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)

We examined the effects of the muscarinic agonist carbachol on ion secretion induced by substance P (SP) in piglet jejunal tissues mounted in Ussing chambers. Tetrodotoxin was present in all solutions to inhibit neural activity. Carbachol added 10 min prior to 0.75 microM SP dose dependently inhibited subsequent SP responses, with 90% inhibition at 10 microM carbachol. Addition of an equipotent dose of SP (7.5 microM) had no effect on subsequent carbachol-induced secretion. Carbachol's inhibition of SP-induced secretion was evident for at least 45 min and was abolished by prior addition of the M3 receptor antagonist 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP), but remained intact in the presence of the M2 antagonist gallamine or the nicotinic antagonist mecamylamine. Atropine added 10 min after carbachol restored subsequent SP responses toward control levels. Carbachol also reduced secretory responses to histamine and, to a lesser extent, prostaglandin E2 (PGE2). SP-induced secretion was not affected by prior addition of histamine and was reduced by PGE2 only at the highest PGE2 concentration. The results suggest that activation of the epithelial M3 receptor by carbachol inhibits subsequent secretory responses to the calcium-mediated agonists SP and histamine in piglet jejunum. This may reflect muscarinic activation of a negative messenger in epithelial cells that limits Cl- secretion.
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PMID:Muscarinic inhibition of substance P induced ion secretion in piglet jejunum. 963 56

To establish a continuous cell line, freshly prepared rat parotid acinar cells were stably transfected with a plasmid vector containing the SV40 large T antigen. The acinar origin of these cells was confirmed by Western blotting, enzyme analysis, and morphological analysis. Transformed cells grown in 10% rat serum showed a modest reduction in cell number after 7 days and a concentration- and time-dependent increase in amylase levels approximately 16 times greater than those observed in fetal bovine serum-treated cells. Ultrastructural analysis revealed that cells grown in rat serum harbored protein-filled secretory granules localized adjacent to the endoplasmic reticulum, and punctate amylase-specific immunofluorescence distributed throughout the cytoplasm was consistent with the presence of amylase in secretory organelles. Clonal cells express tissue-specific proline-rich proteins and the four protein kinase C isozymes present in primary culture. Carbachol and isoproterenol stimulated [3H]protein secretion and isoproterenol enhanced amylase secretion from cells grown in rat serum. Moreover, norepinephrine, carbachol, and substance P produced a time- and concentration-dependent rise in cytoplasmic Ca2+. This continuous cell line of parotid acinar cells, which after treatment with rat serum retains the basic structural and functional properties of primary culture cells, will be utilized as a model system for studying long-term biological processes that regulate parotid cell function.
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PMID:Rat serum induces a differentiated phenotype in a rat parotid acinar cell line. 968 53

Isolated parotid acinar cells embedded in Bio-Gel P-2 resin were perifused in small columns, and the effects of various agonists and their combinations on amylase release were studied. Isoproterenol gradually increased the rate of amylase secretion; its maximum response was attained about 5 min after the stimulation. A similar time course of changes in amylase secretion was elicited by dibutyryl cyclic AMP, forskolin and isobutylmethylxanthine. Carbachol (CCh) and substance P evoked biphasic stimulation of amylase secretion; an initial rapid and large peak and a following sustained plateau. The magnitude of the maximum response induced by CCh or substance P was almost the same as that induced by isoproterenol. In Ca2+-free medium, CCh evoked only the initial peak and did not produce the sustained plateau, but the effect of isoproterenol was little changed. Amylase secretion induced by isoproterenol, but not by CCh and substance P, was markedly decreased by lowering the temperature of the medium. Combined addition of isoproterenol and 1 microM CCh markedly augmented amylase secretion; the magnitude of its response was about three times that induced by isoproterenol alone. Potentiation was also observed between alpha- and beta-adrenergic receptors. Most of these results were very different from those obtained in batch systems. Thus, use of a perifusion system for analysis of amylase secretion is strongly recommended.
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PMID:Characteristics of amylase secretion induced by various secretagogues examined in perifused rat parotid acinar cells. 982 22

Nippostrongylus brasiliensis infection induces jejunal mastocytosis associated with enteric nerve remodelling in rats. The aim of this study was to evaluate the intestinal motility responses to meals and to neurotransmitters involved in the control of gut motility (acetylcholine (carbachol), substance P and neurokinin A) in both control and N. brasiliensis-infected rats 30 days post-infection. All rats were equipped with NiCr electrodes in the jejunum to record myoelectrical activity. The duration of disruption of the jejunal migrating myoelectrical complexes (MMC) induced by the different stimuli was determined. Meal ingestion and substance P administration disrupted the MMC pattern for similar durations in the two groups. Carbachol and neurokinin A induced a significantly longer MMC disruption in post-infected rats than in controls (125 +/- 8.3 vs. 70 +/- 6 min for carbachol 100 microg kg-1 and 51 +/- 4 vs. 40 +/- 2 for neurokinin A 50 microg kg-1). The enhanced motor response in postinfected rats was reduced by previous mast cell stabilization with ketotifen or mast cell degranulation with compound BrX 537 A. In conclusion, the increased intestinal motor reactivity to carbachol and neurokinin A in post-N. brasiliensis-infected rats depends upon intestinal mast cell hyperplasia and degranulation.
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PMID:Alterations of intestinal motor responses to various stimuli after Nippostrongylus brasiliensis infection in rats: role of mast cells. 1086 17

