Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Somatostatin (SS) has both excitatory and inhibitory actions on myenteric cholinergic transmission, which are mimicked by gamma-aminobutyric acid (GABA). We hypothesized that both effects of SS are mediated by neural GABA pathways. In guinea pig ileal longitudinal muscle-myenteric plexus, SS evoked [3H]-GABA release verifying GABA neural activation. SS (10(-9)-10(-5) M) stimulation of atropine-sensitive ileal contraction and evocation of tetrodotoxin-sensitive [3H]acetylcholine (ACh) release was mimicked by the GABAA agonist muscimol but not the GABAB agonist baclofen. SS (10(-7) M)-evoked contraction and [3H]ACh release were markedly reduced by the GABAA antagonist bicuculline (10(-5) M) but not the GABAB antagonist phaclofen. Cholecystokinin (CCK) evokes ileal contraction via an atropine-sensitive pathway and stimulates ACh release via adenylate cyclase activation. SS inhibited contraction and release evoked by CCK (10(-7) M). These inhibitory actions were reversed by phaclofen but not bicuculline and were mimicked by baclofen but not muscimol. Pertussis toxin (200 ng/ml for 3 h) reversed the inhibitory effects of SS and baclofen on CCK-stimulated contraction and release. In conclusion, SS modulates ileal cholinergic pathways by stimulation of GABA neural pathways. The excitatory action of SS is mediated by GABAA receptors, whereas the inhibitory action utilizes GABAB receptors via a pertussis toxin-sensitive G protein.
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PMID:GABA mediation of the dual effects of somatostatin on guinea pig ileal myenteric cholinergic transmission. 809 12

We have characterized the phosphoinositide metabolism in a polyoma-BK-virus-transformed rat pancreatic islet cell line which has highly malignant characteristics, expresses viral T-antigen and has lost insulin-secreting capacity. After incorporation with [3H]inositol to isotopic equilibrium, all inositol metabolites were analyzed. When compared with normal pancreatic islets, increased levels of inositol 1,4,5-trisphosphate (Ins-1,4,5-P3), inositol 1,3,4-trisphosphates and inositol tetrakisphosphate (Ins-P4), and decreased levels of phosphatidylinositol monophosphate (PIP) and phosphatidylinositol bisphosphate (PIP2) were found. The Ins-1,4,5-P3/PIP2 ratio increased, whereas the PIP2/PIP ratio was not altered after the transformation. In the pancreatic islet cell line there was a stable accumulation of inositol phosphates at 3.3 mM glucose. Glucose, KCl, cholecystokinin (CCK) and carbachol with and without LiCl were all without effect on the accumulation of inositol phosphates. Somatostatin inhibited the accumulation of inositol phosphates but a Ca(2+)-free/EDTA solution did not. Preincubation with cholera toxin or pertussis toxin inhibited the accumulation of inositol phosphates at 3.3 mM glucose except for Ins-P4, whereas no effect was observed on the phosphoinositides. NaF stimulated the accumulation of inositol phosphates, with a concomitant decrease in the phosphoinositides, whereas neomycin was without effect on the inositol phosphates. In normal pancreatic islets, pertussis toxin inhibited the CCK-induced increase in Ins-1,4,5-P3, whereas no effect was seen at 3.3 mM glucose. Finally, pertussis toxin inhibited the CCK-induced increase in the Ins-1,4,5-P3/PIP2 ratio in normal pancreatic islets. The same inhibition was also found in the pancreatic islet cell line at 3.3 mM glucose. We conclude that in the transformed pancreatic islet cell line the phosphoinositide hydrolysis is constitutively activated at the level of phospholipase C, with a substantial loss of regulatory control.
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PMID:Phosphoinositide metabolism in a polyoma-BK-virus-transformed pancreatic islet cell line: evidence for constitutively activated phospholipase C. 838 59

