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)

1. Endothelin (1 nM-0.3 microM) produced a concentration-dependent contraction of guinea-pig epithelium-containing (intact) trachea (EC50 = 30.9 nM). Endothelin was a less potent agonist than leukotriene D4 (LTD4; EC50 = 0.77 nM), but was more potent than carbachol (EC50 = 0.15 microM) or substance P (EC50 = 1.4 microM). Endothelin was a more potent contractile agent in rat endothelium-denuded aorta (EC50 = 2.1 nM) than in guinea-pig trachea. 2. Endothelin-induced contraction in guinea-pig trachea was unaffected by mepyramine (10 microM), atropine (1 microM), SK&F 104353 (10 microM), a leukotriene receptor antagonist, or SQ 29,548 (1 microM), a thromboxane receptor antagonist. The contraction produced by 0.3 microM endothelin was potentiated by cyclo-oxygenase inhibition with 5 microM indomethacin. 3. Nicardipine (0.01 or 0.1 microM) or incubation in calcium-free medium +0.1 mM EGTA for 30 min had a relatively minor or no effect on endothelin concentration-response curves in guinea-pig intact trachea, but markedly inhibited responses produced by endothelin in endothelium-denuded aorta of the rat. Increasing the EGTA concentration in calcium-free medium to 1 mM abolished endothelin-induced contraction in guinea-pig trachea. 4. In guinea-pig trachea, ryanodine (10 microM) produced a 2.1 fold shift to the right of endothelin concentration-response curves and reduced the maximum response elicited by 0.3 microM endothelin. 5. Staurosporine (0.01 microM and 0.1 microM), a protein kinase C inhibitor, was without effect on endothelin- or carbachol-induced contraction in guinea-pig trachea, but markedly inhibited the response produced by endothelin in rat aorta. 6. Endothelin (3 nM-0.3 microM) produced a concentration-dependent stimulation of phosphatidylinositol (PI) turnover in guinea-pig intact trachea, with an EC50 value of 45.9 nM. 7. Removal of the epithlium markedly potentiated endothelin-induced contraction in guinea-pig trachea, producing a 4.7 fold leftward shift in endothelin concentration-response curves and an increase in the contractile response elicited by 0.3 microM endothelin. 8. These data indicate that endothelin is a potent agonist in guinea-pig trachea whose response is markedly enhanced by removal of the airway epithelium. Endothelin-induced contraction is not mediated to a marked extent by calcium influx via dihydropyridine-sensitive calcium channels and does not involve the release of histamine, acetylcholine, leukotrienes or thromboxane. Rather, endothelin appears to produce contraction of guinea-pig trachea via a direct action which involves stimulation of PI turnover and utilization of calcium from intracellular stores and, also, calcium influx via a pathway that is not sensitive to dihydropyridine calcium channel inhibitors. Endothelin-induced contraction of rat aorta was more sensitive to the effects of incubation in Ca2 +-free medium, nicardipine or staurosporine, suggesting that differences exist in the relative mechanisms whereby endothelin produces contraction in different tissues.
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PMID:Mechanism of endothelin-induced contraction in guinea-pig trachea: comparison with rat aorta. 169 55

Angiotensin II, bradykinin, and substance P are powerful vasoconstrictors of venous smooth muscle. In this report, we have characterized the receptors and the cellular mechanisms of these vasoactive peptides on a new isolated smooth muscle preparation, the rabbit vena cava. Receptors were characterized using agonists and antagonists and were found to be of the AT, B2, and NK-1 types. The myotropic responses of the vein to KCl was completely abolished in calcium-free medium; in the presence of nicardipine, nifedipine, and verapamil, three calcium channel antagonists; and of trifluoperazine, a calmodulin antagonist. AT II-, BK-, and SP-induced responses were slightly attenuated in calcium-free medium and in the presence of nifedipine and trifluoperazine. Pinacidil inhibited the contractile response of KCl and the three peptides while lidocaine was active against KCl only. Staurosporine and cholera toxin strongly inhibited the contractile responses of the vein to AT II, BK, SP, and KCl, probably by a nonspecific effect. It is concluded that AT II-, BK-, and SP-induced contractions of the rabbit vena cava are mediated by specific receptors and in part by an influx of extracellular Ca2+ through dihydropyridine-insensitive channels. Opening of K+ channels and inhibition of the Ca(2+)-calmodulin complex appear to interfere with the smooth muscle response to the peptides.
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PMID:Pharmacological evaluation of the angiotensin, kinin, and neurokinin receptors on the rabbit vena cava. 172 Aug 40

Substance P (SP) and lipopolysaccharide (LPS) stimulated interleukin-6 (IL-6) gene expression, as well as IL-6 protein secretion in the human astrocytoma cell line U373 MG. Staurosporine, an inhibitor of protein kinase C (PKC), entirely blocked SP- but not LPS-induced IL-6 release. In addition, the down regulation of PKC inhibited the SP response and only marginally altered LPS activation. Differently from SP, LPS-induced IL-6 release was markedly reduced by W7, a calmodulin antagonist. Moreover, SP interacted in a synergistic manner with LPS. Thus, neural (SP) and bacterial (LPS) mediators stimulate U373 MG IL-6 release via distinct, though not antagonistic, activation pathways.
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PMID:Interleukin-6 production by U373 MG, a human astrocytoma cell line: different pathways involved in substance P and lipopolysaccharide activation. 754 Oct 52

