UNIPROT:P20366 - FACTA Search

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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The initiation of saliva formation by parotid acinar cells, which comprise the majority of cells in this salivary gland, is initiated by the release of neurotransmitters (acetylcholine, substance P) from parasympathetic nerves. In response to substance P and the muscarinic agonist carbachol, two ligands that activate phospholipase C-linked receptors, which stimulate fluid secretion, PKC delta was phosphorylated on tyrosine residues. The maximal agonist-dependent tyrosine phosphorylation occurred within seconds of the addition of either agonist and then returned rapidly to a smaller increased level. Phorbol ester also caused a rapid increase in tyrosine phosphorylation, which reached a maximal level 5 min after the addition of phorbol 12-myristate 13-acetate. The increase in tyrosine phosphorylation of PKC delta was blocked by tyrosine kinase inhibitors genistein and staurosporine. Ionophore-mediated elevation of [Ca2+]i or activation of the beta-adrenergic receptor, epidermal growth factor receptor, or insulin receptor did not promote the tyrosine phosphorylation of PKC delta. These results indicate that tyrosine phosphorylation plays a role in early signal transduction events promoted by the activation of muscarinic and substance P receptors and suggests that the tyrosine phosphorylation of PKC delta has a role in the activation of fluid secretion by neurotransmitters binding to phospholipase C-linked receptors.
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PMID:Carbachol, substance P, and phorbol ester promote the tyrosine phosphorylation of protein kinase C delta in salivary gland epithelial cells. 753 27

To clarify the possible mechanisms regulating prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) synthesis, the effects of gonadotropin-releasing hormone (GnRH) and substance P (SP) on the release of these two prostaglandins were studied in the oocytes of the crested newt, Triturus carnifex. Full-grown oocytes of T. carnifex, freed from follicular cells, were incubated in the presence of GnRH or SP and of the inhibitors of several enzymes involved in the release of arachidonic acid (AA) and in the conversion of AA into PGE2 and PGF2 alpha. In parallel, the same experiments were performed on oocytes with membrane phospholipids labelled with [3H]AA. In addition, the PGE2-9-ketoreductase activity was evaluated through the conversion of [3H]PGE2 into [3H]PGF2 alpha. The results showed that GnRH and SP could regulate prostaglandin synthesis through the activation of phospholipase C and diacylglycerol lipase, and through the modulation of PGE2-9-ketoreductase in the oocytes of T. carnifex. In particular, GnRH enhances the activity of PGE2-9-ketoreductase with a consequent increase in PGF2 alpha, while SP inhibits the enzyme which leads to an increase in PGE2. A similar mechanism could also be hypothesized for other vertebrate species.
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PMID:Amphibian oocyte: a model of a possible regulatory mechanism for prostaglandin E2 and prostaglandin F2 alpha synthesis. 754 11

The tachykinins, substance P (SP) and neurokinins A (NKA) and B (NKB), have been identified in the respiratory tract and implicated in mediating neurogenic inflammation of the airways. To the extent that these neuropeptides may be involved in the pathogenesis of asthma, a condition associated with hyperplasia of airway smooth muscle (ASM), we examined the mitogenic effects and mechanisms of action of tachykinins in cultured rabbit ASM cells. SP was found to elicit dose-dependent (10(-14) to 10(-4) M) stimulation of ASM cell proliferation, with a mean (+/- SE) maximal increase in cell number of 169 +/- 6.1% of control. In contrast, NKA and NKB had little and no effect on ASM cell growth, respectively. Because SP is nonselective in its binding to the tachykinin receptors, to identify the specific NK receptor subtype(s) mediating the promitogenic action of SP, in separate studies we found that 1) the NK1-receptor-specific agonist, [beta-Ala4, Sar9, Met(O2)11]SP-(4-11) induced stimulation of ASM cell growth similar in magnitude to that elicited by SP; 2) in contrast, neither the NK1- nor NK2-receptor-specific agonists, [beta-Ala8]NKA-(4-10) and [MePhe7]NKB, respectively, had any effect on ASM cell growth; and 3) the promitogenic action of SP was inhibited by the NK1-receptor antagonist, GR-82,334. Moreover, in extended experiments, we found that the phospholipase C and phospholipase A2 inhibitors, neomycin and quinacrine, respectively, each inhibited SP-induced ASM cell proliferation by approximately 45%. Collectively, these observations provide new evidence that the tachykinin SP induces ASM cell proliferation, and that this action is mediated by transmembrane signaling coupled to selective activation of the NK1 receptor.
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PMID:Tachykinin regulation of airway smooth muscle cell proliferation. 757 67

