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)

1. To clarify the nature of the inhibition of whole-cell inwardly rectifying K+ current (IK1) by isoprenaline (Iso) and its antagonism by acetylcholine (ACh), we studied the effects of Iso and ACh and their surrogates on single channel currents (iK1) carried by inwardly rectifying K+ channels in cell-attached and excised inside-out patches obtained from guinea-pig ventricular myocytes. 2. Bath application of Iso suppressed iK1 channel activity in cell-attached patches. This was inhibited by propranolol. Bath-applied forskolin or dibutyryl cAMP mimicked the effect of bath-applied Iso. 3. Exposure of the cytosolic face of inside-out patches to purified catalytic subunit of the cAMP-dependent protein kinase (PKA) also suppressed iK1 channel activity, mimicking the effect of bath-applied Iso on iK1 recorded from cell-attached patches. 4. When applied directly to cell-attached patches via the patch pipette solution, ACh antagonized Iso-induced (1 microM applied via the bath) suppression of iK1 channels. In contrast, bath-applied ACh (10 microM) partially antagonized the effect of low concentrations of Iso (e.g. < 50 nM) on iK1 channels in cell-attached patches but had no detectable effect when 1 microM or more Iso was used. 5. In myocytes pretreated with pertussis toxin (PTX), ACh failed to antagonize Iso-induced suppression of iK1 channels. When inside-out patches were used, bath-applied preactivated exogenous inhibitory G protein subunit, G1 alpha, antagonized the suppression of iK1 channels induced by bath-applied catalytic subunit of PKA (PKA-CS), suggesting that a PTX-sensitive G1 alpha mediates ACh-induced antagonism of Iso-induced suppression of iK1. 6. Neither GTP gamma S nor G1 alpha antagonized the suppression of iK1 produced by bath-applied PKA-CS in inside-out patches when okadaic acid was present in the bath. In addition, bath application of alkaline phosphatase also reactivated iK1 channels suppressed by PKA-CS. 7. Findings in guinea-pig ventricular myocytes suggest that iK1 can be suppressed by a PKA-mediated phosphorylation of the iK1 channel occurring in response to Iso-induced beta-adrenergic receptor activation and that ACh can antagonize the suppression by mechanisms that involve both intracellular and membrane-delimited pathways. The membrane-delimited pathway appears to involve M2-cholinergic receptors, their associated G protein, G1, and a protein phosphatase, all located in the sarcolemma in close proximity to the involved iK1 channels.
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PMID:Beta-adrenergic and cholinergic modulation of inward rectifier K+ channel function and phosphorylation in guinea-pig ventricle. 747 27

ATP produced whole-cell potassium currents in cultured endothelial cells of the bovine brain cortical arteries. P2 purinoceptor agonists evoked similar currents with the order of their potency: 2-methylthio ATP > ATP >> alpha, beta-methylene ATP > or = UTP > or = ADP >> AMP. ATP-evoked currents were inhibited by GDP beta S, but not by pertussis toxin (PTX). Furthermore, a phospholipase C (PLC) inhibitor, protein kinase C inhibitor, or cAMP-dependent protein kinase inhibitor had no effect on the currents. In addition to these effects, ATP enhanced intracellular free Ca2+ concentration ([Ca2+]i) in the presence and absence of extracellular Ca2+, and this [Ca2+]i increase was not inhibited by a PLC inhibitor. These results, thus, provide an indication that ATP activates the potassium channel and enhances [Ca2+]i via a P2Y purinoceptor linked to a PTX-insensitive G-protein, which is not involved in a PLC-mediated signaling pathway.
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PMID:ATP activates the potassium channel and enhances cytosolic Ca2+ release via a P2Y purinoceptor linked to pertussis toxin-insensitive G-protein in brain artery endothelial cells. 748 26

