Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
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

In this study, we have compared the effects of Substance P (SP) and an SP deprived of the N-terminal tripeptide, SP(4-11), on phosphoinositide metabolism by measuring phosphoinositide breakdown, inositol phosphate production and inositol incorporation into phosphoinositides. This work shows that SP and SP(4-11) have similar effects on phosphatidylinositol-4.5 bisphosphate (PIP2) metabolism. In fact, SP(4-11), like SP, induces a rapid PIP2 breakdown. On the contrary, SP and SP(4-11) have different effects on phosphatidylinositol (PI) metabolism since SP induces a decrease of radioactivity in PI, whereas SP(4-11) does not. Both peptides stimulate [3H]-inositol mono-, bis- and trisphosphate (respectively IP1, IP2, IP3) production in a time and dose-dependent manner. The kinetic of IP3 production is directly correlated with the one of PIP2 breakdown. The time course of IP1 production after SP(4-11) shows a time delay, while the one after SP does not. Since SP evokes an IP1 production without any delay and a large decrease of radioactivity in PI (which cannot account for the small amount measured in IP1 accumulation) we suggest that SP could activate a PI specific phospholipase C (leading to a PI breakdown) and a phospholipase D. These activations would require the complete structure of SP while the classical PIP2 specific phospholipase C activation (which induces PIP2 breakdown) would only require the carboxamide part of the peptide. So the complete structure of SP would be necessary to have a complete response (stimulation of PIP2 and PI metabolism).
 ...
PMID:Importance of the presence of the N-terminal tripeptide of substance P for the stimulation of phosphatidylinositol metabolism in rat parotid gland: a possible activation of phospholipases C and D. 246 32

Porcine or bovine endothelial cells cultured on microcarrier beads, packed into adapted chromatographic columns, perfused with Krebs' buffer and activated with appropriate stimuli (e.g. bradykinin, ADP or phospholipase C) release EDRF and prostacyclin into the perfusing fluid. In the effluent EDRF and prostacyclin might be bio-assayed using the Vane's superfusion cascade (rabbit aortic strips and bovine coronary artery strips, respectively) against nitroglycerine (GTN) and synthetic prostacyclin standards. Prostacyclin might be also quantified as 6-keto-PGF1 alpha by RIA. A spatial separation of the generator (endothelial cells) from the effector (vascular smooth muscle) has allowed to prove that EDRF is nitric oxide, that its activity is inhibited by superoxide anions and by chemicals which act via free radicals, finally, that the release of EDRF and prostacyclin is coupled by a receptor-mediated activation of phospholipase C. Although so successful, the above technique suffers from its essentials, i.e. from using cultured cells instead of fresh intact endothelial cells. Cultured endothelial cells are not responsive to many receptor agonists including acetylcholine, substance P and 5-hydroxytryptamine. Unlike fresh intact endothelial preparations the cultured cells which are perfused with Krebs' buffer generate superoxide anions at such concentrations that it might be obligatory infusing superoxide dismutase in order to detect EDRF. Nonetheless, a couple of data obtained with the cultured endothelial cells have been reproduced in the fresh cell preparations, e.g. release of EDRF by ADP and ATP, a coupled release of EDRF and prostacyclin by phospholipase C or a paradoxical augmentation of the sodium-nitroprusside-induced vasorelaxation by methylene blue.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Endothelium-derived relaxing factor (EDRF) from cultured and fresh endothelial cells. 247 Mar 61

Specific 125I-Bolton-Hunter substance P (125I-BHSP) binding sites are present on intact cortical astrocytes of the newborn mouse in primary culture. Therefore, these cells were used to ascertain the existence of functional substance P (SP) receptors coupled positively to phospholipase C. SP stimulated phosphoinositide breakdown with an EC50 value (4.5 x 10(-10) M) similar to its IC50 value (3.8 x 10(-10) M) for inhibiting 125I-BHSP binding. The maximal response to (10(-6) M SP for 60 min) obtained was approximately 500% of control values. The rank order of potency of tachykinins was SP greater than neurokinin (NK) A greater than NKB. Long SP C-terminal fragments were more potent than shorter ones in stimulating the accumulation of 3H-inositol phosphates. SP free acid and SP N-terminal fragments were without effect. [L-Pro9]SP and SP methyl ester, two selective agonists of NK1 receptors, were almost as potent as SP. An excellent correlation was found when the abilities of tachykinins and their analogs for stimulating phosphoinositide breakdown and for inhibiting 125I-BHSP binding were compared. Finally, when used at a concentration of 3 x 10(-6) M, spantide [( D-Arg1, D-Trp7,9, Leu11]SP), an SP antagonist, competitively reduced the stimulatory effect of SP on accumulation of 3H-inositol phosphates. These results demonstrate the presence of functional SP receptors (NK1) on cortical astrocytes from the newborn mouse in primary culture.
 ...
PMID:Tachykinin receptors of the NK1 type (substance P) coupled positively to phospholipase C on cortical astrocytes from the newborn mouse in primary culture. 247 Aug 56