Neutral endopeptidase 24.11, a membrane-bound metallopeptidase, cleaves, and degrades vasoactive peptides such as atrial natriuretic peptide, endothelin, angiotensin I, substance P, and bradykinin. Therefore, the presence of this metallopeptidase may contribute to the regulation of vascular tone and local inflammatory responses in the vascular endothelium and elsewhere. We determined neutral endopeptidase in cultured human endothelial cells from different vascular beds and studied its regulation by protein kinase C. Neutral endopeptidase was detected in all cultured endothelial cell types. Lowest concentrations were measured in human endothelial cells from umbilical veins (360 +/- 14 pg/mg protein), followed by pulmonary and coronary arteries; higher concentrations were found in endothelial cells from the cardiac microcirculation (1099 +/- 73 pg/mg protein). Neutral endopeptidase content increased during cell growth but was not affected by endothelial cell growth factor or modifications of the growth medium. Stimulation of protein kinase C with 1-oleoyl-2-acetyl-rac-glycerol (0.1 to 1 mumol/L) and phorbol 12-myristate 13-acetate (0.01 to 0.1 mumol/L) induced a time- and concentration-dependent increase of endothelial cells that was inhibited by cycloheximide (5 mumol/L), an inhibitor of protein synthesis. Incubation with phospholipase C (1 mumol/L) and thrombin (10 IU/mL) induced upregulation of neutral endopeptidase, resulting in 158 +/- 26% and 150 +/- 22% increases, respectively, compared with controls. The thrombin effect was inhibited by calphostin C (1 mumol/L), an inhibitor of protein kinase C. Endothelial neutral endopeptidase is constitutively expressed in endothelial cells from different origins and is inducible by thrombin via activation of the protein kinase C pathway.
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PMID:Regulation and differential expression of neutral endopeptidase 24.11 in human endothelial cells. 763 30

It has recently been shown that two novel tachykinins, ranakinin and [Leu3, Ile7]neurokinin A, are present in fibers innervating the frog adrenal gland, and it has been demonstrated that tachykinins stimulate corticosteroid secretion in vitro through activation of chromaffin cells. The purpose of the present study was to investigate the effect of ranakinin on cytosolic free calcium concentrations ([Ca2+]i) and to determine the source of calcium involved. Cultured adrenal cells were loaded with the fluorescent calcium indicator indo-1, and changes in [Ca2+]i were studied using dual emission wavelength microfluorimetry. Administration of a brief pulse of ranakinin (1 microM; 1 sec) in the vicinity of chromaffin cells caused an immediate and transient increase in [Ca2+]i. Repeated pulses of ranakinin resulted in a gradual decline in the [Ca2+]i response, suggesting the occurrence of a desensitization phenomenon. Preincubation of the cells with the calcium channel blockers nifedipine (10 microM) and omega-conotoxin (1 microM) did not alter the response of chromaffin cells to ranakinin. Chelation of extracellular calcium by EGTA (10 mM) caused a marked decrease in the basal [Ca2+]i, but did not suppress the ranakinin-induced [Ca2+]i increase. Conversely, incubation of the cells with thapsigargin (10 microM), an inhibitor of calcium adenosine triphosphatase activity, abolished the stimulatory effect of ranakinin, indicating that the increase in [Ca2+]i can be ascribed to mobilization of calcium from intracellular stores. Preincubation of adrenal cells with the phospholipase C antagonist U-73122 (1 microM; 18 min) or with pertussis toxin (10 microM; 18 h) totally blocked the ranakinin-induced [Ca2+]i rise. Taken together, these data indicate that in frog adrenochromaffin cells, ranakinin causes mobilization of calcium from intracellular stores. The effect of ranakinin is mediated through activation of a phospholipase C via a pertussis toxin-sensitive G protein.
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PMID:Effect of ranakinin, a novel tachykinin, on cytosolic free calcium in frog adrenochromaffin cells. 766 74

