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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic islets stimulated with D-glucose are known to liberate arachidonic acid from membrane phospholipids and release prostaglandin E2 (PGE2). A component of the eicosanoid release induced by D-glucose has been demonstrated to occur without calcium influx and must be triggered by other coupling mechanisms. In this study, we have attempted to identify mechanisms other than calcium influx which might couple D-glucose stimulation to hydrolysis of arachidonate from membrane phospholipids in islet cells. We have found that occupancy of the beta cell plasma membrane D-glucose transporter is insufficient and that D-glucose metabolism is required to induce islet PGE2 release because 3-O-methylglucose fails to induce and mannoheptulose prevents PGE2 release otherwise induced by 17 mM D-glucose. The carbohydrate insulin secretagogues mannose and D-glyceraldehyde have also been found to induce islet PGE2 release, but the non-secretagogue carbohydrates L-glucose and lactate do not. Carbohydrate secretagogues are known to be metabolized to yield ATP and induce depolarization of the beta cell plasma membrane. We have found that depolarization by 40 mM KCl induces PGE2 release only in the presence and not in the absence of extracellular calcium, but exogenous ATP induces islet PGE2 release with or without extracellular calcium. Carbachol is demonstrated here to interact synergistically with increasing concentrations of glucose to amplify PGE2 release and insulin secretion. Pertussis toxin treatment is shown here not to prevent PGE2 release induced by glucose or carbachol but to increase the basal rate of PGE2 release and the islet cyclic AMP content. Theophylline (10 mM) exerts similar effects. Eicosanoid release in pancreatic islets can thus be activated by multiple pathways including muscarinic receptor occupancy, calcium influx, increasing cAMP content, and a metabolic signal derived from nutrient secretagogues, such as ATP.
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PMID:Arachidonic acid metabolism in isolated pancreatic islets. VI. Carbohydrate insulin secretagogues must be metabolized to induce eicosanoid release. 159 16

We have previously shown that extracellular ATP acts as a mitogen via protein kinase C (PKC)-dependent and independent pathways (Wang, D., Huang, N., Gonzalez, F.A., and Heppel, L.A. Multiple signal transduction pathways lead to extracellular ATP-stimulated mitogenesis in mammalian cells. I. Involvement of protein kinase C-dependent and independent pathways in the mitogenic response of mammalian cells to extracellular ATP. J. Cell. Physiol., 1991). The present aim was to determine if metabolism of arachidonic acid, resulting in prostaglandin E2 (PGE2) synthesis and elevation of cAMP levels, plays a role in mitogenesis mediated by extracellular ATP. Addition of ATP caused a marked enhancement of cyclic AMP accumulation in 3T3, 3T6, and A431 cells. Aminophylline, an antagonist of the adenosine A2 receptor, had no effect on the accumulation of cyclic AMP elicited by ATP, while it inhibited the action of adenosine. The accumulation of cyclic AMP was concentration dependent, which corresponds to the stimulation of DNA synthesis by ATP. The maximal accumulation was achieved after 45 min, with an initial delay period of about 15 min. That the activation of arachidonic acid metabolism contributed to cyclic AMP accumulation and mitogenesis stimulated by ATP in 3T3, 3T6, and A431 cells was supported by the following observations: (a) extracellular ATP stimulated the release of [3H]arachidonic acid and PGE2 into the medium; (b) inhibition of arachidonic acid release by inhibitors of phospholipase A2 blocked PGE2 production, cyclic AMP accumulation, and DNA synthesis activated by ATP, and this inhibition could be reversed by adding exogenous arachidonic acid; (c) cyclooxygenase inhibitors, such as indomethacin and aspirin, diminished the release of PGE2 and blocked cyclic AMP accumulation as well as [3H]thymidine incorporation in response to ATP; (d) PGE2 was able to restore [3H]thymidine incorporation when added together with ATP in the presence of cyclooxygenase inhibitors; (e) pertussis toxin inhibited ATP-stimulated DNA synthesis in a time- and dose-dependent fashion as well as arachidonic acid release and PGE2 formation. Other evidence for involvement of a pertussis toxin-sensitive G protein(s) in ATP-stimulated DNA synthesis as well as in arachidonic acid release is presented. In A431 cells, the enhancement of arachidonic acid and cyclic AMP accumulation by ATP was partially blocked by PKC down-regulation, implying that the activation of PKC may represent an additional pathway in ATP-stimulated metabolism of arachidonic acid. In all of these studies, ADP and AMP-PNP, but not adenosine, were as active as ATP.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Multiple signal transduction pathways lead to extracellular ATP-stimulated mitogenesis in mammalian cells: II. A pathway involving arachidonic acid release, prostaglandin synthesis, and cyclic AMP accumulation. 185 Jul 50

