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)

The identity of 3H-labelled material ascribed to Ins(1,4,5)P3 in resting or bombesin-stimulated myo-[3H]inositol-labelled AR4-2J cells was investigated by determining its ability to serve as substrate for partially purified Ins(1,4,5)P3/Ins(1,3,4,5)-P4 5-phosphatase and Ins(1,4,5)P3 3-kinase. This 3H-labelled material was metabolized by these two enzymes at rates which were indistinguishable from those for an internal [32P]Ins(1,4,5)P3 standard, establishing its identity as authentic Ins(1,4,5)P3. In addition, and in contrast with findings in earlier studies utilizing substance P as an agonist, prolonged stimulation with bombesin resulted in an increase in an InsP4 which was degraded by Ins(1,4,5)P3/Ins(1,3,4,5)P4 5-phosphatase. These findings serve to confirm the previous estimate of Horstman, Takemura & Putney [(1988) J. Biol. Chem. 263, 15297-15303] for the intracellular concentrations of Ins(1,4,5)P3 in resting (2 microM) and agonist-stimulated (25 microM) AR4-2J cells. The implications of these findings for the physiological regulation of intracellular Ca2+ through this intracellular messenger are discussed.
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PMID:Identification in extracts from AR4-2J cells of inositol 1,4,5-trisphosphate by its susceptibility to inositol 1,4,5-trisphosphate 3-kinase and 5-phosphatase. 216 94

In rat parotid acinar cells prelabelled with [3H]inositol, substance P (100 nM) induced the formation of [3H]inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. Ins(1,4,5)P3 reached a maximum 7 s after substance P stimulation, and thereafter decreased and reached a stable value at 60 s. When the cells were exposed to substance P for 10, 30, 60, or 300 s, washed, and re-exposed to this peptide, the formation of [3H]inositol trisphosphate (InsP3) was attenuated in a time-dependent manner. In the cells pretreated as described above, the number of [3H]substance-P-binding sites (Bmax) was also decreased. Possible role(s) of Ca2+ and protein kinase (protein kinase C) control mechanisms in regulating substance P responses were investigated. Desensitization of substance P-induced InsP3 was not affected by the Ca2+ ionophore ionomycin, nor was it dependent on Ca2+ mobilization. On the other hand, in the presence of 4 beta-phorbol 12,13-dibutyrate (PDBu) and 12-O-tetradecanoyl-4 beta-phorbol 13-acetate, known activators of protein kinase C, substance P-induced InsP3 formation was inhibited. However, PDBu had no effect on [3H]substance P binding, whether present during the assay or when cells were pretreated. The persistent desensitization of InsP3 formation induced by substance P was not affected by PDBu. These results suggest that the persistent desensitization of InsP3 formation induced by substance P is a homologous process involving down-regulation of the substance P receptor; the mechanism does not appear to involve, or to be affected by, the Ca2+ or protein kinase C signalling systems. Protein kinase C activation can, however, inhibit substance P-induced InsP3 formation, which may indicate the presence of a negative-feedback control on the substance P pathway.
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PMID:Two modes of regulation of the phospholipase C-linked substance-P receptor in rat parotid acinar cells. 246 79

In Chinese hamster ovary cells expressing the substance P (SP) receptor clone (CHO-SPR cells), we examined SP-stimulated [Ca2+]i changes by microscopic fluorescence analysis and electrophysiological recordings. In fura-2-loaded cells, SP (1 microM) induced a prolonged elevation of [Ca2+]i, which comprised a rapid and transient Ca2+ mobilization and a prolonged phase of Ca2+ entry, but thrombin (1 unit/ml) induced only transient elevation of [Ca2+]i. The formation of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) was stimulated to 230% above the control by SP but 10% by thrombin 10 s after stimulation. In whole cell clamp recordings, SP induced a long lasting inward current, whereas thrombin did not evoke an inward current. Gq alpha antibody applied intracellularly blocked the SP-induced current, but GS alpha antibody did not block it. Furthermore, decavanadate and heparin, inhibitors of Ins(1,4,5)P3 binding to its receptor, suppressed the SP-induced current. In cell-attached patch, bath-applied SP activated channel currents carried by Ba2+, Ca2+, or Na+. In inside-out patches, Ins(1,4,5)P3, but neither inositol 1,3,4-trisphosphate nor inositol 1,3,4,5-tetrakisphosphate, activated channel currents carried by Ba2+, Ca2+, or Na+. The channel activity induced by Ins(1,4,5)P3 was abolished by heparin. These results demonstrate that SP induces Ca2+ entry through activation of cation channels and suggest that Ins(1,4,5)P3 may regulate both SP-induced Ca2+ mobilization and Ca2+ entry in CHO-SPR cells.
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PMID:Characterization of the substance P receptor-mediated calcium influx in cDNA transfected Chinese hamster ovary cells. A possible role of inositol 1,4,5-trisphosphate in calcium influx. 751 91

