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)

Jurkat and HUT 78 T cell lines, as well as peripheral blood human T cells activated with PHA plus PMA were used to investigate the capacity of substance P (SP) neuropeptide to regulate IL-2 production. By using Northern blot analysis and dosage of the IL-2 release in cell supernatants, we show that SP can act as cosignal with PHA + PMA to enhance the expression of specific IL-2 mRNA and IL-2 secretion in T cells. By using the N-terminal SP(1-4) or the C-terminal SP(4-11) fragments of the entire molecule, we show that the cosignal activity is carried by the C-terminal portion of SP. The SP and SP(4-11) optimal effects were observed at 10(-12) M and 10(-10) M when a broad range of concentrations from 10(-6) M to 10(-13) M was tested. The increase of IL-2 mRNA obtained with 10(-12) M of SP in the activated Jurkat cells was reduced by adding 10(-10) or 10(-9) M of the SP antagonist (D-Pro2,-D-Phe7,-D-Trp9)SP to the culture, indicating the specificity of SP action. The up-regulation observed when 10(-12) M of SP was applied together with the mitogens on Jurkat cells, persisted after a 16-h culture period, time at which the IL-2 mRNA signal is normally back to a minimum level when the mitogens are used alone. Furthermore, an induction of IL-2 mRNA accumulation, in a 2-h pulse, was obtained with 10(-12) M of SP on Jurkat cells previously activated with mitogens for 16 h.
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PMID:Substance P enhances IL-2 expression in activated human T cells. 137 46

Taurine (Tau), calcium (Ca+2) and opiates each produce antinociception when injected i.t. in mice. This study was initiated to determine whether there is a common mechanism underlying their antinociceptive effects. Using the abdominal stretch assay, the antinociceptive effects of both Tau (12 nmol) and Ca+2 (72 nmol) were antagonized by i.t. TAG (4.4 nmol), a Tau antagonist, but not by i.p. injection of the opiate antagonist naloxone (5 mg/kg). The antinociceptive effects of Tau and Ca+2 correlated with their ability to inhibit the intensity of caudally-directed biting and scratching behaviors produced by i.t. NMDA or kainic acid. The inhibitory effects of both Tau and Ca+2 on the biting and scratching behaviors behaviors induced by substance P or excitatory amino acids were reversed by TAG, suggesting a common mediation by Tau. These data indicate that the antinociceptive effects of both Tau and Ca+2 appear to be mediated, at least in part, by Tau but not by the release of endogenous opioid compounds. In addition, inhibition of chemical irritant-induced nociception may be produced by a simple blockade of excitatory amino acid activity.
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PMID:Antinociceptive effects of intrathecal taurine and calcium in the mouse. 137 74

1. Dual-excitation microfluorometry (Fura-2 as indicator) was employed to monitor directly changes in the cytosolic calcium concentration [( Ca2+]i) in single cells. We investigated and compared the effects of stimulation of AR42J rat pancreatic acinar cells by two peptide agonists, substance P and bombesin. 2. Substance P (10(-7) M) and bombesin (10(-8) M) each gave rise to a marked, but transient, elevation in [Ca2+]i. The calcium signals evoked by the two peptides were qualitatively and quantitatively very similar. However, in the absence of extracellular Ca2+ the response to substance P, but not bombesin, was abolished. These results suggest that substance P induces calcium influx across the cell surface membrane but does not release calcium from internal stores. Bombesin in marked contrast releases calcium from intracellular stores in the absence of any detectable calcium influx. 3. Depolarization by high-K+ extracellular solutions evoked a marked, but transient, rise in [Ca2+]i. This elevation in [Ca2+]i was strictly dependent upon the presence of Ca2+ in extracellular media. 4. Nifedipine (5 x 10(-6) M), an antagonist of L-type voltage-dependent Ca2+ channels, blocked the elevations in [Ca2+]i induced by either substance P or high-K+ solutions, but not that evoked by application of bombesin. 5. Patch-clamp, single-channel current recordings from cell-attached patches of membrane confirmed the presence of voltage-dependent calcium channels in the surface membranes of AR42J cells. Whole-cell current recordings demonstrated voltage-dependent inward Ca2+ (Ba2+) currents which were increased in amplitude by substance P and blocked by nifedipine. 6. The protein kinase C (PKC) activators, the phorbol diester, phorbol 1,2-myristate 13-acetate (PMA, 10(-7) M), and cell-permeable diacylglycerol analogues, 1-oleoyl-2-acetyl-sn-glycerol (OAG, 2.5 x 10(-6) M) and sn-2-dioctanoyl glycerol (DiC8, 2.5 x 10(-6) M), mimicked the effect of substance P, but not bombesin, in elevating [Ca2+]i in a manner that was blocked by removal of extracellular Ca2+ or application of nifedipine. 7. The PKC inhibitor, polymyxin B (2.5 x 10(-6) M), applied 2 min prior to stimulation blocked the effects of substance P and PKC activators, but not bombesin, in elevating [Ca2+]i. 8. The calcium signals evoked by substance P and bombesin are achieved by activation of different molecular mechanisms. Substance P, the evidence suggests, activates PKC which in turn stimulates calcium influx by opening voltage-dependent Ca2+ channels in the cell surface membranes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Substance P and bombesin elevate cytosolic Ca2+ by different molecular mechanisms in a rat pancreatic acinar cell line. 170 Jan 6

