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)

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

Substance P-induced inositol trisphosphate (InsP3) formation was inhibited by 1 microM-4 beta-phorbol 12,13-dibutyrate (PDBu) in rat parotid acinar cells. The inhibitory effect of PDBu was reversed by the protein kinase C inhibitors H-7 or K252a. Substance P also elicits a persistent desensitization of subsequent substance P-stimulated InsP3 formation. However, this desensitization was not inhibited by H-7. In addition, H-7 had no effect on the time course of substance P-induced InsP3 formation. These results suggest that, although activation of protein kinase C by phorbol esters can inhibit the substance P receptor-linked phospholipase C pathway, this mechanism apparently plays little, if any, role in regulating this system after activation by substance P.
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PMID:Protein kinase C-dependent and -independent mechanisms regulating the parotid substance P receptor as revealed by differential effects of protein kinase C inhibitors. 246 97

1. Removal of the endothelium (DE) enhanced the in vitro release of prostacyclin (PGI2) by rat aortae in response to adrenaline (Ad), noradrenaline (NA), thromboxane A2 analogue U46619, phorbol dibutyrate (PDBU) and sodium fluoride (NaF) when assessed at 3 h post DE. At 6 h post DE, there were no differences between the dose-response curves obtained from aortic rings with or without endothelium. 2. At 3 h post DE the antagonism of Ad- and NA-stimulated PGI2 synthesis by yohimbine and prazosin, and NA-stimulated PGI2 synthesis by nifedipine was markedly reduced in aortae without endothelium when compared with controls. These effects were reversed by protracted incubation of aortic tissue post DE (6 h and 9 h). 3. Acetylcholine, carbachol, substance P and nitroprusside were without effect on de novo or NA-stimulated PGI2 synthesis, whether or not the endothelium was present and irrespective of incubation time, post-DE. 4. These results indicate that: (a) PGI2 synthesis linked to excitatory receptors (alpha-adrenoceptors, thromboxane A2) and associated systems (G proteins, protein kinase C) in the smooth muscle component of the rat aorta is not influenced by endothelium-derived relaxing factor (EDRF); (b) the changes of response to stimulators and inhibitors of PGI2 synthesis may be due to an increased reactivity of the vessels caused by the trauma of DE; and (c) vasodilators (parasympathomimetics, substance P and nitroprusside) that do not act directly on excitatory receptors do not influence PGI2 synthesis.
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PMID:Effect of endothelium removal on stimulatory and inhibitory modulation of rat aortic prostacyclin synthesis. 246 14

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

Frog sympathetic ganglion cells were studied under whole-cell voltage clamp to determine whether protein kinase C (PKC) mediates peptide-induced suppression of M current (IM) or desensitization of peptide receptors. Low concentrations (10 mM) of chicken II luteinizing hormone-releasing hormone (LHRH) or substance P (SP) suppressed IM; in addition, higher concentrations (1 microM) desensitized receptors. Desensitization is homologous (specific to the peptide) and lasts at least 25 min. Two stimulators of PKC, phorbol 12-myristate 13-acetate and dioctanoylglycerol, partially depressed IM and occluded the response to SP but not to LHRH. The two actions of PKC stimulators were blocked by PKC inhibitors (staurosporine, a pseudosubstrate peptide, and H-7), but SP- and LHRH-mediated suppression of IM and receptor desensitization were not affected. Thus, we conclude that PKC is not necessary for normal IM suppression or receptor desensitization.
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PMID:Protein kinase C is not necessary for peptide-induced suppression of M current or for desensitization of the peptide receptors. 246 64

R 59022, a compound which causes the accumulation of diacylglycerol by inhibition of the enzyme diacylglycerol kinase, was tested for its effect on stimulated motor activity of the longitudinal muscle from the guinea-pig ileum. Motor responses to histamine were very potently inhibited by R 59022 (greater than or equal to 0.03 microM), which confirms its known activity as a histamine receptor antagonist. Contractions elicited by acetylcholine, substance P, or K+ depolarization were also concentration dependently depressed by R 59022 (1-30 microM); further analysis showed that substance P was antagonized in a non-competitive manner. R 59022 was significantly more active to block the tonic than the phasic component of the contractile response to K+ depolarization. The Ca2+-induced activation of the contractile apparatus in chemically skinned muscle strips was depressed by similar concentrations of R 59022 (3-30 microM). These data indicate that R 59022 suppresses the contractile activity of intestinal smooth muscle at an intracellular site of action but it is not yet clear whether this action can be accounted for by the accumulation of diacylglycerol and subsequent stimulation of protein kinase C.
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PMID:The diacylglycerol kinase inhibitor, R 59022, suppresses contractility of intestinal smooth muscle. 246 9

(1) The study investigated a possible involvement of protein kinase C (PKC) in the substance P-induced contraction of the longitudinal muscle of the guinea-pig isolated ileum. (2) The predominant effect of the PKC activator, phorbol-12,13-dibutyrate (PDB), was to change the time course of the response to substance P. While the initial peak contraction was hardly influenced by PDB, the fading of the contraction was accelerated to an extent that any tonic contraction which normally followed the initial peak response was prevented. This inhibitory effect of PDB on the tonic contraction was immediate in onset and related to its concentration (20-200 nM); responses to half-maximally (2-7 nM) or maximally effective (0.74 microM) concentrations of substance P were affected in the same manner. Tetrodotoxin (0.6 microM) did not alter the effect of PDB. Phorbol-13-monoacetate (2 microM), a phorbol ester which does not stimulate PKC, failed to change the time course of the substance P-induced contraction. (3) The tonic component of half-maximal contractile responses to histamine (0.2-0.4 microM) was also depressed by PDB (0.2 microM) whereas the tonic component of maximal responses to histamine (9 microM) was enhanced. (4) PDB (0.2 microM) reduced desensitization to substance P as judged by the reduction of the peak response to substance P (2-7 nM) following a 10-min exposure to a high concentration of the peptide (0.74 microM). (5) The PKC inhibitor, polymyxin B (0.1-0.3 mM), reduced the peak contractile response to substance P, slowed the fading of the contraction, and antagonized the inhibitory effect of PDB on the tonic contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein kinase C may regulate the tonic component of intestinal smooth muscle contraction in response to substance P. 247 Oct 86