As previously reported, alveolar macrophages (AMs) from ovalbumin-sensitized guinea pigs present an enhanced responsiveness to tachykinins but not to N-formylmethionyl-leucyl-phenylalanine (fMLP). We have investigated the biochemical mechanisms underlying this varied responsiveness to tachykinins. The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) induced a larger superoxide anion (O2-) production in AMs from sensitized guinea pigs, as did tachykinins. Pretreatment of AMs with pertussis toxin abolished tachykinin-evoked respiratory burst, had no effect on PMA-evoked O2- production and strongly inhibited fMLP-evoked one, with no appreciable variation between control or sensitized AMs. Staurosporine and its derivative cgp 41251, significantly decreased PMA- and tachykinin-evoked O2- production in both populations, being more potent in control AMs, but exerted little effects against fMLP. Pretreatment of AMs with PMA significantly inhibited fMLP-, PMA- and tachykinin-evoked O2- production in both control and sensitized AMs. fMLP, substance P (SP), neurokinin A (NKA) and the NK2 agonist [beta-Ala8]-NKA(4-10) dose-dependently increased [3H] phorbol 12, 13 dibutyrate (PDBu) binding to control and sensitized AMs. While fMLP exerted similar effects in both populations, dose-response curves for SP1 NKA and the NK2 receptor agonist were shifted leftwards (1, 4 and 3 orders of magnitude, respectively) in sensitized AMs. These results indicate a possible PKC involvement in the enhanced responsiveness to tachykinins in actively sensitized AMs.
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PMID:Modulation by protein kinase C of the enhanced responsiveness to tachykinins in ovalbumin-sensitized guinea pig alveolar macrophages. 881 49

We have investigated cross-talk between the cAMP/protein kinase A (PKA) and protein kinase C (PKC)/inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) messenger systems probed by vasoactive intestinal peptide (VIP) and substance P (SP), respectively, in rat pituitary cell cultures enriched in lactotrophs. VIP and forskolin had no effect on the basal distribution pattern of the four PKC isozymes (alpha, beta, delta, and zeta) detectable in lactotroph-enriched cell cultures derived from peripubertal male rats, whereas both compounds significantly increased translocation of PKC alpha and beta from the cytosol to the plasma membrane induced by SP. The delta and zeta subspecies were not affected by VIP and forskolin. Moreover, VIP and forskolin also stimulated SP-induced formation of Ins(1,4,5)P3 while having no effect on basal inositol phosphate turnover. The effects of VIP and forskolin on PKC isozyme distribution could be blocked by pretreating cells with the PKA inhibitor rp-cAMP. On the other hand, SP potentiated the effect of VIP and forskolin on cAMP formation while having no effect on the cAMP pathway when it was not triggered by an appropriate agonist. Down-regulation of PKC activity by long term 12-O-tetradecanoylphorbol 13-acetate (TPA) treatment (24 h) diminished, but did not abolish, the effect of SP on VIP-stimulated cAMP production. Staurosporine and dopamine inhibited the potentiating effect of SP on cAMP accumulation. TPA, which translocates PKC alpha, beta, and delta in lactotrophs, had a synergistic effect on cAMP formation induced by VIP, but did also, unlike SP, display cAMP rising abilities when cells were not exposed to VIP and forskolin. Discharging intracellular Ca2+ by thapsigargin pretreatment had no effect on the basal cAMP concentration or the VIP-induced cAMP response, whereas exposure of cells to SP, thapsigargin, and VIP resulted in a decrease of the cAMP response compared with SP + VIP. The potentiating effect of SP on the VIP response could also be inhibited, but not blocked, by staurosporine. On the basis of these results, it is concluded that there exists substantial cross-talk between the cAMP/PKA and PKC/Ins(1,4,5)P3 messenger systems in lactotroph-enriched cell cultures. Key effectors seem to be PKA, one or more of PKC alpha, beta, deleta and Ins(1,4,5)P3-sensitive Ca2+ stores.
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PMID:Cross-talk between cellular signaling pathways activated by substance P and vasoactive intestinal peptide in rat lactotroph-enriched pituitary cell cultures. 907 34