Substance P (SP) induces an elevation in cytosolic Ca2+ concentration ([Ca2+]i) in porcine coronary artery endothelial cells by way of Ca2+ influx and release from intracellular stores. We tested the hypothesis that SP-induced Ca2+ influx occurs due to activation of a Ca(2+)-permeable influx pathway coupled to depletion of intracellular stores. With the use of the perforated patch technique and fura 2 microfluorimetry, a fivefold greater increase in [Ca2+]i per unit decrease in membrane potential was obtained in the presence of SP (10 nM) compared with resting state, implying that SP increased Ca2+ conductance. When K+ channels were blocked, SP activated a net inward current with a reversal potential (2.5 +/- 1 mV) not significantly different from that (2 +/- 1 mV) for inward current recorded in response to store depletion by (2,5-di-tert-butylhydroquinone) (BHQ, 10 microM). Increasing bath [Ca2+] induced a similar shift in reversal potential for SP- and BHQ-induced currents. Inositol 1,4,5-trisphosphate (20 microM), applied through the patch pipette, activated an inward current with Ca2+ selectivity similar to SP- and BHQ-activated currents. Dialysis of cells with heparin (5 mg/ml) completely blocked SP-induced inward current but not BHQ-induced current. These results suggest that the SP-induced increase in Ca2+ conductance can be completely explained by activation of a Ca(2+)-permeable influx pathway coupled to depletion of intracellular stores.
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PMID:Substance P-induced calcium entry in endothelial cells is secondary to depletion of intracellular stores. 753 10

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

The present study has investigated transients in the intracellular calcium concentration [Ca2+]i in response to substance P (SP) in single pituitary cells. SP raised [Ca2+]i in three subtypes of pituitary cells: lactotrophs, somatotrophs, and gonadotrophs. In all three cell subtypes the [Ca2+]i response to SP was amplitude-modulated and a concentration of 100 nM was necessary to elicit well pronounced two phased [Ca2+]i transients. The first phase was associated with increased generation of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) in all three cell types. In lactotrophs, the second phase, but not the first, was blunted by depletion of extracellular Ca2+ (Ca2+ free EGTA incubation buffer) and by addition of dopamine (1 microM). In somatotrophs, the second phase of the SP-induced [Ca2+]i response was inhibited by depletion of extracellular Ca2+ and by addition of somatostatin (100 nM), while the first phase was unaffected by this treatment. In gonadotrophs, the second phase, but not the first, was inhibited by the Ca2+ channel blocker methoxyverapamil and depletion of extracellular Ca2+. SP was compared with other agonists having an action on lactotrophs, somatotrophs or gonadotrophs. These experiments demonstrated that SP was a weaker agonist in terms of maximal [Ca2+]i response than thyrotropin-releasing hormone (TRH) (in lactotrophs), growth hormone-releasing hexapeptide (in somatotrophs) and GnRH (in gonadotrophs). On the basis of these results it is concluded that SP exerts direct Ca2+ mobilizing effects in single lactotrophs, somatotrophs, and gonadotrophs derived from male peripubertal rats. The first phase in SP-induced [Ca2+]i transients is likely to be brought about by inositol 1,4,5-trisphosphate-mediated Ca2+ release from internal stores while the second phase reflects an influx of calcium through voltage-gated calcium channels.
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PMID:Substance P increases intracellular Ca2+ in individual rat pituitary lactotrophs, somatotrophs, and gonadotrophs. 908 57

Ca2+ mobilization in the rat alveolar macrophage cell line NR8383 was examined with the Ca2+-sensitive fluorescent probe Fura-2. ATP and norepinephrine elicited a 108 and 46% increase, respectively, in cytosolic free Ca2+ concentration ([Ca2+]i). Acetylcholine, nicotine, isoproterenol, substance P, and vasoactive intestinal polypeptide did not alter [Ca2+]i. Inositol 1,4,5-trisphosphate (IP3) formation was also activated by ATP. The carbohydrate-rich cell wall preparation, zymosan, induced a gradual [Ca2+]i, increase only in the presence of external Ca2+, but did not activate IP3 formation. This increase was abolished by laminarin and by removal of extracellular Ca2+, suggesting that the [Ca2+]i increase was activated by beta-glucan receptors and mediated by Ca2+ influx. This influx was significantly reduced by SKF96365, but not by nifedipine, (omega-conotoxin GVIA, (omega-agatoxin IVA, or flunarizine. These results suggest that release of intracellular Ca2+ in NR8383 cells is regulated by P2-purinoceptors and that zymosan causes Ca2+ influx via a receptor-operated pathway.
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PMID:Regulation of cytosolic free Ca2+ in cultured rat alveolar macrophages (NR8383). 930 72