Release of endothelin, vasopressin and substance P from isolated rabbit tracheal epithelial cells was monitored after incubation for 2 h with thrombin (10 U/ml) in the presence and absence of cycloheximide (100 micrograms/ml) and 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (NCDC, 0.6 mM). Thrombin stimulated the release of endothelin and vasopressin. Inhibition of the thrombin-stimulated release of endothelin and vasopressin by cycloheximide (44 and 56%, respectively) and NCDC (59 and 88%, respectively) indicates that the release of these peptides is at least partially dependent on the ability of thrombin to stimulate protein synthesis and activate the phospholipase C pathway. Substance P, which is also present in tracheal epithelial cells, was not released by thrombin.
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PMID:Thrombin stimulates release of endothelin and vasopressin, but not substance P, from isolated rabbit tracheal epithelial cells. 767 94

1. This study was undertaken to compare the potency and selectivity of the nonpeptide (RP 67580, (+/-)-CP-96,345 and its chloro-derivative [(+/-)-cis-3-(2-chlorobenzylamino)-2-benzhydrylquinuclidine] (CP-C1)) and peptide (GR 71,251 and spantide) neurokinin1 (NK1) antagonists in mouse and rat preparations. 2. Among the NK1 antagonists tested, RP 67580 was the most potent in inhibiting the specific binding of [125I]-Bolton Hunter substance P ([125I]-BHSP) to crude synaptosomes from the rat brain (Ki: 2.9 nM). (+/-)-CP-96,345 was about ten fold less potent (Ki: 31 nM) than RP 67580 while other compounds exhibited even less affinity. 3. All NK1 antagonists inhibit competitively the activation of phospholipase C by [Pro9]substance P ([Pro9]SP) in cultured cortical astrocytes from the newborn mouse, a preparation rich in NK1 receptors but devoid of NK2 and NK3 receptors. pA2 values for the most potent compounds, RP 67580 and (+/-)-CP-96,345, were 8.28 and 7.08 respectively. When used alone, all antagonists showed some agonist activity at 10(-5) M, except spantide which was already effective at 10(-6) M. 4. An excellent correlation was found between the potency of the NK1 antagonists in blocking the stimulation by [Pro9]SP of phosphoinositide breakdown in cortical astrocytes and in inhibiting [125I]-BHSP specific binding to rat brain synaptosomes. 5. As shown on single cells by use of the Indo-1 microfluorometric method, RP 67580 (10(-7) M) prevented reversibly the elevation of cytosolic calcium concentration induced by [Pro9]SP (10(-8) M) in cultured cortical astrocytes. 6. Several experiments indicated that the antagonists were highly selective for NK1 receptors. RP 67580 did not modify the noradrenaline-evoked activation of phospholipase C in cortical astrocytes; when used at 10-5 M all antagonists had no or only little affinity for NK2 or NK3 binding sites and did not block the NKA (10-8 M)-induced activation of phospholipase C in the hamster urinary bladder (a selectiveNK2 test).7. In conclusion, RP 67580 appears to be a potent NK1 antagonist in the mouse and the rat. Results obtained with (+/-)-CP-96,345 confirm the lower potency of this compound in these two species when compared with reported data obtained in the guinea-pig or man.
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PMID:Higher potency of RP 67580, in the mouse and the rat compared with other nonpeptide and peptide tachykinin NK1 antagonists. 768 38

