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)

12-O-tetradecanoylphorbol-13-acetate (TPA, 1 to 30 ng/ml) produced a dose-related inhibition of substance P (SP)-induced histamine release from rat peritoneal mast cells. TPA itself induced some histamine release over this concentration range (maximum release about 20% of total). Maximum inhibition of SP-induced release by TPA required preincubation with TPA for at least 10 min. The inhibitory action of TPA was observed in the absence as well as in the presence of extracellular calcium (0.4 mM). Inhibition of diacylglycerol kinase by R 59022 or of diacylglycerol lipase by RHC 80267 reduced SP-induced histamine release. Oleolylacetylglycerol (OAG, 50 microM) inhibited histamine release induced by SP but was less potent than TPA. It is concluded that protein kinase C activation in rat peritoneal mast cells is associated with inhibition of SP-induced histamine release.
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PMID:Effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on substance P-induced histamine release from rat peritoneal mast cells. 169 35

Histone 10 to 50 micrograms/ml released histamine from rat peritoneal mast cells in the absence of extracellular calcium. Extracellular calcium, 1 mM produced a slight shift of the histone dose-response curve to the right. In the absence of extracellular calcium, the histamine release-response to combined stimulation with histone and substance P was saturable. Neither histone nor substance P elicited any further response when one of these agonists alone was already eliciting a maximum response, although the cells were capable of a greater degree of histamine release in the presence of compound 48/80. In the presence of extracellular calcium, substance P at a concentration not by itself producing a response, acted synergistically with histone to induce histamine release. The substance P antagonist, SP-A, inhibited histamine release by histone. The phorbol ester, TPA, released histamine in a dose-dependent manner and this response was inhibited by SP-A. It is suggested that substance P and histone interact with a common site to release histamine and the role of protein kinase C in this release mechanism is discussed.
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PMID:Histamine release induced by histone and phorbol ester from rat peritoneal mast cells. 241 41

A method is described for the isolation and short-term culture of canine antral gastrin (G) cells. Tissue was dispersed by enzymes and G cells enriched by elutriation and cultured for 40 h. These cultures contained 12% G cells and less than 2% somatostatin- or serotonin-containing cells. Bombesin (0.001-100 pM) potently stimulated gastrin release from cell cultures in a linear fashion over 2 h. The bombesin-specific monoclonal antibody 2A11 dose-dependently blocked bombesin stimulation. Somatostatin (0.001-1,000 nM) inhibited bombesin-stimulated gastrin release. Antibody to somatostatin (Mab S8) prevented the inhibition by exogenous somatostatin but did not alter bombesin-stimulated or basal gastrin release. The substance P (SP) analogue spantide (1 nM-1 microM) did not inhibit bombesin-stimulated gastrin release. Postreceptor activation of adenylate cyclase by forskolin and of protein kinase C by the phorbol ester, beta-TPA, caused gastrin release. The calcium ionophore A23187 also released gastrin in a dose-dependent fashion. This methodology allows enrichment and short-term culture of antral G cells; these cells have stimulatory bombesin and inhibitory somatostatin receptors, suggesting that these peptides have a direct action on antral G cells. Furthermore, G cells are activated by cAMP and calcium/phosphatidylinositol-dependent mechanisms.
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PMID:Bombesin stimulation of gastrin release from canine gastrin cells in primary culture. 243 71

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

The distribution of six isoforms of protein kinase C (PKC) in seromucous acinar cells of rat submandibular gland was examined and their translocation from the cytosolic- to the membrane fraction after different stimuli investigated. Western blotting, immunostaining with isoform-specific antibodies and scanning densitometry showed that PKC-alpha and epsilon were distributed fairly evenly between the cytosol and membranes in resting cells, while isoforms- beta, delta and zeta were all predominantly localized (over 80%) in membranes. PKC-gamma was not detected. PKC-alpha was mobilized to the membrane fraction by the phorbol ester, TPA, but not by the phosphoinositide-coupled agonists carbachol, methoxamine and substance P (SP). PKC-epsilon was translocated by TPA and carbachol but not by SP or methoxamine. Biochemical assay of total PKC confirmed that cytosolic enzyme activity was significantly reduced by TPA and carbachol to 29% and 75% respectively of control levels. These results suggest that muscarinic regulation of the mucosecretory response in the rat submandibular gland may be mediated by the PKC-epsilon isoform.
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PMID:Distribution and translocation of isoforms of protein kinase C in rat submandibular acinar cells. 747 51

