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. The effects of metabotropic glutamate receptor (mGluR) agonists on excitatory postsynaptic potentials (EPSPs) evoked by stimulation of mossy fibers (MF) and parallel fibers (PF) were examined in turtle cerebellar Purkinje cells. 2. The mGluR agonist 1S,3R-ACPD (1-25 microM) reversibly potentiated the amplitude of the MF-evoked EPSPs, but was without effect on PF-evoked EPSPs. The potentiation of MF-evoked EPSPs was dose-dependent, with a median effective dose (ED50) of approximately 4.4 microM. At higher doses (15-25 microM) 1S,3R-ACPD produced a direct depolarization of Purkinje cells in 58% of cells examined. 3. The enhancement of MF EPSPs by 1S,3R-ACPD was mimicked by 1S,3S-ACPD (50 microM) and blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonovalerate (D-AP5), but not by the mGluR antagonist L-2-amino-3-phosphonopionic acid (L-AP3; 1 mM), or the 1R,3S isomer of ACPD (25-500 microM). 4. Quisqualate (1 microM) produced a biphasic effect on MF EPSPs, producing an initial blockade of the EPSP followed by a D-AP5-sensitive potentiation. 5. The potentiation of MF EPSPs by 1S,3R-ACPD was not blocked by prior exposure to the protein kinase C activator phorbol 12-myristate 13-acetate (10 microM), the protein kinase C inhibitor calphostin C (1 microM), the adenylate cyclase activator forskolin (25 microM), or the nitric oxide donator sodium nitroprusside (1 mM). Preincubation of the tissue for 24-48 h in pertussis toxin also failed to prevent the ability of 1S,3R-ACPD to potentiate the NMDA receptor-mediated component of the MF EPSP. PF EPSPs were also not significantly affected by these agents. 6. The results demonstrate that the mGluR agonists 1S,3R-ACPD, 1S,3S-ACPD, and quisqualate produce a potent, stereospecific potentiation of NMDA receptor-mediated transmission at the MF-granule cell synapse. Agents that modulate the intracellular messengers protein kinase C, adenylate cyclase, nitric oxide, or pertussis toxin-sensitive G proteins failed to mimic or block this effect. This would suggest that the potentiation of NMDA receptor-mediated transmission at this synapse is not mediated via these systems, and reflects a different site of action of mGluR agonists on the NMDA receptor. The observed interaction between mGluR and NMDA receptors in granule cells provides a means for activity-dependent modulation of synaptic transmission, which may play a role in synaptic integration at the MF-granule cell synapse.
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PMID:Potentiation of NMDA receptor-mediated transmission in turtle cerebellar granule cells by activation of metabotropic glutamate receptors. 768 76

Endothelins (ET) produce endothelium-dependent vasodilation through nitric oxide (NO) synthesis. The present study was designed to elucidate the cellular mechanism by which ET induces synthesis and release of endothelium-derived NO by cultured bovine endothelial cells (EC). Binding studies revealed that bovine EC membrane had the binding sites of a novel agonist (BQ3020) for non-isopeptide-selective receptor subtype (ETB). Affinity labeling studies showed a major labeled band with the apparent molecular mass of 50 kD. Northern blot analysis demonstrated the expression of mRNA for ETB receptor. BQ3020 rapidly and dose dependently induced formation of inositol-1,4,5-triphosphate and increased intracellular Ca2+ concentrations in fura-2-loaded cells. Concomitantly, BQ3020 dose dependently stimulated production of both nitrate/nitrite (NOx) and cyclic GMP; a highly significant correlation existed between NOx and cGMP production. The stimulatory effect on NOx and cGMP production by ETB agonist was inhibited by NO synthase inhibitor monomethyl-L-arginine; this effect was reversed by coaddition of L-arginine, but not D-arginine. NOx and cGMP production stimulated by BQ3020 was inhibited by pretreatment with pertussis toxin. ETB agonist-induced NOx production was blocked by a calmodulin inhibitor and an intracellular Ca2+ chelator, but not by an extracellular Ca2+ chelator or a Ca2+ channel blocker. These data suggest that endothelins stimulate ETB receptor-mediated phosphoinositide breakdown via pertussis toxin-sensitive G-protein(s), which triggers release of intracellular Ca2+, thereby activating Ca2+/calmodulin-dependent NO synthase in EC.
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PMID:Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells. 768 70

We investigated the effects of the M-cholinoceptor agonist carbachol on cyclic GMP (cGMP) content and contractile response in the absence and presence of the nitric oxide synthase inhibitor NG-nitro-L-arginine in guinea-pig isolated ventricular cardiomyocytes. Carbachol (10 mumol/l, 10 min) increased basal cGMP content to approximately 200% and contractile response to 118%. Preincubation of the cardiomyocytes with NG-nitro-L-arginine (0.1 mumol/l, 60 min) did not alter the effects of carbachol on neither cGMP content or contractile response. Moreover, nitric oxide synthase activity was undetectable in crude or ADP-agarose purified cytosolic and particulate fractions of homogenized isolated ventricular cardiomyocytes. Pretreatment with pertussis toxin did not affect the carbachol-mediated increase in cGMP content or contractile response. However, methylene blue abolished the elevation in cGMP content by carbachol, without changing contractile response. It is concluded that the carbachol-mediated increase in cGMP content and contractile response in ventricular cardiomyocytes is neither mediated via a nitric oxidebiosynthesis pathway nor via a pertussis toxin-sensitive GTP-binding protein. Furthermore, the cGMP increase by carbachol is due to an activation of soluble guanylyl cyclase and is dissociated from the contractile response. We therefore assume that carbachol activates two independent effector cascades, one leading to an elevation in cGMP content and the other to an increase in contractile response and that none of the effects are mediated via endogenous nitric oxide formation.
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PMID:Ca(++)-dependent constitutive nitric oxide synthase is not involved in the cyclic GMP-increasing effects of carbachol in ventricular cardiomyocytes. 768 6