We detected expression of two Raf isoforms, c-Raf and A-Raf, in neonatal rat heart. Both isoforms phosphorylated, activated, and formed complexes with mitogen-activated protein kinase kinase 1 in vitro. However, these isoforms were differentially activated by hypertrophic stimuli such as peptide growth factors, endothelin-1 (ET1), or 12-O-tetradecanoylphorbol-13-acetate (TPA) that activate the mitogen-activated protein kinase cascade. Exposure of cultured ventricular myocytes to acidic fibroblast growth factor activated c-Raf but not A-Raf. In contrast, TPA produced a sustained activation of A-Raf and only transiently activated c-Raf. ET1 transiently activated both isoforms. TPA and ET1 were the most potent activators of c-Raf and A-Raf. Both utilized protein kinase C-dependent pathways, but stimulation by ET1 was also partially sensitive to pertussis toxin pretreatment. cRaf was inhibited by activation of cAMP-dependent protein kinase although A-Raf was less affected. Fetal calf serum, phenylephrine, and carbachol were less potent activators of c-Raf and A-Raf. These results demonstrate that A-Raf and c-Raf are differentially regulated and that A-Raf may be an important mediator of mitogen-activated protein kinase cascade activation when cAMP is elevated.
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PMID:Hypertrophic agonists stimulate the activities of the protein kinases c-Raf and A-Raf in cultured ventricular myocytes. 759 40

Leukocyte recruitment is a key step in the inflammatory reaction. Several changes in the cell morphology take place during lymphocyte activation and migration: spheric-shaped resting T cells become polarized during activation, developing a well defined cytoplasmic projection designated as cellular uropod. We found that the chemotactic and proinflammatory chemokines RANTES, MCP-1, and, to a lower extent, MIP-1 alpha, MIP-1 beta, and IL-8, were able to induce uropod formation and ICAM-3 redistribution in T lymphoblasts adhered to ICAM-1 or VCAM-1. A similar chemokine-mediated effect was observed during T cells binding to the fibronectin fragments of 38- and 80-kD, that contain the binding sites for the integrins VLA-4 and VLA-5, respectively. The uropod structure concentrated the ICAM-3 adhesion molecule (a ligand for LFA-1), and emerged to the outer milieu from the area of contact between lymphocyte and protein ligands. In addition, we found that other adhesion molecules such as ICAM-1, CD43, and CD44, also redistributed to the lymphocyte uropod upon RANTES stimulation, whereas a wide number of other cell surface receptors did not redistribute. Chemokines displayed a selective effect among different T cell subsets; MIP-1 beta had more potent action on CD8+ T cells and tumor infiltrating lymphocytes (TIL), whereas RANTES and MIP-1 alpha targeted selectively CD4+ T cells. We have also examined the involvement of cAMP signaling pathway in uropod formation. Interestingly, several cAMP agonists were able to induce uropod formation and ICAM-3 redistribution, whereas H-89, a specific inhibitor of the cAMP-dependent protein kinase, abrogated the chemokine-mediated uropod formation, thus pointing out a role for cAMP-dependent signaling in the development of this cytoplasmic projection. Since the lymphocyte uropod induced by chemokines was completely abrogated by Bordetella pertussis toxin, the formation of this membrane projection appears to be dependent on G proteins signaling pathways. In addition, the involvement of myosin-based cytoskeleton in uropod formation and ICAM-3 redistribution in response to chemokines was suggested by the prevention of this phenomenon with the myosin-disrupting agent butanedione monoxime. Interestingly, this agent also inhibited the ICAM-3-mediated cell aggregation, but not the cell adhesion to substrata. Altogether, these results demonstrate that uropod formation and adhesion receptor redistribution is a novel function mediated by chemokines; this phenomenon may represent a mechanism that significantly contributes to the recruitment of circulating leukocytes to inflammatory foci.
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PMID:Chemokines regulate cellular polarization and adhesion receptor redistribution during lymphocyte interaction with endothelium and extracellular matrix. Involvement of cAMP signaling pathway. 759 74

The results presented here show that the metabotropic glutamate receptor agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) is capable of markedly stimulating the survival of rat cerebellar granule cells in culture. This is the first demonstration of a neurotrophic role for metabotropic glutamate receptors. The survival promoting action of L-AP4 does not involve a large, rapid rise in [Ca2+]i which is seen with other neurotrophic agents in granule cells such as N-methyl-D-aspartate, ionomycin and high potassium. In addition, the survival-promoting effect of L-AP4 did not appear to be related to changes in cAMP levels. Survival due to L-AP4 was enhanced by pertussis toxin and by forskolin and was unaffected by inhibitors of cAMP-dependent protein kinase. Measurement of cAMP levels after long-term treatment with neurotrophic agents showed no clear relationship between cAMP concentration and granule cell survival. The mechanism of L-AP4 stimulated cell survival is unknown but seems unlikely to involve an acute rise in [Ca2+]i or modulation of cAMP levels. Survival induced by L-AP4 was not blocked by the antagonist (RS)-alpha-methyl-4-carboxyphenylglycine. Similarity in these properties with those of the mGLu7 receptor suggests that granule cell survival was stimulated by an mGlu7-like metabotropic receptor.
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PMID:Activation of metabotropic glutamate receptors by L-AP4 stimulates survival of rat cerebellar granule cells in culture. 770 63