The human c-kit receptor ligand, rhSCF, is the only cytokine known to be active on human mast cells, but its intracellular signal transduction pathway is still unknown. We compared the effect of rhSCF on intracellular Ca2+ levels in purified (> 70% pure) adult skin mast cells with two other immunologic stimuli, namely, anti-IgE and substance P. Both rhSCF (1 microgram/mL) and anti-IgE (3 micrograms/mL) induced a rapid (< 20 sec) and sustained (T1/2 for decay > 10 min) increase in free cytosolic Ca2+ concentration. In contrast, substance P (5 microM) elicited a very rapid (< 1 sec) and transient (T1/2 for decay congruent to 5 sec) rise in intracellular Ca2+ levels. Intracellular cAMP levels were then increased by pharmacologic means to examine the role of the cyclic nucleotide in controlling the Ca2+ response in skin mast cells. A combination of the general phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX) (200 microM) and the adenylate cyclase activator, forskolin (30 microM) was effective in inhibiting the Ca2+ response induced by rhSCF or anti-IgE (82 and 68% inhibition, respectively), while IBMX and forskolin alone were much less effective. The phosphodiesterase isozyme IV inhibitor, rolipram (10 microM), variably affected the increase in Ca2+ levels induced by anti-IgE, but it exerted a significant inhibitory activity on anti-IgE- or rhSCF-induced response in the presence of forskolin (30 micrograms/mL) (33 and 67%, respectively). Two different protein kinase C (PKC) activators TPA (200 nM) and bryostatin 1 (200 nM) similarly inhibited rhSCF- (22 and 32%, respectively) and anti-IgE-induced (24 and 32%) Ca2+ response. Finally, the kinase inhibitor genistein (30 micrograms/mL) was a somewhat more effective inhibitor of the rise in intracellular Ca2+ induced by rhSCF (100%) than that activated by anti-IgE (54%) (P < 0.05). These data indicate that rhSCF and anti-IgE may act on human mast cells through a common pathway to increase free cytosolic Ca2+ levels and this effect is similarly modulated by various drugs.
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PMID:Studies of the intracellular Ca2+ levels in human adult skin mast cells activated by the ligand for the human c-kit receptor and anti-IgE. 751 34

