ventricularly) administered synthetic substance P on the metabolism of cAMP in 19 brain areas were investigated. Substance P administration increased cAMP levels considerably in the frontal cortex, the central gray matter and in the nucleus of the solitary tract, and to a lesser extent in the bed nucleus of the stria terminalis and in the anterior hypothalamic nucleus. Cyclic AMP levels were decreased in the globus pallidus, the habenula, the posterior hypothalamic nucleus and in the locus coeruleus while other brain areas showed no changes in cAMP levels.
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PMID:Effects of centrally administered substance P on cyclic AMP levels in particular brain areas of rats. 171 15

Activity-dependent expression of vasoactive intestinal peptide (VIP) was investigated in spinal cord/dorsal root ganglia cultures derived from embryonic mice. Since all spinal cord neurons appear to exhibit spontaneous action potentials after one week in vitro, activity-dependent regulation of VIP-transcripts (mRNAVIP) could be studied with or without electrical blockade induced by tetrodotoxin (TTX). In 10-day-old cultures, a 50% decrease in mRNAVIP was observed after 3 days of treatment with TTX. The decrease in mRNAVIP was reversed upon removal of the TTX and was dependent on the age of the cultures: no decreases from control were observed in 5-day-old cultures and much smaller decrements were produced in one month old cultures treated with TTX. A variety of neuroactive substances were tested for effects on mRNAVIP in electrically active and electrically blocked cultures. Application of 8-bromo-cAMP (cAMP), N-methyl-D-aspartate (NMDA), substance P, muscimol, A23187 and VIP to electrically active cultures resulted in a 2- to 3-fold increase in mRNAVIP, while phorbol myristate 13-acetate (PMA) and 8-bromo-cGMP (cGMP) had no effect. In contrast, electrically inactive cultures exhibited a 3 to 4-fold increase in mRNAVIP after treatment with PMA, cAMP and VIP, while NMDA, substance P, muscimol, A23187 and cGMP produced no increases. In summary, the regulation of VIP gene expression in embryonic spinal cord neurons shows a temporal sensitivity to TTX-induced electrical blockade and may be mediated by multiple neurotransmitter inputs which converge on cAMP- and calcium-related processes in an activity-dependent manner.
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PMID:Spontaneous electrical activity regulates vasoactive intestinal peptide expression in dissociated spinal cord cell cultures. 171 67

C6-2B rat glioma cells were stably transfected with substance K receptor cDNA and used to study interactions between cAMP and Ca2+ signaling pathways. Activation of the newly expressed receptors by substance K increased the intracellular free Ca2+ concentration, as monitored by single-cell fura-2 imaging, and markedly inhibited agonist-stimulated cAMP accumulation. Blockade of intracellular Ca2+ mobilization abolished the substance K receptor-mediated inhibition of isoproterenol-induced cAMP production. Phosphodiesterase inhibitors, down-regulation or inhibition of protein kinase C, and pertussis toxin failed to prevent substance K-induced inhibition of agonist-stimulated cAMP accumulation. An increased intracellular Ca2+ concentration caused by either calcium ionophores or activation of endogenous bradykinin receptors was found to markedly reduce cAMP production in wild-type cells. These results demonstrate that elevated intracellular Ca2+ concentration can negatively modulate agonist-stimulated adenylate cyclase activity in C6-2B glioma cells.
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PMID:Inhibition of cAMP accumulation by intracellular calcium mobilization in C6-2B cells stably transfected with substance K receptor cDNA. 171 1