1. Neurokinin (NK)A is the endogenous ligand for the tachykinin NK2 receptor. In the present study, tachykinins and selective receptor agonists were tested as contractile agonists in human colon circular muscle and [125I]-NKA was used to localize binding sites in human colon. 2. In strips of circular muscle, removal of mucosa and submucosa significantly (P < 0.05) increased the potency and the maximum response achieved by NKA. 3. The rank order of potency of tachykinin and selective receptor agonists in contracting circular muscle strips was NKA > or = [Lys5,MeLeu9,Nle10]NKA(4-10) > or = neuropeptide (NP)gamma > or = [betaAla8]NKA(4-10) >> NKB > substance P (SP) >> senktide approximate to [Pro9]SP. 4. Specific binding sites for [125I]-NKA were densely localized over circular muscle and muscularis mucosae. Weak specific binding was seen on longitudinal muscle and taenia coli, whereas no binding sites were seen on mucosa, ganglia or blood vessels. 5. In circular muscle, the selective NK2 receptor agonist [LysS,MeLeu9,Nle10]NKA(4-10) produced weak increases (maximum 37%) in inositol monophosphate formation with a pD2 of 6.8+/-0.51 (n = 3). Carbachol (100 micromol/L) was also a weak stimulant (maximum 45%). These agonists were over 10-fold more efficacious in stimulation of inositol monophosphate in rat urinary bladder. 6. In conclusion, [125I]-NKA binding sites localized on human colon circular muscle were characterized as NK2 receptors. Functionally, the tachykinin NK2 receptor is mediating circular smooth muscle contraction. Although the human NK2 receptor is coupled to the phosphatidylinositol pathway, other second messenger mechanisms may also operate in this tissue.
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PMID:Circular muscle contraction, messenger signalling and localization of binding sites for neurokinin A in human sigmoid colon. 1107 12

Protein kinase C (PKC) delta becomes tyrosine phosphorylated in rat parotid acinar cells exposed to muscarinic and substance P receptor agonists, which initiate fluid secretion in this salivary cell. Here we examine the signaling components of PKCdelta tyrosine phosphorylation and effects of phosphorylation on PKCdelta activity. Carbachol- and substance P-promoted increases in PKCdelta tyrosine phosphorylation were blocked by inhibiting phospholipase C (PLC) but not by blocking intracellular Ca2+ concentration elevation, suggesting that diacylglycerol, rather than D-myo-inositol 1,4,5-trisphosphate production, positively modulated this phosphorylation. Stimuli-dependent increases in PKCdelta activity in parotid and PC-12 cells were blocked in vivo by inhibitors of Src tyrosine kinases. Dephosphorylation of tyrosine residues by PTP1B, a protein tyrosine phosphatase, reduced the enhanced PKCdelta activity. Lipid cofactors modified the tyrosine phosphorylation-dependent PKCdelta activation. Two PKCdelta regulatory sites (Thr-505 and Ser-662) were constitutively phosphorylated in unstimulated parotid cells, and these phosphorylations were not altered by stimuli that increased PKCdelta tyrosine phosphorylation. These results demonstrate that PKCdelta activity is positively modulated by tyrosine phosphorylation in parotid and PC-12 cells and suggest that PLC-dependent effects of secretagogues on salivary cells involve Src-related kinases.
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PMID:Modulation of PKCdelta tyrosine phosphorylation and activity in salivary and PC-12 cells by Src kinases. 1135 Jul 45

The properties of K+ channels in these cells were studied using patch-clamp methods. Two channels, with conductances of 165+/-13 pS (n=6) and 30+/-1 pS (n=3), were identified in single-channel experiments. In cell-attached patches the reversal potentials were -67+/-8 and -74+/-2 mV for the large and small conductance channel, respectively, suggesting that both channels are K+-selective. The large conductance channel was also shown to be K+-selective in inside-out patches. The open probability (P(o)) of this channel was increased at depolarizing potentials and by increasing intracellular Ca2+ concentration ([Ca2+]i). These properties suggest that the large conductance channel is a 'maxi' Ca2+-activated K+ channel (BK(Ca)). The small conductance channel was not observed in inside-out patches. Carbachol (CCh; 10(-5) M) activated the BK(Ca) channel, but not the small conductance channel, in cell-attached patches. CCh also caused a dose-dependent increase in [Ca2+]i measured by fura-2 in microspectrofluorimetric studies, with a half-maximal response at approximately 3x10(-6) M. Neither isoproterenol (10(-5) M) nor substance P (10(-6) M) affected K+-channel activity or [Ca2+]i. In whole-cell experiments, CCh caused an increase in outward current. Charybdotoxin (10(-7) M), a BK(Ca) blocker, inhibited a large component of the CCh-induced current. A large component of the charybdotoxin-insensitive current may be carried by Ca2+-activated Cl- channels, which were also observed in human parotid acinar cells. The results indicate that BK(Ca) channels make a significant contribution to the whole-cell conductance in human parotid acinar cells.
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PMID:Identification and regulation of K+ and Cl- channels in human parotid acinar cells. 1142 52