In human U373 MG astrocytoma cells, histamine and substance P stimulated similar peak increases in intracellular free calcium concentrations ([Ca2+]i), as measured by single cell imaging of Fura-2 fluorescence. Best-fit EC50 values for the peak Ca2+ response were 1.86 microM for histamine and 0.93 nM for substance P. The histamine Ca2+ response was manifest as either a series of repetitive spikes, or, at higher concentrations, a peak followed by a lower plateau level of Ca2+. In contrast, the substance P response became more transient at higher agonist concentrations. Substance P (10 nM) stimulated a biphasic increase in levels of inositol (1,4,5) trisphosphate (Ins(1,4,5)P3) with a peak of 97 +/- 5 pmoles/mg protein at 10 s. In contrast, the Ins(1,4,5)P3 response to 100 microM histamine was only marginally above basal levels of around 12 pmoles/mg protein. However, concentrations of histamine and substance P giving similar Ins(1,4,5)P3 responses produce similar peak increases in [Ca2+]i. HPLC analysis indicated that histamine stimulated the production of [3H]-Ins(1,4,5)P3 and its metabolites, although the magnitude of response was smaller than that observed with substance P. The initial Ca2+ responses to histamine and substance P did not require the presence of extracellular Ca2+. The Ca2+ response to histamine was unaffected by treatment with ryanodine, and was shifted to areas of lower agonist concentration by thimerosal. These results demonstrate that extremely small increases in Ins(1,4,5)P3 can stimulate large increases in [Ca2+]i in U373 MG cells, and suggest a marked redundancy for Ins(1,4,5)P3 production in the Ca2+ signalling pathway.
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PMID:Determination of the inositol (1,4,5) trisphosphate requirement for histamine- and substance P-induced Ca2+ mobilisation in human U373 MG astrocytoma cells. 979 89

We used the Ca2+-sensitive fluorescent dye fura 2, together with measurements of intracellular D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], to assess the inhibitory effects of caffeine on signal transduction via G protein-coupled receptor pathways in isolated rat mandibular salivary acinar cells. ACh, norepinephrine (NE), and substance P (SP) all evoked substantial increases in the intracellular free Ca2+ concentration ([Ca2+]i). Responses to ACh and NE were markedly inhibited by prior application of 20 mM caffeine. The inhibitory effect of caffeine was not reproduced by phosphodiesterase inhibition with IBMX or addition of cell-permeant dibutyryl cAMP. In contrast to the ACh and NE responses, the [Ca2+]i response to SP was unaffected by caffeine. Despite this, SP and ACh appeared to mobilize Ca2+ from a common intracellular pool. Measurements of agonist-induced changes in Ins(1,4,5)P3 levels confirmed that caffeine inhibited the stimulus-response coupling pathway at a point before Ins(1,4,5)P3 generation. Caffeine did not, however, inhibit [Ca2+]i responses evoked by direct activation of G proteins with 40 mM F-. These data show that caffeine inhibits G protein-coupled signal transduction in these cells at some element that is common to the muscarinic and alpha-adrenergic signaling pathways but is not shared by the SP signaling pathway. We suggest that this element might be a specific structural motif on the G protein-coupled muscarinic and alpha-adrenergic receptors.
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PMID:Caffeine does not inhibit substance P-evoked intracellular Ca2+ mobilization in rat salivary acinar cells. 1019 23

The activity of nitric oxide synthase (NOS) in rat parotid acinar cells was measured using a newly synthesized fluorescent NO indicator DAF-2/DA. Our results show that NO production is most effectively stimulated by activation of the beta-adrenergic receptor, and to a minor extent by substance P (SP). NO activates the production of cGMP, an intracellular messenger that has been shown to release Ca2+ from ryanodine-sensitive intracellular stores. We found that cGMP is also able to release Ca2+ from ryanodine-insensitive intracellular stores. Our data show that a rise in the cGMP concentration induces inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] synthesis and Ca2+ release from intracellular stores.
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PMID:Nitric oxide synthesis causes inositol phosphate production and Ca2+ release in rat parotid acinar cells. 1089 22


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