Nerve fibers immunoreactive for cholecystokinin (CCK) have been observed in the rat ovary, but the function of this gut peptide in the ovary is not known. These studies were designed to investigate the effects of the CCK C-terminal octapeptide (CCK-8) on the intracellular calcium ion concentration ([Ca2+]i), protein kinase-C (PKC) activity, and progesterone secretion in granulosa cells obtained from the two largest preovulatory follicles (F1 and F2) of hens. [Ca2+]i was measured in cells loaded with the Ca(2+)-responsive fluorescent dye fura-2. The resting [Ca2+]i in these cells was 96 +/- 5 nM. There was a rapid (i.e. within 5-10 sec) 2- to 4-fold increase in [Ca2+]i in 70% of the cells examined after the addition of 10(-7) M CCK-8. The CCK-8-triggered [Ca2+]i transient was not affected by incubating the cells in Ca(2+)-free medium containing 2 mM EGTA or by pretreating the cells with a Ca2+ channel blocker, such as La3+ (1 mM) or D600 (100 microM). The CCK-8-triggered [Ca2+]i surge was abolished by pretreating the cells with the inhibitor of inositol phospholipid hydrolysis, neomycin (1.5 mM), the CCK antagonists proglumide (1 mM) and benzotript (1 mM), or pertussis toxin (50 ng/ml for 12 h). Incubating granulosa cells with CCK-8 (2 x 10(-7) M) for 10 min stimulated a 1.60 +/- 0.04-fold increase in membrane-associated PKC activity over control levels. In 3-h incubations, CCK-8 (10(-6)-10(-8) M) did not affect basal or LH (20 or 100 ng/ml-stimulated progesterone production. These studies demonstrate that CCK-8 causes a transient increase in chicken granulosa cell [Ca2+]i through the release of Ca2+ from intracellular stores and activates membrane-associated PKC activity, but does not affect progesterone production. These results suggest the presence of G-protein-coupled phospholipase-C-activating CCK receptors on the surface of these cells.
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PMID:The effect of cholecystokinin on intracellular Ca2+, membrane-associated protein kinase-C activity, and progesterone production in chicken granulosa cells. 840 42

Phospholipase C is involved in the insulinotropic effect of carbachol (CCh) and cholecystokinin octapeptide (CCK-8). The involvement of the type of G protein was investigated in rat pancreatic islets. Guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S; a nonhydrolyzable GTP analogue) increased insulin release in electrically permeabilized islets. Both CCh and CCK-8 increased the GTP gamma S effect indicative of an involvement of G proteins. Pretreatment of the islets with pertussis toxin (PT) impaired the CCh-induced insulin secretion in the presence of 3.0 mM glucose and inhibited the stimulatory CCh effect on inositol 1,4,5-trisphosphate (IP3) levels at low and high glucose. In contrast to CCh, the CCK-8 effect on both insulin release and IP3 levels of islets was not modified by a PT pretreatment at various glucose concentrations. Two types of experiments indicate the type of G protein involved: first, long-term agonistic stimulation by either CCh or CCK-8 led to a downregulation of alpha o and alpha q/11, respectively; second, introduction of specific anti-alpha o or -alpha q/11 antibodies into electrically permeabilized islets nearly completely abolished the effects of CCh and CCK-8, respectively. The data indicate that both CCh and CCK-8 act as insulinotropic agents via the phospholipase C system; in the effect of CCh the PT-sensitive alpha o and in the effect of CCK-8 the PT-insensitive alpha q/11 is involved.
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PMID:Involvement of G proteins in the effect of carbachol and cholecystokinin in rat pancreatic islets. 876 83

Using acutely isolated rat substantia nigra neurons, our previous studies indicated that sulfated cholecystokinin octapeptide (CCK-8) excites substantia nigra dopaminergic neurons by increasing the cationic conductance and that pertussis toxin-insensitive G proteins mediate CCK-8 induction of cationic currents. G alpha q and G alpha 11 are expressed in various tissues, including the brain, and likely to mediate pertussis toxin-insensitive neural signal transductions. In the present study, two different experiments were performed to test the hypothesis that G alpha q/11 mediates CCK-8 enhancement of the cationic conductance. First, we investigated the expression of G alpha q and G alpha 11 mRNAs in CCK-8-responsive substantia nigra dopaminergic neurons by combining whole-cell patch-clamp recordings with a single-cell reverse transcriptase-polymerase chain reaction assay. After CCK-8-evoked cationic currents were recorded, cellular RNA was harvested from single neurons and used as a template for the subsequent reverse transcriptase-polymerase chain reaction analysis. G alpha q and G alpha 11 mRNAs were present in all substantia nigra dopaminergic neurons that responded to CCK-8. Substantia nigra dopaminergic neurons were also internally perfused with the antibody raised against the common C-terminus of G alpha q and G alpha 11 during whole-cell recordings. CCK-8 failed to induce cationic currents after dopaminergic neurons were dialyzed with the anti-G alpha q/11 antibody. Our studies suggest that CCK-8 activation of the cationic conductance in substantia nigra dopaminergic neurons is transduced by G alpha q and/or G alpha 11.
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PMID:G alpha q/11 mediates cholecystokinin activation of the cationic conductance in rat substantia nigra dopaminergic neurons. 876 67