In order to determine whether tachykinins alter the function of chief cells and to characterize the receptors mediating the effect, we investigated the abilities of various substance P (SP)-related peptides to inhibit the binding of 125I-Bolton-Hunter labeled substance P (125I-BH-SP) and their abilities to alter cell function in dispersed chief cells from guinea pig stomach. Binding of 125I-BH-SP was saturable, reversible, time- and temperature-dependent and was inhibited by several SP-related peptides with relative potencies of SP = physalaemin (IC50:0.19 nM) > SP methyl ester (SP-ME) (IC50:3.3 nM) > eledoisin (IC50:6.1 nM) > neurokinin A (NKA) (IC50: 65 nM) > neurokinin B (NKB) (IC50:80 nM). Analyses of these binding data demonstrated that chief cells possess a high and low affinity class of binding sites. Neither 125I-NKA nor [phenylalanyl-3,4,5-3H]senktide demonstrated saturable binding to chief cells. Acid stripping experiments demonstrated rapid ligand internalization with 55% of the bound radioligand internalized by 10 min. Phospholipase C activating agents (carbachol, CCK-8), adenylate cyclase activating agents (secretin, VIP), TPA and the calcium ionophore, A23187, all inhibited the binding of 125I-BH-SP and it was due to inhibition of ligand internalization with no change in surface bound parameters. SP (0.1 microM) stimulated pepsinogen secretion but was 4-times less efficacious than CCK-8 (10 nM) or carbachol (1 mM). 10 nM SP stimulated a rapid increase in cytoplasmic free calcium concentration ([Ca2+]i) followed by a sustained elevation lasting 2 min. Single cell spectroscopy demonstrated SP (10 pM to 1 microM) did not cause calcium oscillations. The NK1 receptor antagonist, CP96,345 specifically inhibited the SP-stimulated changes in [Ca2+]i and pepsinogen secretion. The relative potencies of SP-related peptides to stimulate pepsinogen secretion and [Ca2+]i demonstrated a close agreement with their abilities to inhibit the binding of 125I-BH-SP, and comparison of the dose-response curves suggests occupation of the low affinity sites mediate changes in biologic activity. In conclusion, the present study demonstrates that chief cells possess a NK1 subtype of tachykinin receptor, occupation of the low affinity sites of this receptor cause calcium mobilization and pepsinogen secretion, and that binding to this receptor is regulated by agents that activate phospholipase C, adenylate cyclase, protein kinase C and calcium mobilization.
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PMID:Gastric chief cells possess NK1 receptors which mediate pepsinogen secretion and are regulated by agents that increase cAMP and phospholipase C. 867 32

The neurokinin receptor family is known to modulate phospholipase C activity. In order to find new compounds modulating the activity of these receptors we have developed a cellular screening system that measures the biological activity of receptors coupled to the IP3/DAG signal transduction pathway via the transcriptional activation of a reporter gene. For the establishment of neurokinin test cell lines the reporter cell line A20, stably transformed with the luciferase gene under the control of a promoter containing TPA response elements (TRE), which did not respond to neurokinin agonists, was used. Stable test cell lines were developed by transfecting the reporter cell line A20 with the genes for the human neurokinin receptors NK1, NK2 or NK3, respectively. In these cell lines, expression of luciferase was inducible by substance P, neurokinin A and neurokinin B, respectively. The order of potency of the three neurokinins substance P, neurokinin A and neurokinin B was consistent with published data and results from ligand binding studies performed with the NK1 and NK2 test cell lines. The agonistic effect of the neurokinins could be inhibited in a dose-dependent manner by simultaneous addition of neurokininspecific antagonists like the non-peptide antagonists CP-99,994 and SR 48968.
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PMID:Functional characterization of the human neurokinin receptors NK1, NK2, and NK3 based on a cellular assay system. 890 68

Astrocytes play an important role in initiating and modulating inflammatory responses within the central nervous system. Extensive studies in rodents have shown that TPA, substance P, calcium ionophore A21387, and lipopolysaccharide (LPS) induce formation and release of arachidonic acid metabolites which have immunoregulatory properties. To better understand the immunopathology of brain injury, we studied the role of inflammatory cytokines such as tumor necrosis factor alpha, interleukin (IL) 6, IL-2, interferon gamma and IL-1 beta in the production of arachidonic acid metabolites in cells from fetal human brain. Among these cytokines, only IL-1 beta significantly stimulated production of prostaglandins E2 and F2 alpha but not PGD2, thromboxane B2 and 6-keto-PGF1 alpha. Under our experimental conditions, these astrocyte cultures did not produce metabolites in the lipoxygenase pathway such as leukotrienes B4 and C4 upon IL-1 beta stimulation. The stimulatory effects of IL-1 beta on the induction of arachidonic acid metabolites have been studied in various human cell types but not in astrocytes. Human astrocyte production of PGF2 alpha and PGE2 but not PGD2, 6-keto-PGF1 alpha and TXB2 when stimulated by IL-1 beta, is thus a novel finding. This observation should initiate investigations into the mechanism of arachidonic acid metabolism and the role of its metabolites in inflammation in the human nervous system.
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PMID:Recombinant human interleukin 1 beta induces production of prostaglandins in primary human fetal astrocytes and immortalized human fetal astrocyte cultures. 898 97