The molecular mechanisms underlying activation of a K+ channel by adenosine (Ado) and acetylcholine (ACh) were examined in single atrial cells of guinea-pig. Whole cell clamp and patch clamp techniques were used to characterize the K+ channel. In the whole cell clamp conditions, Ado and ACh increased the K+ channel current in a dose-dependent manner. The maximum responses and the apparent dissociation constants were different for Ado and ACh activations of the current. Theophylline blocked activation of the K+ current by Ado, while atropine blocked ACh-activation, indicating that two different membrane receptors were involved. Measurements of the conductance and kinetic properties of both whole cell and single channel currents indicate that Ado and ACh regulate the same K+ channels. In "inside-out" patch conditions, GTP was required in the intracellular side of the membrane for activation of the K+ channel by agonists (present in the patch electrode). The A promoter of pertussis toxin inhibited the channel activation only when NAD was also present. Furthermore, GTP-gamma S, a non-hydrolyzable GTP analogue, gradually caused activation of the K+ channel in the absence of agonists. Therefore, it was concluded that Ado and m-ACh receptors link with the same population of K+ channels via GTP-binding proteins Ni and/or No in the atrial cell membrane.
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PMID:On the mechanism of activation of muscarinic K+ channels by adenosine in isolated atrial cells: involvement of GTP-binding proteins. 242 51

1. The effects of adenosine on adenosine 5'-triphosphate (ATP)-evoked dopamine release from rat phaeochromocytoma PC12 cells was investigated to determine whether adenosine exerts a regulatory effect on the ATP-evoked response. Adenosine potentiated ATP (30 microM)-evoked dopamine release in a concentration-dependent manner over a concentration-range of 1 to 100 microM. Adenosine (100 microM) shifted the concentration-dependence of the ATP-evoked response to the left without affecting the maximal response. 2. Aminophylline, a non-selective adenosine receptor antagonist, and CP66713, a selective antagonist at the A2 subclass of adenosine receptors, abolished the adenosine-induced potentiation. Furthermore, 8-cyclopentyltheophylline, a selective antagonist at the adenosine A1 receptor partially inhibited the adenosine-evoked potentiation. CGS22492, a selective A2 receptor agonist, potentiated ATP-evoked dopamine release whereas N6-cyclohexyladenosine (CHA), a selective A1 receptor agonist, had no effect. 3. Pertussis toxin (PTX), a bacterial exotoxin which catalyzes the ADP-ribosylation of guanosine 5'-triphosphate (GTP)-binding proteins (G-proteins), inhibited the adenosine-induced potentiation of dopamine release. Dibutyryl cyclic AMP (db cyclic AMP), an analogue of cyclic AMP, had no effect on the release on the ATP-evoked response. 4. Adenosine potentiated the ATP-evoked rise in intracellular Ca2+ concentration ([Ca]i) in PC12 cells. This potentiation was also observed with CGS 22492 but not with CHA. PTX completely inhibited the adenosine-induced potentiation of the rise in [Ca]i. 5. On the basis of these findings, we suggest that the adenosine-induced potentiation of ATP-evoked dopamine release was due to an increase in [Ca]i in the cells. Although the potentiation is most likely mediated by a subclass of A2 receptors, the subclass may be different from those previously reported since the potentiation was sensitive to PTX and was not reproduced by db cyclic AMP.
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PMID:Potentiation by adenosine of ATP-evoked dopamine release via a pertussis toxin-sensitive mechanism in rat phaeochromocytoma PC12 cells. 792 29