Production of O2- in response to FMLP, TNF, IFN-gamma, platelet activating factor, LPS, substance P, and PMA by human eosinophils in suspension and in contact with polystyrene ELISA plastic (PL) or biologic surfaces was studied. Monolayers of human endothelial cells (HEC) or PL coated with FCS, fibronectin, laminin, collagen types I and IV, fibrinogen, or fibrin were used as biologic surfaces. Only PMA and FMLP stimulated O2- generation by eosinophils in suspension. Eosinophils residing on HEC monolayers, either untreated or treated with LPS, were unresponsive to all stimuli except PMA. PMA induced O2- generation by eosinophils on all surfaces; FMLP on all surfaces but HEC monolayers; TNF and platelet-activating factor only on PL, fibrinogen, and fibrin; LPS and substance P only on PL. PMA was equally effective on eosinophils on surfaces and in suspension, whereas the effect of FMLP was greater on eosinophils on surfaces than on eosinophils in suspension. IFN-gamma was ineffective on any of the surfaces tested. These results indicate that biologic surfaces may profoundly affect the ability of eosinophils to respond with a respiratory burst to physiologically relevant soluble stimuli, the effect varying according to the nature of both the stimulus and the surface. Since the respiratory burst generates products of oxygen reduction that are toxic to several tissue components, it follows that biologic surfaces may modulate eosinophil-induced tissue injury.
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PMID:Eosinophil activation on biologic surfaces. Production of O2- in response to physiologic soluble stimuli is differentially modulated by extracellular matrix components and endothelial cells. 171 13

Nodose (inferior vagal sensory) ganglia were removed from neonatal rats, enzymatically dispersed using neutral protease, and maintained on previously dispersed rat atriacytes. After 7-10 days in culture, calcitonin gene-related peptide (CGRP) was present in 1-3 times the molar amount of substance P (SP). The content of SP was doubled by the addition of nerve growth factor (NGF) whereas CGRP was significantly less increased by 50% or less. The addition of forskolin increased SP and CGRP levels in cultures with or without NGF by 60-80 percent. Phorbol ester (PMA) did not alter SP content but significantly raised CGRP content by 40% in NGF supplemented cultures (P less than 0.001). Corticosterone, 0.01-0.1 microM, reduced SP content by 30% independently of NGF but had no effect on CGRP. These studies demonstrate that SP in vagal sensory neurons is more sensitive than CGRP to the effects of NGF or corticosterone. Both peptides are up-regulated by presumed increases in intracellular cyclic AMP, while CGRP (or CGRP neurons) may be independently regulated by protein kinase C.
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PMID:Differential regulation of calcitonin gene-related peptide and substance P in cultured neonatal rat vagal sensory neurons. 246 32