Neurokinin receptors can couple to several second messenger systems including phospholipase C and intracellular calcium mobilisation. Using FURA-2 microspectrofluorimetry, this study examines the mobilisation of calcium in CHO cells which had been stably transfected with the long isoform of the human NK1 receptor. Substance P caused a concentration-dependent rise in inositol phosphate production which was correlated with a reversible increase in intracellular calcium levels. The mobilisation of calcium was reduced by the removal of extracellular calcium from the bathing solution, and almost totally abolished by depletion of intracellular calcium pools with 1 microM thapsigargin. These data suggest that the transduction mechanism associated with NK1 (long) receptor activation can utilise both intracellular and extracellular calcium pools in this expression system.
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PMID:Thapsigargin blocks the mobilisation of intracellular calcium caused by activation of human NK1 (long) receptors expressed in Chinese hamster ovary cells. 768 71

1. Sensitization of the contractile system in response to combinations of excitatory agonists acetylcholine (ACh), methacholine, histamine and neurokinin A (NKA) was investigated in colonic circular smooth muscle of dog, NKA (1 nM) potentiated the contractile response to 1 microM ACh, but did not increase the fura-2 fluorescence ratio (R340/380). Contraction in response to low concentrations of either methacholine or histamine was potentiated significantly by 0.1 microM 4-phorbol 12,13-dibutyrate (PDBu), suggesting that activation of protein kinase C can potentiate contraction at threshold concentrations of agonists. 2. Variability in the sensitivity of the contractile system to Ca2+ was demonstrated over a range of agonist concentrations. KCl, ACh, histamine and NKA each produced a concentration-dependent increase in the amplitude of phasic contractions and R340/380. However, ACh, histamine and NKA each induced maximal increases in R340/380 at concentrations less than that needed to induce maximum force. 3. In depolarized muscles, NKA (50 nM) and PDBu (1 microM) each increased the magnitude of tonic contraction with no change or a decrease in both R340/380 and myosin light chain phosphorylation. In alpha-toxin-permeabilized fibres, 0.1 microM PDBu and 1 microM NKA shifted the Ca(2+)-force response to the left. Ca(2+)-induced contractions were also potentiated by 100 microM GTP-gamma-S or 1 microM NKA plus 10 microM GTP. Potentiation of contraction by NKA and GTP was antagonized by 10 microM GDP-beta-S. 4. The results suggest that endogenous agonists acting via G-proteins sensitize the contractile element of colonic smooth muscle in part by activation of protein kinase C. In some cases, sensitization may be secondary to increased myosin phosphorylation (ACh), but in other cases it appears to be independent of increased myosin light chain phosphorylation (NKA and PDBu). Therefore regulatory mechanisms in addition to myosin phosphorylation contribute to the apparent sensitization of the contractile system to Ca2+.
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PMID:Sensitization of the contractile system of canine colonic smooth muscle by agonists and phorbol ester. 770 35

The G protein-linked receptor for neurokinin A (NKA) couples to stimulation of phospholipase C and, in some cells, adenylyl cyclase. We have examined the function of the C-terminal cytoplasmic domain in receptor signaling and desensitization. We constructed C-terminal deletion mutants of the human NK-2 receptor (epitope tagged) to remove potential Ser/Thr phosphorylation sites, and expressed them in both mammalian and insect cells. When activated, truncated receptors mediate stronger and more prolonged phosphoinositide hydrolysis than wild-type receptor; however, the amplitude and kinetics of the NKA-induced rise in cytosolic Ca2+ remain unaltered. Protein kinase C (PKC)-activating phorbol ester abolishes wild-type receptor signaling but not mutant receptor signaling. Mutant receptors also mediate enhanced and prolonged cAMP generation, at least in part via PKC activation. When expressed in COS cells or Sf9 insect cells, the wild-type receptor is phosphorylated; receptor phosphorylation increases after addition of either NKA or phorbol ester. In contrast, mutant receptors are not phosphorylated by either treatment. Our results suggest that C-terminal Ser/Thr phosphorylation sites in the NK-2 receptor have a critical role in both homologous and heterologous desensitization. Removal of these phosphorylation sites results in a receptor that mediates sustained activation of signaling pathways and is insensitive to inhibition by PKC.
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PMID:C-terminal truncation of the neurokinin-2 receptor causes enhanced and sustained agonist-induced signaling. Role of receptor phosphorylation in signal attenuation. 772 3

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