1. We studied the effects of P2-purinoceptor stimulation on the delayed rectifier K+ current (IK) in guinea-pig atrial myocytes using a whole-cell voltage-clamp technique. 2. External application of ATP increased IK, evoked by a 500 ms depolarizing pulse from a holding potential of -40 mV, under conditions in which the L-type Ca2+ channel was blocked; the effect was dose dependent with a half-maximal concentration (K1/2) of 0.95 microM. ATP (50 microM) produced a maximal increase of IK of about a factor of 2. 3. External ADP also enhanced IK in a dose-dependent manner with a K1/2 of 3.65 microM, whereas adenosine (100 microM) failed to evoke this response. Theophylline (500 microM), a blocker of the Pi-purinoceptor, did not antagonize the stimulating action of ATP on IK. These results indicate that IK was enhanced via P2-purinoceptors. 4. External ATP or ADP did not produce a significant change in the current kinetics of IK. 5. Pre-incubation of the atrial myocytes with pertussis toxin (PTX, 5 micrograms ml-1) did not affect the stimulating action of ATP on IK, indicating that PTX-sensitive G proteins did not mediate the ATP action. 6. The enhancement of IK by ATP developed slowly; the effects usually reached a maximum approximately 30-60 s after the application of ATP. This suggests the involvement of a diffusible cytosolic second messenger(s) in the response. ATP could further increase IK after maximal enhancement by isoprenaline (0.5-1.0 microM), suggesting that the intermediate steps were independent of cyclic AMP-dependent protein kinase (protein kinase A). 7. Potentiation of IK by ATP was not attenuated by either (i) pretreatment of the cells with 5 microM 1-(5-isoquinolinylsulphonyl)-2-methylpiperazine dihydrochloride (H-7) or (ii) intracellular perfusion of 20 mM 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), suggesting that protein kinase C and intracellular Ca2+ did not mediate the response. 8. It is concluded that the activation of P2-purinoceptors increases IK through intracellular mechanisms independent of protein kinase A, protein kinase C or intracellular free Ca2+ in guinea-pig atrial myocytes.
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PMID:Enhancement of delayed rectifier K+ current by P2-purinoceptor stimulation in guinea-pig atrial cells. 868 64

1. Whole-cell voltage clamp and cell-attached patch-clamp techniques were applied to single atrial myocytes enzymatically dissociated from adult guinea-pig hearts. 2. In whole-cell clamp conditions, external applications, of ATP activated the muscarinic K+ (KACh) current, identified by its inward rectification, its reversal potential near the calculated K+ equilibrium potential (EK) and its relaxation properties during step changes of whole-cell membrane potential. Theophylline, an antagonist for Pi-purinoceptors, did not affect the action of ATP on the KACh current, indicating that the response was evoked through P2-purinoceptors. 3. The concentration-response relationship for ATP was well described by a Hill equation with a half-maximal concentration of 1.84 microM and a Hill coefficient of 0.94. ATP (100 microM) produced a maximal increase of the KACh current to 10.92 microA microF-1, which corresponds to 44.9 and 80.9% of the maximal increases evoked by ACh (10 microM) and adenosine (100 microM), respectively. 4. The activation of KACh current gradually declined to a steady level despite the continuous presence of ATP (desensitization). Recovery from the desensitization was relatively rapid with a half-time of approximately 1.5 min. 5. The activation of KACh current by ATP was completely abolished by pre-incubating myocytes with pertussis toxin (PTX, 5 micrograms ml-1), indicating that P2-purinoceptors are coupled to PTX-sensitive G proteins to activate the KACh channel. 6. In the cell-attached patch recording, ATP (5 microM) applied to the pipette solution enhanced the activity of a channel with single-channel conductance of 52.7 +/- 0.9 pS (mean +/- S.E.M., n = 10), reversal potential near EK and mean open time of 1.1 +/- 0.1 ms. These conductance and kinetic properties are identical to those of the KACh channel in the heart. In contrast, ATP applied to the bath solution did not significantly affect the basal activity of KACh channel openings. These observations suggest that the mechanism coupling the P2-purinoceptor to the activation of the KACh channel involves membrane-delimited component(s) rather than soluble second messenger(s). 7. These results strongly suggest a direct coupling of the P2-purinoceptor to the KACh channel through PTX-sensitive G proteins, analogous to the coupling mechanism of the muscarinic ACh receptor and Pi-purinoceptor to this channel.
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PMID:Activation of the muscarinic K+ channel by P2-purinoceptors via pertussis toxin-sensitive G proteins in guinea-pig atrial cells. 868 65