The effect of Gi coupled receptor activation (adenosine A1 and 5-HT1B receptors) on cholecystokinin receptor-stimulated inositol phosphate accumulation has been investigated in Chinese hamster ovary cells transfected with the human adenosine A1 receptor cDNA (CHO-A1). CHO cells constitutively express the 5-HT1B receptor [Berg, Clarke, Sailstad, Saltzman and Maayani (1994) Mol. Pharmacol. 46, 477-484]. Our previous studies using CHO-A1 cells have revealed that both the adenosine A1 and 5-HT1B receptor are negatively coupled to adenylyl cyclase activity and stimulate increases in [Ca2+]i, through a pertussis toxin-sensitive pathway. In the present study the selective adenosine A1 receptor agonist N6-cyclopentyladenosine stimulated a pertussis toxin-sensitive increase in total [3H]inositol phosphate accumulation. The sulphated C-terminal octapeptide of cholecystokinin (CCK-8) stimulated a robust and pertussis toxin-insensitive increase in [3H]inositol phosphate accumulation through the activation of CCKA receptors. Co-stimulation of CHO-A1 cells with N6-cyclopentyladenosine and CCK-8 produced a synergistic increase in [3H]inositol phosphate accumulation. The synergistic interaction between N6-cyclopentyladenosine and CCK-8 was abolished in pertussis toxin-treated cells. Synergy between N6-cyclopentyladenosine and CCK-8 still occurred in the absence of extracellular calcium. The 5-HT1B receptor agonist 5-carboxyamidotryptamine did not stimulate a measurable increase in [3H]inositol phosphate accumulation. Furthermore, 5-carboxyamidotryptamine had no significant effect on CCK-8 mediated [3H]inositol phosphate production. Activation of endogenous P2U receptors (Gq/Gll coupled) with ATP gamma S produced a significant increase in [3H]inositol phosphate accumulation. Co-stimulation of CHO-A1 cells with ATP gamma S and CCK-8 produced additive increases in [3H]inositol phosphate accumulation. These data indicate that CHO-A1 cells may prove a useful model system in which to investigate further the mechanisms underlying the intracellular 'cross-talk' between phospholipase C coupled receptors (Gq/Gll linked) and Gi/Go coupled receptors.
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PMID:Synergistic interactions between human transfected adenosine A1 receptors and endogenous cholecystokinin receptors in CHO cells. 879 Oct 2

Whole-cell patch-clamp recordings were performed to study ionic and molecular mechanisms by which cholecystokinin (CCK) peptides modulate the membrane excitability of acutely dissociated rat neostriatal neurons. Immunohistochemical staining studies indicated that about 95% of acutely isolated neostriatal neurons were GABA(gamma-aminobutyric acid)ergic medium-sized cells. During current-clamp recordings, sulfated cholecystokinin octapeptide (CCK-8) depolarized neostriatal neurons and evoked action potentials. During voltage-clamp recordings, CCK-8 induced inward currents at negative membrane potentials by increasing the voltage-insensitive and non-selective cationic conductance. Cholecystokinin tetrapeptide (CCK-4), a selective CCKB receptor agonist, also evoked cationic currents. The CCK-8-induced cation currents were antagonized by PD135,158 (4-{[2-[[3-(1H-indol-3yl)-2-mehtyl-1-oxo-2-[[[1.7.7.-trimeth yl-bicyclo [2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino-4- oxo- [1S-1 alpha, 2 beta [S*(S*)]4 alpha]}-butanoate N-methyl-D-glucamine), a highly specific and potent CCKB receptor antagonist. The CCK-8-evoked inward currents were blocked by the internal perfusion of 1 mM GDP-beta-S. In neostriatal neurons dialyzed with 0.5 mM GTP-gamma-S, the cationic currents produced by CCK-8 became irreversible. Pretreating neostriatal neurons with 500 ng/ml pertussis toxin did not prevent CCK-8 from evoking cationic currents. Internal administration of heparin (2 mg/ml), an inositol 1,4,5-trisphosphate (IP3) receptor antagonist, and buffering of intracellular calcium with the Ca(2+)-chelator, BAPTA (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, 10 mM), suppressed CCK-8-evoked cationic currents. These findings suggest that, by activating CCKB receptors, CCK-8 excites rat neostriatal neurons through enhancing a non-selective cationic conductance and that pertussis toxin-insensitive G-proteins mediate CCK-8 enhancement of the cationic conductance. The coupling mechanism via G-proteins is likely to involve the production of IP3, and the subsequent IP3-evoked Ca2+ release leads to the opening of non-selective cation channels.
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PMID:The excitatory effect of cholecystokinin on rat neostriatal neurons: ionic and molecular mechanisms. 883 13