The action of substance P on protein kinase C in cerebral microvessels, isolated from bovine, was investigated. We found that in untreated microvessels 85% of the total activity was localized to the cytosolic fraction. Substance P caused a shift of activity to the membrane fraction, accompanied by a loss of activity in the cytosolic fraction. This effect resulted in dose-dependence and it was evident after 5 min treatment. These data suggest that substance P may be involved in the regulation of processes underlying protein phosphorylation in the blood-brain barrier.
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PMID:Substance P stimulates translocation of protein kinase C in brain microvessels. 247 74

It is well established now that activation of Ca2+ -mobilizing receptors results in the phosphodiesteratic breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2), instead of phosphatidylinositol (PI), into myoinositol 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol (DG). There is also accumulating experimental evidence which indicates that IP3 and DG may function as second messengers, the former to mobilize Ca2+ from intracellular sites and the latter to activate protein kinase C (PKC). In this review, I have recounted our early studies, which began in 1975 with the original observation that activation of muscarinic cholinergic and adrenergic receptors in the rabbit iris smooth muscle leads to the breakdown of PIP2, instead of PI, and culminated in 1979 in the discovery that the stimulated hydrolysis of PIP2 results in the release of IP3 and DG and that this PIP2 breakdown is involved in the mechanism of smooth muscle contraction. In addition, I have summarized more recent work on the effects of carbachol, norepinephrine, substance P, the platelet-activating factor, prostaglandins, and isoproterenol on PIP2 hydrolysis, IP3 accumulation, DG formation, myosin light chain (MLC) phosphorylation, cyclic AMP production, arachidonic acid release (AA) and muscle contraction in the iris sphincter muscle. These studies suggest: (a) that the IP3-Ca2+ signalling system, through the Ca2+ -dependent MLC phosphorylation pathway, is probably the primary determinant of the phasic component of the contractile response; (b) that the DG-PKC pathway may not be directly involved in the tonic component of muscle contraction, but may play a role in the regulation of IP3 generation; (c) that there are biochemical and functional interactions between the IP3-Ca2+ and the cAMP second messenger systems, cAMP may act as regulator of muscle responses to agonists that exert their action through the IP3-Ca2+ system; and (d) that enhanced PIP2 turnover is involved in desensitization and sensitization of alpha 1-adrenergic- and muscarinic cholinergic-mediated contractions of the dilator and sphincter muscles of the iris, respectively. The contractile response is a typical Ca2+ -dependent process, which makes smooth muscle an ideal tissue to investigate the second messenger functions of IP3 and DG and their interactions with the cAMP system.
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PMID:Calcium-mobilizing receptors, polyphosphoinositides, generation of second messengers and contraction in the mammalian iris smooth muscle: historical perspectives and current status. 254 19

Bombesin is a potent mitogen for Swiss 3T3 cells and acts synergistically with insulin and other growth factors. We show here that addition of bombesin to quiescent Swiss 3T3 cells causes a striking increase in the levels of c-fos and c-myc mRNAs. Enhanced expression of c-fos (122 +/- 14-fold) occurred within minutes of peptide addition followed by increased expression of c-myc (82 +/- 16-fold). The concentrations of peptide required for half-maximal increase in the levels of c-fos and c-myc mRNAs were 1.0 and 0.9 nM, respectively. The peptide [D-Arg1, D-Pro2, D-Trp7,9, Leu11] substance P which inhibits the binding of bombesin to its receptor and bombesin-stimulated DNA synthesis in Swiss 3T3 cells blocked the increase in c-fos and c-myc mRNA levels promoted by bombesin. Down-regulation of protein kinase C by long-term exposure to phorbol esters prevented c-fos and c-myc induction by bombesin. This and other results indicate that the induction of these proto-oncogenes by bombesin could be mediated by the coordinated effects of protein kinase C activation and Ca2+ mobilization. The marked synergistic effect between bombesin and insulin was used to assess whether the increase in the induction of c-fos and c-myc is an obligatory event in cell activation. In the presence of insulin, bombesin stimulated DNA synthesis at subnanomolar concentrations but had only a small effect on c-fos and c-myc mRNA levels. This apparent dissociation of mitogenesis from proto-oncogene induction was even more dramatic in 3T3 cells with down-regulated protein kinase C. In these cells bombesin stimulated DNA synthesis in the presence of insulin but failed to enhance c-fos and c-myc mRNA levels at comparable concentrations. Thus, the induction of c-fos and c-myc may be a necessary step in the mitogenic response initiated by ligands that act through activation of protein kinase C but the expression of these proto-oncogenes may not be an obligatory event in the stimulation of mitogenesis in 3T3 cells by mitogens that utilise other signalling pathways.
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PMID:Bombesin induction of c-fos and c-myc proto-oncogenes in Swiss 3T3 cells: significance for the mitogenic response. 310 67


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