Incubation of rat peritoneal mast cells with substance P resulted in the transient stimulation of phosphoinositol breakdown and histamine secretion through an exocytotic process. These effects were inhibited markedly by a prior 2-hr exposure of the cells to pertussis toxin. Pertussis toxin also inhibited exocytosis induced by substance P, mastoparan and compound 48/80, but did not modify the secretory effect of the ionophore A23187. The transfer of rat peritoneal mast cells from balanced salt solution to calcium-free buffer led to a similar time-dependent decrease in their response to substance P and mastoparan. The concomitant absence of potassium from the calcium-free buffer enabled the mast cells to retain their secretory response. These data demonstrate identical dependency for calcium and monovalent ions of the secretory process elicited by substance P, mastoparan and compound 48/80. Pretreatment of mast cells with neuraminidase decreased the secretagogic effect of substance P, mastoparan and compound 48/80 without modifying the efficiency of the ionophore A23187. Thus, sialic acid residues might be involved in the initial binding of peptides and compound 48/80 to mast cells, which activate a pertussis toxin-sensitive G-protein and allows the increase in phospholipase C activity to induce exocytosis. This sequence of events might characterize the physiological pathway of mast cell activation by peptides, without necessarily requiring selective membrane receptors.
 ...
PMID:Activation of rat peritoneal mast cells by substance P and mastoparan. 247 89

The hypothesis that acetylcholine, substance P, and LHRH suppress M-current by activating phospholipase C was tested. Each agonist caused turnover of phosphoinositide, as measured by release of inositol phosphates, and a modest transient rise in intracellular free Ca2+ ([ Ca2+]i), as determined with fura-2. Active phorbol esters depressed M-current only 50% and did not prevent further suppression by LHRH. M-current, its control by agonists, and its depression by phorbol esters were not affected by adding inositol trisphosphate or Ca2+ buffers with high or low Ca2+ to the whole-cell, voltage-clamp pipette. We conclude that phospholipase C activation does occur but does not mediate the suppression of M-current by agonists. Caffeine produced large [Ca2+]i transients and acted as an agonist to suppress M-current.
 ...
PMID:Agonists that suppress M-current elicit phosphoinositide turnover and Ca2+ transients, but these events do not explain M-current suppression. 248 99

In the anterior segment of the eye, phosphoinositides of the iris-ciliary body are the major source of AA for PG biosynthesis. In the past several years, we have demonstrated that these phospholipids are highly enriched in AA and have an extremely high metabolic turnover. We have also discovered that their metabolism by phospholipase C, which leads to the formation of IP3 and DG and the liberation of AA, is controlled by the following Ca2+-mobilizing receptors: alpha 1-adrenergic, M3- or M4-muscarinic cholinergic, substance P, and PGs. The release of IP3, DG, and AA in the iris was also demonstrated under in vivo conditions. Furthermore, it was demonstrated that this release is associated with denervation supersensitivity and subsensitivity of the iris. Two pathways have been demonstrated in the iris through which AA can be released directly from phosphoinositides: (a) Phosphoinositides can be hydrolyzed by phospholipase C, followed by hydrolysis of DG via lipases to liberate AA, and (b) AA can be released directly from phosphoinositides via phospholipase A2. Although the evidence for a link between Ca2+-mobilizing receptors and phospholipase C, via G proteins, has been well established, the precise link between these receptors and phospholipase A2 is still unclear. Our studies indicated that PGs may be involved in regulation of contraction and relaxation of the smooth muscles of the iris by increasing IP3 accumulation and consequently Ca2+ mobilization and by elevating the level of cAMP which in turn facilitates muscle relaxation. In addition, evidence of a link between the two pathways through the Ca2+ signaling system has been suggested. In the iris, PAF was found to liberate AA from phosphoinositides through the phospholipase A2, but not the phospholipase C pathway, thus emphasizing the role of this pathway in PG synthesis in the eye. These findings demonstrate that AA release and, consequently, PG synthesis in the iris of the eye are exquisitely regulated. In some species, such as bovine, cat and dog, PGs were found to act as full Ca2+ mobilizing agonists. It is possible that PGs function to maintain muscle tone in the resting iris smooth muscle cells, in addition to their involvement in various Ca2+-dependent processes. Our studies indicate that PGs may be involved in regulation of contraction and relaxation of the smooth muscles of the iris by increasing IP3 accumulation and consequently Ca2+ mobilization and by elevating the level of cAMP which in turn facilitates muscle relaxation.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Regulation of arachidonate release, prostaglandin synthesis, and sphincter constriction in the mammalian iris-ciliary body. 255 69