We investigated Ca2+-dependent, depolarization-induced release of substance P (SP) and LH-RH from medial basal hypothalamic (MBH) and substantia nigra (SN) synaptosomes prepared from male rat brain. Depolarization of MBH synaptosomes evoked significant release of SP from 10.0 +/- 0.1 (5 mM K+) to 28.0 +/- 2.4 (75 mM K+) pg released/10 seconds. Fractional release was 1.0% and 2.7% respectively. In contrast, LH-RH was not released by depolarization of MBH synaptosomes: 11.6 +/- 0.9 (5 mM K+) to 11.0 +/- 0.7 (75 mM K+) pg released/10 seconds. Fractional release was 1.1 and 1.0% respectively. Depolarization-induced LH-RH release also did not occur in the presence of 10(-4) or 10(-6) M norepinephrine, 10(-7) M 12-O-tetradecanoylphorbol-13-acetate (TPA, PMA), 10(-5) M forskolin or in female rats. The inability of depolarizing concentrations of K+ to stimulate LH-RH release in physiological buffers remains an enigma. Significant depolarization-induced SP release was seen from MBH and SN synaptosomes at 20, 15, 10, 5 and only 1 second of release. Despite comparable basal release of SP from MBH and SN synaptosomes, the rate and magnitude of evoked release were much more pronounced in SN synaptosomes. The initial rate (0-1 second) of SP release was 4.5-fold greater from SN than from MBH synaptosomes [krel = 0.027(-1) (SN), krel = 0.006(-1) (MBH)]. The magnitude of SP release from SN synaptosomes was 2- to 3-fold greater at any given time interval compared with release from MBH synaptosomes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Rapid release of substance P and LH-RH from synaptosomes prepared from the medial basal hypothalamus and substantia nigra. 247 48

Spontaneous dorsal root potentials (sDRPs) were recorded from the dorsal roots of the isolated frog spinal cord using sucrose gap techniques. sDRPs were always negative (depolarizing) in sign and ranged in size from about 100 microV to 6.0 mV. The largest sDRPs were 25-40% of the amplitude of DRPs evoked by stimulation of adjacent dorsal roots. Hypoxia or accumulation of extracellular K+ ions did not appear responsible for the generation of this spontaneous activity since exposing the cord to unoxygenated Ringer's solution decreased sDRPs and K+-sensitive microelectrodes indicated that only small changes in extracellular K+ (approximately 0.15 mM) were produced coincidently with the largest sDRPs. Chemically-mediated synaptic transmission was found to be necessary for the production of sDRPs because the addition of Mn2+ or Mg2+ ions or tetrodotoxin to the Ringer's solution or reduction of its Na+ concentration blocked sDRPs, whereas application of 4-aminopyridine enhanced them. It did not seem that a direct action of GABA on afferent fiber terminals was responsible for the generation of spontaneous potentials since an increase in sDRPs was seen after: application of the GABA antagonists, bicuculline and picrotoxin; exposure to the glutamic acid decarboxylase inhibitor, semicarbazide (which significantly reduced the concentration of GABA in the cord); and lowering of the external Cl- concentration. Similarly taurine is probably not significant since the taurine antagonist, TAG, increased the amount of spontaneous activity. On the other hand, (--)-baclofen, which is thought to reduce excitatory amino acid release, D,L-alpha-aminoadipic acid, alpha, epsilon-diaminopimelic acid, and 2-amino-4-phosphonobutyric acid, which are believed to be selective postsynaptic excitatory amino acid antagonists, and [D-Pro2-D-Phe7-D-Trp9]-substance P, a postsynaptic blocker of the action of substance P, markedly and reversibly reduced sDRPs. Experiments were performed on isolated cords without supraspinal or afferent input; therefore sDRPs must be generated by intraspinal structures. It would seem that interneurons are responsible because addition of mephenesin or pentobarbital--compounds which inhibit polysynaptic reflex transmission involving interneurons--reduced the production of sDRPs. sDRPs may result from the action of excitatory transmitters such as L-glutamate, L-aspartate, or substance P released by interneuronal firing in the spinal cord. Moreover, because sDRPs were increased by application of yohimbine, corynanthine and propanolol and reduced by haloperidol, such interneurons may be under descending control of adrenergic and dopaminergic fibers.
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PMID:Spontaneous dorsal root potentials arise from interneuronal activity in the isolated frog spinal cord. 620 11