The inhibitory pathway of cardiac cAMP-dependent protein kinase regulated Cl- conductance was investigated using the whole-cell configuration of patch-clamp techniques in single guinea pig ventricular myocytes. Pertussis toxin-sensitive G proteins (Gi), mediating the signal transductions between muscarinic receptors and adenylate cyclase, have a substantial tonic activity even in the absence of muscarinic receptor modulators. Muscarinic agonists or antagonists (like atropine) either increase or decrease this basal activity of Gi by altering the proportion of active and inactive forms of the receptors. Similar to L-type Ca-channel currents, the Cl- conductance showed a transient over-recovery upon cessation of brief muscarinic receptor stimulation by carbachol (CCh) (rebound). Atropine alone enhanced the Cl- conductance elicited by low concentrations of Iso (reverse agonist). After washout of atropine, the over-suppression of the conductance was observed as a mirror image of CCh-induced rebound (reverse rebound). Both types of rebound became prominent when cell dialysis with pipette solutions containing 100 microM GTP was minimized with high-resistance pipettes. Endogenous GTP is therefore an intracellular modulator, and not simply a mediator, of Gi-dependent signal transduction.
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PMID:Inhibitory pathway of cardiac PKA-dependent Cl- conductance via pertussis toxin-sensitive G proteins. 775 28

Activation of muscarinic receptors has been shown to inhibit L-type calcium conductances by mechanisms sensitive to pertussis toxin (PTX). In this study we show that agonist stimulation of the m4 muscarinic receptor leads to an increase in an L-type calcium conductance in the AtT-20 pituitary cell line, by a PTX-sensitive mechanism. The amplitude of the dihydropyridine (DHP)-sensitive or L-type calcium current was increased by acetylcholine (ACh), with no shift in the voltage dependence. This action of ACh was completely inhibited by PTX pre-treatment. Forskolin, cAMP and phorbol 12,13-dibutyrate reduced, while RpcAMPs, an inhibitor of cAMP-dependent protein kinase (PKA), increased the L-type calcium conductance. We propose that the m4 muscarinic receptor activates the L-type calcium channel by inhibition of adenylyl cyclase resulting in reduced cAMP levels and, hence, reduced PKA activity. This novel increase in calcium current via the m4 muscarinic receptor appears to reflect the coupling with an L-type channel of the D class, due to the sensitivity of the L-type calcium conductance to both DHPs and omega-conotoxin, and, thus, is distinct from the skeletal muscle and cardiac L-type channels of the C class previously studied.
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PMID:Enhancement of an L-type calcium current in AtT-20 cells; a novel effect of the m4 muscarinic receptor. 779 45

Constitutive membrane trafficking events are regulated by heterotrimeric G-proteins (G-proteins) in addition to their regulation by small GTP-binding proteins (smgs). Here, we used streptolysin O-permeabilized mouse pancreatic acini and compounds that interact with G-proteins, but not smgs, to examine whether G-proteins are also involved in regulated pancreatic exocytosis. The wasp venom mastoparan (10 microM) inhibited by 25-50% amylase release from permeabilized acini stimulated by various combinations of Ca2+, cyclic AMP (cAMP), 12-O-tetradecanoylphorbol 13-acetate, and guanosine (5'-[gamma-thio]triphosphate (GTP gamma S), while the inactive analogue Mas17 was without effect. Pretreatment of intact acini with pertussis toxin resulted in an approximately 30% reduction of amylase secretion from cells subsequently permeabilized and stimulated with calcium and GTP gamma S. Pretreatment of intact acini with cholera toxin increased stimulated amylase release by 30% from subsequently permeabilized cells, and this effect was mimicked by 8-Br-cAMP. The cAMP-dependent protein kinase inhibitor H-89 (3 microM) largely reversed the effect of cholera toxin, indicating that cholera toxin's effect is due to increased cellular cAMP levels. The inhibitory effects of mastoparan and pertussis toxin suggest that a Gi/Go-type G-protein(s) is (are) involved in the regulation of exocytosis. Since mastoparan inhibited exocytosis stimulated by all intracellular mediators tested, it indicates that the G-protein acts at a distal step in the exocytic process.
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PMID:Evidence of heterotrimeric G-protein involvement in regulated exocytosis from permeabilized pancreatic acini. 779 94