The neurokinin (NK) receptors, NK(1) and NK(2), which are activated by substance P (SP) and NKA, have been identified as potential therapeutic targets in irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Here we have investigated the effects of a novel dual NK(1) and NK(2) receptor antagonist, namely DNK333 upon responses elicited by [Sar(9), Met(O(2))(11)]-SP (SMSP) and [betaAla(8)]-NKA(4-10) in isolated human colon mucosa mounted in Ussing chambers. A selective NK(1) receptor antagonist, SR140333 and NK(2) receptor antagonist, SR48968 have been tested for comparison. Additions of SMSP (100 nM) or [betaAla(8)]-NKA(4-10) (100 nM) increased basal short-circuit current and responses to both peptides were inhibited by DNK333, while SR140333 only inhibited SMSP and SR48968 blocked only [betaAla(8)]-NKA(4-10) responses. SR140333 did not attenuate [betaAla(8)]-NKA(4-10) effects and SR48968 had no effect upon SMSP responses. Carbachol (1 micro M) responses were not altered by any of the three NK antagonists. We conclude that activation of either NK(1) or NK(2) receptors can stimulate epithelial ion transport in human colon mucosa and that the novel dual antagonist, DNK333 may be of potential therapeutic interest in the treatment of IBD and IBS.
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PMID:Dual and selective antagonism of neurokinin NK(1) and NK(2) receptor-mediated responses in human colon mucosa. 1259 50

Tachykinins (TKs) colocalize with acetylcholine in excitatory motor neurones supplying human colonic circular muscle (CCM). Some children with slow-transit constipation (STC) have reduced TK-immunoreactivity in nerve terminals in CCM suggesting a deficit in neuromuscular transmission. This study aimed to test this possibility. Seromuscular biopsies of transverse colon were obtained laparoscopically from STC children (37, 17 with low density of TK-immunoreactivity). Specimens of transverse (17) and sigmoid colon (20) were obtained from adults undergoing colonic resection for cancer. CCM contractions were measured isotonically and responses to carbachol, neurokinin A (NKA) and electrical field stimulation (EFS) recorded. Carbachol and NKA-evoked contractions in adult and STC colon. Hyoscine (2 micromol L-1) significantly depressed responses to EFS in all preparations. Blockade of NK2 receptors (SR 48968, 2 micromol L-1) significantly depressed EFS-evoked contractions of adult transverse CCM, but had no effect on STC preparations. Thus, neuromuscular transmission in both adults and STC children is predominantly cholinergic and this component is unimpaired in the latter, indicating that reduced TK-immunoreactivity is not a marker for depressed cholinergic responses. Although pharmacologically responsive TK receptors are present in STC colon, we did not detect neuromuscular transmission mediated by release of TKs in these preparations.
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PMID:Cholinergic transmission to colonic circular muscle of children with slow-transit constipation is unimpaired, but transmission via NK2 receptors is lacking. 1465 3

Changes in intracellular Ca(2+) concentration ([Ca(2+)]i) induced by agonists were simultaneously monitored in rat submandibular acini and ducts using a Ca(2+) imaging system. Substance P (SP) elicited marked increases in [Ca(2+)]i in acini but not in ducts. Carbachol (CCh) increased [Ca(2+)]i in both acini and ducts, but the maximal level was higher in acini than in ducts. In contrast, epinephrine (Epi) also induced an increase in [Ca(2+)]i in acini and ducts, but to a greater extent in ducts than in acini. Isoproterenol (ISO) caused a small but significant increase in [Ca(2+)]i in ducts but not acini. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis using total RNA extracted from highly purified acinar and ductal cells showed that substance P receptor mRNA was present in acini at higher levels than in ducts. In contrast, alpha(1a)-adrenoceptor mRNA was more strongly expressed in ducts than in acini. The muscarinic receptors (M(3) and M(5)) and beta-adrenoceptors (beta(1) and beta(2)) were expressed at equivalent levels in both cell types. These results confirm that acini and ducts exhibit significant differences in agonist-induced Ca(2+) responses. Furthermore, substance P- and epinephrine-induced Ca(2+) responses were consistent with receptor mRNA expression in acini and ducts, but carbachol- and isoproterenol-induced [Ca(2+)]i increases were not.
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PMID:Comparison of agonist-induced Ca2+ responses in rat submandibular acini and ducts. 1584 52


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