1. In human U373 MG astrocytoma cells agonist-induced increases in intracellular Ca2+ ([Ca2+]i) are rapidly returned towards prestimulated levels. Examination of the effect of histamine and substance P on [Ca2+]i in thapsigargin-treated cells has allowed a mechanism contributing to this effect to be characterized. 2. Histamine and substance P stimulated [3H]-inositol monophosphate ([3H]-IP1) accumulation in U373 MG cells. Concentration-response curves of [3H]-IP1 accumulation in suspensions of U373 MG cells in HEPES buffer containing 30 mM Li+ yielded best-fit EC50 values of 19.1+/-1.5 microM for histamine and 5.7+/-1.3 nM for substance P. 3. In confluent monolayers of fura-2 loaded U373 MG cells perfusion with 100 microM histamine resulted in a transient 597+/-50 nM increase in [Ca2+]i. The best-fit EC50 for histamine was 4.6+/-2.2 microM. The initial, transient, histamine response was often followed by further small transient increases in [Ca2+]i. 4. Treatment of U373 MG cells with 5 microM thapsigargin, followed by the readdition of 1.8 mM Ca2+ to the perfusion buffer, resulted in a steady-state level of [Ca2+]i 97+/-5 nM above pretreated levels (measured 400 s after readdition of Ca2+). Perfusion of histamine (100 microM, 100 s) caused a rapid decline in the thapsigargin-induced steady state level of [Ca2+]i. This effect of histamine was normally reversible upon washout. The best-fit EC50, for the histamine response was 0.8+/-0.2 microM. Substance P (10 nM, 100s) also caused a reduction in thapsigargin-induced steady-state levels of [Ca2+]i. 5. Neither 100 microM histamine nor 10 nM substance P inhibited the rate of quench of fura-2 fluorescence by Mn2+ in U373 MG cells pretreated with 5 microM thapsigargin, indicating that the depressant effect on steady-state raised [Ca2+]i was probably not due to a block of Ca2+ entry. 6. The depressant effect of histamine on [Ca2+]i was blocked by 1 microM mepyramine, and was partially reduced by pre-incubation with 1 microM staurosporine (61+/-7% reduction) and with Ro 31-8220 (24+/-10% and 50+/-6% reduction by 1 and 10 microM Ro 31-8220, respectively). Pre-incubation with H-89 did not alter the depressant effect of histamine. 7. Neither 1 microM staurosporine nor 10 microM KN-62 inhibited the binding of [3H]-mepyramine to guinea-pig cerebellar membranes, whereas it was reduced by 17+/-1% and 55+/-2% by 1 and 10 microM Ro 31-8220, respectively. However, [3H]-IP1 accumulation stimulated by histamine in U373 MG cells was not inhibited by 1 or 10 microM Ro 31-8220 and in 2 out of 3 experiments there was a significant potentiation of the response to histamine with both concentrations of Ro 31-8220. Staurosporine, 1 microM, similarly potentiated the response to 100 microM histamine in 3 out of 4 experiments. KN-62 (10 microM) did not stimulate histamine-induced [3H]-IP1 accumulation. 8. In HEPES buffer to which no Ca2+ had been added, histamine stimulated a transient 451+/-107 nM increase in [Ca2+]i. Pretreatment with 1 microM and 10 microM Ro 31-8220 did not significantly alter the initial peak response to histamine, but slowed the rate at which histamine-induced increases in [Ca2+]i were returned to prestimulated levels. Pretreatment with KN-62 had no significant effect on the response to histamine, but consistently inhibited the secondary slower phase of the decline in [Ca2+]i. H-89 did not alter the histamine response. 9. The effect of histamine in stimulating Ca2+ extrusion was not confined to U373 MG cells, since 100 microM histamine also caused a rapid decrease in steady-state levels of [Ca2+]i in thapsigargin-treated human HeLa cells. 10. The results indicate that agonists which increase [Ca2+]i via activation of phosphoinositide metabolism can also stimulate a homeostatic mechanism which acts to reduce [Ca2+]i. The balance of the evidence indicates that in U373 MG cells the latter effect most likely involves a PKC-mediated stimulation of a Ca2+-extrusion pump.
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PMID:Dual effects of histamine and substance P on intracellular calcium levels in human U373 MG astrocytoma cells: role of protein kinase C. 950 96

Substance P is known to modulate neuronal nicotinic acetylcholine receptors (nAChRs) in the sympathetic nervous system. There are two conflicting proposals for the mechanism of this effect, an indirect action mediated by protein kinase C (PKC) and a direct interaction with receptor subunits. We studied the mechanisms of this effect in PC-12 cells. Substance P enhanced the decay of the nicotine-induced whole cell current. This effect was fast in its onset and was not antagonized by guanosine 5'-O-(2-thiodiphosphate), a G protein blocker, or staurosporine, a nonselective PKC blocker. Staurosporine failed to reverse the inhibition by 1-oleoyl-2-acetyl-sn-glycerol (OAG), a synthetic diacylglycerol analog known to activate PKC. The inhibitory effects of the peptide and OAG were preserved in excised patches, but substance P applied to the extra patch membrane was ineffective in the cell-attached patch configuration. We conclude that substance P modulates neuronal nAChRs most likely by direct interactions with the receptors but independently from activation of PKC or G proteins and that PKC does not participate in modulation by OAG.
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PMID:Mechanisms of modulation of neuronal nicotinic receptors by substance P and OAG. 1169 45