The inhibition of voltage-activated Ca2+ channel currents by cortisol (hydrocortisone), the principal glucocorticoid in man and guinea pig, was examined in freshly dissociated pyramidal neurons from the adult guinea pig hippocampal CA1 region using whole-cell voltage-clamp recordings. Steady-state inhibition by cortisol of the peak Ca2+ channel current evoked by depolarization from -80 to -10 mV increased in a concentration-dependent fashion, with a maximal inhibition of 63 +/- 4% of the total current at 100 microM. Cortisone had a maximal 17 +/- 2% inhibition at 10 microM. Corticosterone and the metabolite allotetrahydrodeoxycorticosterone exhibited a plateau of inhibition of around 15% and 25%, respectively, between 10 pM and 100 nM; both compounds continued to inhibit at concentrations > 10(-7) M. Analysis of tail currents at -80 mV showed that cortisol and corticosterone had no effect on the voltage-dependent activation or deactivation of the Ca2+ channel current. However, cortisol slowed the activation of the current. Cortisol inhibited both the N-type or omega-conotoxin (CgTX)-sensitive, and the L-type or nifedipine (NIF)-sensitive Ca2+ channel current but had no effect on the CgTX/NIF-insensitive Ca2+ channel current. In neurons isolated from pertussis toxin (PTX)-treated animals, the cortisol inhibition was significantly diminished. Intracellular dialysis with GDP-beta-S (500 microM) or with the specific inhibitors of protein kinase C (PKC), the pseudosubstrate PKC inhibitor (PKCI 19-31) (2 microM) and bisindolylmaleimide (BIS) (1 microM) significantly diminished the cortisol inhibition of the Ca2+ channel current. The specific inhibitor of cAMP-dependent protein kinase (PKA) inhibitor, Rp-cAMPS (100 microM) had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cortisol inhibition of calcium currents in guinea pig hippocampal CA1 neurons via G-protein-coupled activation of protein kinase C. 782 88

For "leaky" epithelia the transepithelial resistance (Rt) is an electrophysiological measure of the paracellular pathway within the epithelial barrier. The Rt across a monolayer of LLC-PK1 porcine renal epithelial cells is specifically an inverse measure of paracellular transepithelial permeability and displays a multiphasic and reversible response to the cytokine tumor necrosis factor-alpha (TNF). The Rt response to TNF can be inhibited by the nonhydrolyzable adenosine 3',5'-cyclic monophosphate (cAMP) analogue, dibutyryl-cAMP. In addition, activation of adenylate cyclase (forskolin) or inhibition of phosphodiesterase (3-isobutyl-1-methylxanthine, Ro-20-1724, and pentoxifylline), each of which have been reported to elevate cellular cAMP levels, also inhibited the Rt response to TNF. Incubation of the LLC-PK1 cell sheet with N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide, an inhibitor of cAMP-dependent protein kinase (PKA), potentiated the Rt response to TNF. The Rt response to TNF was completely prevented by preincubation of the cultures with cholera toxin, whereas pertussis toxin pretreatment had a slight but significant potentiating effect on the response. Pretreatment with cholera toxin was associated with an approximately 18-fold elevation in cAMP levels in both control and TNF-treated cultures. Measurements of cellular cAMP content at selected intervals after TNF administration showed a significant elevation (P < 0.01) of 140% above time-matched controls at 1 h after the administration of TNF to the cell sheet. The level of cAMP then declined to approximate control level within 2.5 h of TNF administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:cAMP modulates transepithelial resistance response of LLC-PK1 renal epithelia to tumor necrosis factor. 786 72


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