Calcitonin gene-related peptide (CGRP), a vasoactive neuropeptide present in peripheral neurons, is released at local sites of inflammation. In these studies specific high affinity adenylyl cyclase linked CGRP receptors were characterized on rat lymphocytes. The distribution, affinity, and specificity of CGRP receptors was analyzed by radioligand binding. 125I-[His10]CGRP binding to rat lymphocytes was rapid, reaching equilibrium by 20 to 30 min at 22 degrees C, and dependent on cell concentration. The dissociation constants, Kd, for the CGRP receptor on purified T and B lymphocytes are 0.807 +/- 0.168 nM and 0.387 +/- 0.072 nM and the densities are 774 +/- 387 and 747 +/- 244 binding sites/cell, respectively. Competition binding studies determined that rat CGRP inhibits 125I-[His10]CGRP binding to lymphocytes with the highest affinity (Ki = 0.192 +/- 0.073) followed by human CGRP and the CGRP receptor antagonist CGRP8-37. 125I-[His10]CGRP binding to rat lymphocytes was not inhibited by the neuropeptides substance P, calcitonin, or neuropeptide Y. Lymphocyte CGRP receptor proteins were identified by affinity labeling by using disuccinimidyl suberate to covalently cross-link 125I-[His10]CGRP to its receptor. Specifically labeled CGRP binding proteins visualized by SDS-PAGE analysis had molecular masses of 74.5 and 220 kDa. A third high molecular mass protein band which did not penetrate the gel was also observed. In functional studies, CGRP stimulated a rapid, sustained increase in cAMP with an ED50 of approximately 8 pM. In experiments comparing optimal concentrations of isoproterenol, a beta 2-adrenergic agonist, and CGRP, intracellular cAMP elevation after isoproterenol treatment returned to basal levels by 30 min, whereas cAMP was still elevated at 60 min after CGRP treatment. The response to CGRP was specific in that it could be completely blocked by CGRP8-37. The presence of high affinity functional CGRP receptors on T and B lymphocytes provides evidence for a modulatory role for CGRP in regulating lymphocyte function.
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PMID:Characterization of functional calcitonin gene-related peptide receptors on rat lymphocytes. 171 79

An increase in inositol 1, 4, 5-trisphosphate (IP3) formation in rat mast cells precedes an elevation in intracellular Ca2+ levels, which triggers the process(es) leading to histamine release. By means of a transmission electron microscope, it was revealed that when permeabilized mast cells were exposed to potassium antimonate, antimonate precipitates in the endoplasmic reticulum (ER) in the form of calcium antimonate, indicating that the ER is the intracellular Ca store in rat mast cells. IP3 at concentrations higher than 0.5 microM preferentially releases Ca2+ from the isolated ER of mast cells. GTP was also effective in releasing Ca2+ from the ER. IP3-induced Ca2+ release was inhibited by pretreatments with cAMP and antiallergic drugs. An increase in the intracellular Ca2+ concentration may lead to an activation of calmodulin, C kinase and cytoskeletal elements in sequence. Furthermore, microtubules may play an important role in the process(es) leading to Ca2+ release from the intracellular Ca store and subsequent histamine release, without affecting IP3 formation. In contrast, microfilaments seem to participate not only in the extrusion but also in the reincorporation of the mast cell granules, having no influence on intracellular Ca2+ release. Substance P (SP) is one of the most effective neuropeptides for releasing histamine from mast cells. Structure-activity relationship studies indicate that basicity at the N-terminal and hydrophobicity at the C-terminal are requisite for its histamine releasing activity. SP effectively released Ca2+ from the intracellular Ca store. The site of action of SP on the mast cell surface seems to be the same as that of compound 48/80. Eosinophil major basic protein (MBP) and histone are also effective for releasing histamine. The cDNA sequences of two subclasses of guinea pig MBP have been determined. These proteins may be released at the site of inflammation from the cells activated by the chemical mediators released from mast cells, and consequently, mast cell activation was reinforced. Such cell-to-cell interaction may be the reason for the augmentation of inflammation.
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PMID:[Recent advances in the research on histamine release]. 172 Jul 58