The antineoplastic drug mitoxantrone (MTX) elicits a fast noncytotoxic and nonimmunological histamine release from peritoneal and pleural rat mast cells. The non specific phosphodiesterase inhibitor isobuthyl-methylxantine (1 mM) decreases the potency of MTX. Theophylline (10 mM) decreases both the potency and the efficacy of MTX-induced histamine secretion. The protein kinase C (PKC) activator, tetradecanoyl-phorbol-13-acetate (50 ng/mL), enhances the effect of MTX, whereas the non specific PKC inhibitor trifluoperazine (10 microM) exerts no effect. Histamine release was also unaffected by substances acting on G-proteins, namely pertussis toxin (200 ng/mL), cholera toxin (300 mg/mL) and benzalkonium chloride (10 micrograms/ mL). The inhibition of protein phosphatases 1 and 2A by okadaic acid (1 microM) does not modify the response. The results indicate that mitoxantrone elicits the exocytosis in mast cells by a mechanism similar to the parent compound adriamycine, but different to the polyamine compound 48/80.
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PMID:Mitoxantrone induces nonimmunological histamine release from rat mast cells. 868 88

The regulation of the furosemide-sensitive Na+-ATPase activity and ouabain-sensitive (Na+ + K+)ATPase activities from proximal tubules by adenosine was investigated. When the concentration of adenosine was increased the furosemide-sensitive ATPase activity decreased with maximal inhibition at 10(-8) M (56% of inhibition). However, the (Na+ + K+)ATPase activity was not affected by adenosine. Theophylline, an antagonist of P1 adenosine receptor, completely reversed the effect of adenosine on the furosemide-sensitive ATPase activity in a dose-response manner. The adenosine effect was mimicked by N6-cyclohexyladenosine (CHA), an agonist for A1 adenosine receptor. 5'-N-ethylcarboxamideadenosine (NECA), an agonist for A2 adenosine receptor, did not affect the furosemide-sensitive ATPase activity. When adenosine was used in the presence of 1 microg ml(-1) pertussis toxin, a Gi protein inhibitor, no change in the furosemide-sensitive ATPase activity was observed. The addition of 1 nM cholera toxin increased the Na+-ATPase activity by 60%. Adenosine decreased the cholera toxin stimulated Na+-ATPase in 42%, similar to the effect observed in the absence of cholera toxin. Dibutyryl-cAMP reversed the effect of adenosine in a dose dependent manner while the protein kinase A peptide inhibitor mimicked it. These data are compatible with a modulatory effect of adenosine on the Na+-ATPase activity via A1 subtype receptor.
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PMID:Effect of adenosine on the ouabain-insensitive Na+-ATPase activity from basolateral membrane of the proximal tubule. 937 25

1. Adenosine A(1), A(2A), and A(3) receptors (ARs) and extracellular signal-regulated kinase 1/2 (ERK1/2) play a major role in myocardium protection from ischaemic injury. In this study, we have characterized the adenosine receptor subtypes involved in ERK1/2 activation in newborn rat cardiomyocytes. 2. Adenosine (nonselective agonist), CPA (A(1)), CGS 21680 (A(2A)) or Cl-IB-MECA (A(3)), all increased ERK1/2 phosphorylation in a time- and dose-dependent manner. The combined maximal response of the selective agonists was similar to adenosine alone. Theophylline (nonselective antagonist) inhibited completely adenosine-mediated ERK1/2 activation, whereas a partial inhibition was obtained with DPCPX (A(1)), ZM 241385 (A(2A)), and MRS 1220 (A(3)). 3. PD 98059 (MEK1; ERK kinase inhibitor) abolished all agonist-mediated ERK1/2 phosphorylation. Pertussis toxin (PTX, G(i/o) blocker) inhibited completely CPA- and partially adenosine- and Cl-IB-MECA-induced ERK1/2 activation. Genistein (tyrosine kinase inhibitor) and Ro 318220 (protein kinase C, PKC inhibitor) partially reduced adenosine, CPA and Cl-IB-MECA responses, without any effect on CGS 21680-induced ERK1/2 phosphorylation. H89 (protein kinase A, PKA inhibitor) abolished completely CGS 21680 and partially adenosine and Cl-IB-MECA responses, without any effect on CPA response. 4. Cl-IB-MECA-mediated increases in cAMP accumulation suggest that A(3)AR-induced ERK1/2 phosphorylation involves adenylyl cyclase activation via phospholipase C (PLC) and PKC stimulation. 5. In summary, we have shown that ERK1/2 activation by adenosine in cardiomyocytes results from an additive stimulation of A(1), A(2A), and A(3)ARs, which involves G(i/o) proteins, PKC, and tyrosine kinase for A(1) and A(3)ARs, and Gs and PKA for A(2A)ARs. Moreover, the A(3)AR response also involves a cAMP/PKA pathway via PKC activation.
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PMID:Characterization of ERK1/2 signalling pathways induced by adenosine receptor subtypes in newborn rat cardiomyocytes. 1475 70