Somatostatin (SS) alters colonic motility. To investigate whether SS has a direct effect on colonic smooth muscle cells, we prepared isolated muscle cells from the descending guinea pig colon and compared the effects of SS with those on isolated gastric smooth muscle cells. In gastric cells, SS had no effect on carbachol-induced contraction, whereas in colonic cells it caused inhibition. In colonic muscle cells, SS-28 caused >85% inhibition of contraction by cholecystokinin octapeptide (CCK-8), bombesin, 12-O-tetradecanoylphorbol-13-acetate, and ionomycin, whereas it had no effect on contraction by these agents in gastric cells. In gastric cells, SS inhibited relaxation. Three synthetic SS analogs had different relative affinities for causing effects in gastric and colonic cells. Pertussis toxin inhibited the action of SS-28 in each muscle cell type by 50-75%. SS-28 alone had a small contractile effect on cells from the circular layer of the colon. SS-28 inhibited carbachol-induced contraction in colonic cells from both the longitudinal and circular layers. These results demonstrate that the action of SS differs in colonic and gastric smooth muscle cells. SS inhibits contractants in colonic cells and relaxants in gastric cells. In colonic cells, SS has a weak contractile effect due to an effect on circular muscle cells and an inhibitory effect on cells from both longitudinal and circular layers. A different SS receptor subtype mediates the actions of SS in colonic and gastric muscle cells. In both cell types, the actions of SS are mediated by pertussis toxin-sensitive and -insensitive G proteins.
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PMID:Colonic smooth muscle cells possess a different subtype of somatostatin receptor from gastric smooth muscle cells. 914 97

We investigated cell proliferation modulated by cholecystokinin (CCK) and somatostatin analogue RC-160 in CHO cells bearing endogenous CCKA receptors and stably transfected by human subtype sst5 somatostatin receptor. CCK stimulated cell proliferation of CHO cells. This effect was suppressed by inhibitor of the soluble guanylate cyclase, LY 83583, the inhibitor of the cGMP dependent kinases, KT 5823, and the inhibitor of mitogen-activated protein (MAP) kinase kinase, PD 98059. CCK treatment induced an increase of intracellular cGMP concentrations, but concomitant addition of LY 83583 virtually suppressed this increase. CCK also activated both phosphorylation and activity of p42-MAP kinase; these effects were inhibited by KT 5823. All the effects of CCK depended on a pertussis toxin-dependent G protein. Somatostatin analogue RC-160 inhibited CCK-induced stimulation of cell proliferation but it did not potentiate the suppressive effect of the inhibitors LY 83583 and KT 5823. RC-160 inhibited both CCK-induced intracellular cGMP formation as well as activation of p42-MAP kinase phosphorylation and activity. This inhibitory effect was observed at doses of RC-160 similar to those necessary to occupy the sst5 recombinant receptor and to inhibit CCK-induced cell proliferation. We conclude that, in CHO cells, the proliferation and the MAP kinase signaling cascade depend on a cGMP-dependent pathway. These effects are positively regulated by CCK and negatively influenced by RC-160, interacting through CCKA and sst5 receptors, respectively. These studies provide a characterization of the antiproliferative signal mediated by sst5 receptor.
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PMID:Characterization of the antiproliferative signal mediated by the somatostatin receptor subtype sst5. 925 84

We have previously observed that gastrin has a cholecystokinin B (CCK-B) receptor-mediated growth-promoting effect on the AR42J rat pancreatic acinar cell line and that this effect is paralleled by induction of expression of the early response gene c-fos. We undertook these experiments to elucidate the mechanism for induction of c-fos and the linkage of this action to the trophic effects of gastrin. Gastrin (0.1-10 nM) dose dependently induced luciferase activity in AR42J cells transfected with a construct consisting of a luciferase reporter gene coupled to the serum response element (SRE) of the c-fos promoter. This effect was blocked by the specific CCK-B receptor antagonist D2 but not by the specific CCK-A receptor antagonist L-364,718 or by pertussis toxin, indicating that gastrin targets the SRE via specific CCK-B receptors through a mechanism independent of Gi. Inhibition of protein kinase C (PKC) either by prolonged (24 h) exposure of the cells to the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (100 nM) or by incubation with the selective inhibitor GF-109203X (3.5 microM) resulted in an 80% reduction in luciferase activity. Similar results were observed in the presence of the specific extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor PD-98059 (50 microM). We measured ERK2 activity in AR42J cells via in-gel kinase assays and observed that gastrin (1 pM-100 nM) induced ERK2 enzyme activity in a dose-dependent manner. Addition of GF-109203X and PD-98059, either alone or in combination, produced, respectively, partial and total inhibition of gastrin-induced ERK2 activity. Gastrin induction of ERK2 activity also resulted in a threefold increase in the transcriptional activity of Elk-1, a factor known to bind to the c-fos SRE and to be phosphorylated and activated by ERK2. PD-98059 blocked the growth-promoting effect of gastrin on the AR42J cells, demonstrating that this effect depends on activation of MEK. Our data lead us to conclude that the trophic actions of gastrin are mediated by ERK2-induced c-fos gene expression via PKC-dependent and -independent pathways.
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PMID:Molecular mechanisms for the growth factor action of gastrin. 935 32


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