The effects of extracellular ATP on intracellular free calcium concentration [( Ca2+]i), phosphatidylinositol (PtdIns) turnover, amylase release and Ca2+-activated membrane currents were examined in isolated rat parotid acinar cells and contrasted with the effects of receptor agonists known to activate phospholipase C. ATP was more effective than muscarinic and alpha-adrenergic agonists and substance P as a stimulus for elevating [Ca2+]i (as measured with quin2). The ATP effect was selectively antagonized by pretreating parotid cells with the impermeant anion-exchange blocker 4,4'-di-isothiocyano-2,2'-stilbenedisulphonate (DIDS), which also inhibited binding of [alpha-32P]ATP to parotid cells. By elevating [Ca2+]i, ATP and the muscarinic agonist carbachol both activated Ca2+-sensitive membrane currents, which were measured by whole-cell and cell-attached patch-clamp recordings. However, there were marked contrasts between the effects of ATP and the receptor agonists linked to phospholipase C, as follows. (1) Although the combination of maximally effective concentrations of carbachol, substance P and phenylephrine had no greater effect on [Ca2+]i than did carbachol alone, there was some additivity between maximal ATP and carbachol effects. (2) Intracellular dialysis with guanosine 5'-[beta-thio]diphosphate did not block activation of ion channels by ATP, but did block channel activation by the muscarinic agonist carbachol. This suggests that a G-protein is involved in the muscarinic response, but not in the response to ATP. (3) Despite its pronounced effect on [Ca2+]i, ATP had little effect on PtdIns turnover in these cells, in contrast with the effects of carbachol and other Ca2+-mobilizing agents. (4) Although ATP was able to stimulate amylase release from parotid acinar cells, the stimulation was only 33 +/- 9% of that obtained with phospholipase C-linked receptor agonists. These differences suggest that ATP increases [Ca2+]i through specific activation of a pathway which is distinct from that shared by the classical phospholipase C-linked receptor agonists.
 ...
PMID:Extracellular ATP increases free cytosolic calcium in rat parotid acinar cells. Differences from phospholipase C-linked receptor agonists. 284 7

Bombesin caused a marked stimulation of 32Pi into phosphatidylinositol (PI), with no apparent lag, and into phosphatidylcholine (PC), after a lag of about 20 min. Stimulation was blocked by the bombesin receptor antagonist, [D-Arg1, D-Pro2, D-Trp7,9, Leu11] substance P, indicating that the effects on both PI and PC were mediated through the same receptor. The tumor-promoting phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA) and dioctanoylglycerol (diC8) both directly activate protein kinase C and in this report were shown to stimulate 32Pi incorporation into PC but not into Pl. In addition, TPA stimulated the release of [3H]choline and [3H]phosphocholine and the accumulation of [3H]diacyglycerol from prelabelled cells. These results strongly suggest that TPA activates a phospholipase C specific for PC. Pretreatment of cells with phorbol-12, 13-dibutyrate (PDBu) for 24 h depleted cellular protein kinase C activity and inhibited the ability of TPA to induce these effects suggesting a direct involvement of protein kinase C. Similarly the bombesin stimulation of 32Pi into PC and of [3H]choline and [3H]phosphocholine release was inhibited by PDBu pretreatment. DiC8 and, to a lesser extent, TPA stimulated the translocation of CTP:phosphocholine cytidylytransferase from the cytosolic to the particulate fraction. DiC8 also stimulated this translocation in cells depleted of protein kinase C. It was concluded that both bombesin and TPA activated protein kinase C leading to activation of a phospholipase C specific for PC.
 ...
PMID:Bombesin and phorbol ester stimulate phosphatidylcholine hydrolysis by phospholipase C: evidence for a role of protein kinase C. 355 93

Substance P, muscarinic and alpha-adrenoceptor agonists stimulated the incorporation of [3H]inositol into phosphatidylinositol in rat parotid gland slices. Surgical denervation of the sympathetic input to the rat parotid gland by superior cervical ganglionectomy produced marked reductions in these responses. The stimulated incorporation of radiolabelled precursors into phosphatidylinositol is a measure of its resynthesis after receptor-mediated breakdown of inositol phospholipids. We therefore examined the enzymic site of the lesion induced by sympathetic denervation using parotid gland slices labelled with either [3H]inositol or [32P]phosphate and stimulated with substance P. Receptor-activated phospholipase C attack upon [3H]inositol phospholipids was assayed by measuring the formation of [3H]inositol 1-phosphate in the presence of 10 mM-Li+ to inhibit further breakdown. It was not affected by denervation. Substance P elicited a rapid breakdown of phosphatidylinositol 4,5-bisphosphate and this response was reduced in the denervated gland. The second step in stimulated phosphatidylinositol turnover, phosphorylation of diacylglycerol to phosphatidate was not affected by denervation. Sympathetic denervation appears to induce a specific enzymic lesion in the parotid gland that impairs receptor-stimulated resynthesis of phosphatidylinositol from phosphatidate. This change in membrane lipid metabolism may be related to a number of the effects of sympathetic denervation, such as agonist supersensitivity, reduced gland cell proliferation and induction of new surface receptors.
 ...
PMID:Sympathetic denervation impairs agonist-stimulated phosphatidylinositol metabolism in rat parotid glands. 619 86


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>