1. Somatostatin produces a voltage-dependent inhibition of N-type Ca2+ current in chick sympathetic neurons. Pretreatment of chick sympathetic ganglion neurons with protein kinase C (PKC) activators has no effect on calcium current (ICa) but reduces the inhibition of ICa by somatostatin. 2. The effects of the alkaloid PKC activator (-)-indolactam V were indistinguishable from those of 4 beta-phorbol-12-myristate-13-acetate (4 beta-PMA). The inactive isomers (+)-indolactam V and 4 alpha-PMA did not alter the modulation of ICa by somatostatin. 3. Modulation of ICa by somatostatin desensitizes, with a time for half desensitization of approximately 3 min. PKC activation mimics the normal desensitization process in that responses to 30 nM somatostatin are inhibited to a greater extent than are responses to 1 microM somatostatin. 4. PKC appears to act at the level of the somatostatin receptor or receptor-G protein interaction because PKC activation does not alter Ca2+ current inhibition in response to a nonhydrolyzable analog of GTP, GTP-gamma-S, which directly activates G proteins. 5. The specific PKC inhibitor calphostin C largely reverses the effects of phorbol esters, but does not slow the normal rate of desensitization of somatostatin responses. This indicates that PKC is not involved in the homologous desensitization of the somatostatin receptor. 6. Neither substance P, which activates PKC in these cells, nor arachidonic acid, another PKC activator, altered the action of somatostatin on ICa.
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PMID:Protein kinase C blocks somatostatin-induced modulation of calcium current in chick sympathetic neurons. 750 59

There is increasing evidence that the neurologic system is capable of modulating a wide range of immunologic responses, including certain inflammatory processes in the lung, gastrointestinal tract, and skin. It has been proposed that secreted neuropeptides such as substance P (SP) may mediate these neuroinflammatory interactions by binding to and stimulating immune cells such as mast cells and lymphoid cells. SP is secreted in a variety of tissues by an extensive network of neurosensory C and A5 fibers in response to a wide range of noxious stimuli and injury. Previous studies to examine the effect of SP on mast cells have focused on its role in triggering histamine release and mediating immediate hypersensitivity responses. Recently it was demonstrated that mast cells are also capable of secreting multiple cytokines including TNF-alpha, IL-1, IL-3, IL-4, IL-6, and GM-CSF. In this study we tested the possibility that SP may also influence mast cell-mediated late inflammatory events by modulating the production of one or several of these cytokines. Our results indicate that SP induces TNF-alpha mRNA expression and TNF-alpha secretion in a dose-dependent manner in a murine mast cell line, CFTL12. Likewise, SP stimulates TNF-alpha secretion in freshly isolated murine peritoneal mast cells. The induction of mast cell TNF-alpha is selective, since SP does not stimulate the production of IL-1, IL-3, IL-4, IL-6, or GM-CSF in these cells. The CFTL 12 mast cell line constitutively expresses high levels of SP receptor mRNA which is not modulated by PMA/cycloheximide treatment or SP. These results further support the concept that the neurologic system modulates inflammatory events by neuropeptide-mediated mast cell cytokine release.
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PMID:Substance P selectively activates TNF-alpha gene expression in murine mast cells. 768 20

The ability of T cells to adhere to and interact with components of the blood vessel walls and the extracellular matrix is essential for their extravasation and migration into inflamed sites. We have found that the beta1 integrin-mediated adhesion of resting human T cells to fibronectin, a major glycoprotein component of the extracellular matrix, is induced by physiologic concentrations of three neuropeptides: calcitonin gene-related protein (CGRP), neuropeptide Y, and somatostatin; each acts via its own specific receptor on the T cell membrane. In contrast, substance P (SP), which coexists with CGRP in the majority of peripheral endings of sensory nerves, including those innervating the lymphoid organs, blocks T cell adhesion to fibronectin when induced by CGRP, neuropeptide Y, somatostatin, macrophage inflammatory protein-1beta, and PMA. Inhibition of T cell adhesion was obtained both by the intact SP peptide and by its 1-4 N-terminal and its 4-11, 5-11, and 6-11 C-terminal fragments, used at similar nanomolar concentrations. The inhibitory effects of the parent SP peptide and its fragments were abrogated by an SP NK-1 receptor antagonist, suggesting they all act through the same SP NK-1 receptor. These findings suggest that neuropeptides, by activating their specific T cell-expressed receptors, can provide the T cells with both positive (proadhesive) and negative (antiadhesive) signals and thereby regulate their function. Thus, neuropeptides may influence diverse physiologic processes involving integrins, including leukocyte-mediated migration and inflammation.
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PMID:Neuropeptides, via specific receptors, regulate T cell adhesion to fibronectin. 955 39


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