The effects of substance P (SP) on inositol trisphosphate (IP3) accumulation, myosin light chain (MLC) phosphorylation, cAMP formation and contraction were studied in iris sphincter smooth muscle of different mammalian species. SP receptor density was also examined in membrane fractions from this tissue. The data obtained can be summarized as follows. (1) In the iris sphincters of rabbit, bovine and pig, SP receptors are coupled to the phospholipase C system, whereas in dog, cat and human these receptors are coupled to the adenylate cyclase system. (2) In those species which employ the phospholipase C system, SP induced IP3 accumulation, MLC phosphorylation and contraction in a dose-dependent manner; in contrast, in those species in which SP induced the formation of cAMP we found the neuropeptide to cause muscle relaxation. The findings on cAMP formation in intact tissue were confirmed in iris sphincter membranes. Both the effect of SP on IP3 accumulation in rabbit and bovine sphincters and its effect on cAMP formation in the dog were blocked by the SP antagonist, (D-Pro2, D-Trp7, 9)-SP. (3) The density of SP receptors in rabbit, bovine and dog were found to be 227, 110.9 and 13.6 fmol mg-1 protein, respectively, and the Kd values were 1.9, 1.8 and 1.3 nM, respectively. (4) Of the neuropeptides investigated SP, neurokinin A and neurokinin B had significant stimulatory effects on IP3 accumulation and on contraction in the rabbit iris sphincter; however, neither neurokinin Y nor the calcitonin gene-related peptide (CGRP) had any effect on these responses. In addition, none of the neuropeptides studied had any effect on IP3 or on contraction in the dog iris sphincter. While it is possible that SP may have dual actions, with the predominant action dependent on the species, the data presented could suggest the presence of two SP receptor subtypes, one coupled to phospholipase C and the other to adenylate cyclase. The results of this investigation indicate major species differences in biochemical and functional responsiveness to SP and in SP receptor density in the iris sphincter of the mammalian eye, and support a modulatory role for the neuropeptide in muscle response in this tissue.
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PMID:Species differences in the effects of substance P on inositol trisphosphate accumulation and cyclic AMP formation, and on contraction in isolated iris sphincter of the mammalian eye: differences in receptor density. 172 88

Substance P-induced histamine release and Ca2+ release from the intracellular Ca store of rat peritoneal mast cells were inhibited by both antiallergic drugs and microtubule inhibiting agents. It was found that in the case of antiallergic compounds, histamine release inhibition may be intimately related to the inhibition of Ca2+ release from the intracellular store in which the microtubules play an important role. When mast cells were pretreated with either theophylline or dibutyryl cAMP, the inhibition of histamine release was closely related to the inhibition of Ca2+ release from the intracellular Ca store. Calmodulin inhibitors were also effective in inhibiting histamine release from mast cells induced by substance P. The inhibitory potencies of calmodulin inhibitors on histamine release from mast cells were closely correlated with those exerted on calmodulin activity.
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PMID:Substance P-induced histamine release from rat peritoneal mast cells and its inhibition by antiallergic agents and calmodulin inhibitors. 172 34

Airway submucosal glands are by volume the most important source of macromolecules in airway secretions. These secretions, containing gel-forming mucins, antibacterial proteins, and antiproteases, comprise the major defensive barrier protecting the host against airborne pathogens. The identification of the mechanisms regulating secretion from the submucosal glands is key to understanding the genesis of this barrier and how it is altered by disease processes. Using a variety of methods, we and others have identified on the gland cells of several species receptors specific for ACh, norepinephrine, substance P, VIP, PGE1, PGE2, PGA1, PGD2, histamine and bradykinin. These receptors all participate in modulating the secretory activity of the airway submucosal glands. Studies of homogeneous cultures of bovine airway serous cells have yielded detailed information regarding the beta-adrenergic receptor on these cells. Using radioligand binding techniques, we found evidence for the presence of a single high affinity beta receptor of beta-2 subtype. Occupancy of this receptor by isoproterenol causes an elevation in the concentration of intracellular cAMP, which in turn stimulates the phosphorylation of a subset of cytoplasmic and membrane proteins. Based on the kinetics and pharmacology of these effects, it is likely that cAMP functions as a second messenger in the serous cell secretory pathway, probably acting through protein kinases. Current efforts are directed at identification of those phosphoproteins whose phosphorylation and dephosphorylation times are consistent with their possible roles in secretion.
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PMID:Receptors on airway gland cells. 215 62

Somatostatin (SRIF), cholecystokinin (CCK), gastrin and substance P, as single agents, do not influence baseline cellular cAMP levels in human thyroid cultures. SRIF inhibits TSH-induced cAMP accumulation in human thyroid cell, while CCK, gastrin and substance P do not modify cAMP response to TSH. Vasoactive intestinal peptide (VIP) increases cellular cAMP levels in human thyroid cultures and its effect is additive to increases produced by norepinephrine (NE) and isoproterenol (ISO). Neither SRIF nor the other tested peptides influence adrenergic and VIP-ergic cAMP stimulation.
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PMID:Neuropeptidergic control of cyclic AMP accumulation in human thyroid cell. 241 54


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