Nitric oxide (NO), a free-radical gas produced endogenously by some neurons, functions as a diffusible intercellular messenger and appears to play a role in activity-dependent modification of synaptic efficacy in the mammalian CNS. The molecular targets and mechanisms of action of NO in neurons remain largely uncharacterized. Employing in vitro brain slices and isolated synaptosomes, we show here that exposure to exogenous or endogenously generated NO results in the modification of cysteine residues within neuronal proteins, as revealed by reduced binding of agents which react with cysteine sulfhydryls. In particular, exposure of synaptosomes to NO inhibits subsequent thiol-linked ADP-ribosylation of the heterotrimeric G-protein, G(o), by pertussis toxin. Our results demonstrate directly that NO may exert its neuronal effects through modification of protein cysteine thiols, and identify G(o) as a potential synaptic target of NO.
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PMID:Modification of cysteine residues within G(o) and other neuronal proteins by exposure to nitric oxide. 787 Feb 85

1. The potassium currents evoked in isolated and identified neurones of molluscan pedal ganglia by either glutamate, dopamine or the muscarinic agonist F-2268 were investigated using voltage and patch clamp techniques. 2. Potassium currents induced by either dopamine or F-2268 could be blocked by pertussis toxin, as well as by a prolonged intracellular injection of the G protein inhibitor, GDP-beta-S. Loading the neurones with the G protein activator, GppNHp, on the other hand, induced a potassium current. This current was not additive to the currents evoked by agonist application. 3. Intracellular injection of the calcium buffer BAPTA failed to affect any of the agonist-induced currents, although it effectively blocked the after-hyperpolarization following directly evoked action potentials. 4. The activity of the potassium channels seen in cell-attached patches was greatly enhanced by application to the bath of either glutamate, dopamine, or F-2268. 5. The only effect of an addition of agonists to the bath was to increase the open probability (Po) of the K+ channel already active in the control conditions. The identity of the spontaneously active and agonist-activated channels was concluded from the identity of their channel conductances, rectification properties and current amplitudes. 6. Phorbol-12,13-dibutyrate, when applied to the bath, induced an increase in open time and caused an increase in Po, as did the agonists. Staurosporine completely prevented changes of Po induced by the phorbol ester but not those induced by the agonists. 7. The same inwardly rectifying potassium channel may be opened by both the receptor-linked G protein (with glutamate, dopamine, F-2268) and by protein kinase C (with phorbol ester) activation. 8. Strong evidence was obtained against the involvement of any known secondary messenger systems (formation of nucleotides, phosphoinositide turnover and subsequent activation of protein kinase C, formation of nitric oxide, metabolism of arachidonic acid) in the transduction mechanism of F-2268-, dopamine- and glutamate-induced responses. 9. Since none of the known secondary messenger systems seems to affect the activation by agonists applied to receptors outside the patch of channels located under the patch electrode, it appears that some as yet undescribed linking system must exist that could connect the spatially separated receptor-G protein complex and the potassium channel.
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PMID:Activation of a common potassium channel in molluscan neurones by glutamate, dopamine and muscarinic agonist. 790 68

Toxigenic bacteria such as Bordetella pertussis and Staphylococcus aureus have been implicated in some cases of sudden infant death syndrome (SIDS). We have previously demonstrated that the Lewis(a) antigen is an epithelial cell receptor for S. aureus, and this study demonstrated that Lewis(a) on human monocytes is also a receptor for staphylococcal enterotoxin B (SEB). Values obtained in assays for production of TNF-alpha and nitric oxide were greater for monocytes treated with SEB compared with those treated with lipopolysaccharide (LPS). Exposure to LPS increased the expression of Lewis(a) on monocytes. These results are discussed with reference to the reported enhancement of endotoxic shock by pyrogenic toxins.
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PMID:Lewis antigen expression on human monocytes and binding of pyrogenic toxins. 791 70

Exposure of cultured endothelial cells to shear stress resulting from well-defined fluid flow stimulates the production of nitric oxide (NO). We have established that an initial burst in production is followed by sustained steady-state NO production. The signal transduction events leading to this stimulation are not well understood. In the present study, we examined the role of regulatory guanine nucleotide binding proteins (G proteins) in shear stress-mediated NO production. In endothelial cells not exposed to shear stress, AIF4-, a general activator of G proteins, markedly elevated the production of guanosine 3',5'-cyclic monophosphate (cGMP). Pretreatment with NO synthase inhibitor N omega-nitro-L-arginine completely blocked this stimulation. Incubation with guanosine 5'-O-(2-thiodiphosphate) (GDP beta S), a general G protein inhibitor, blocked the flow-mediated burst in cGMP production in a dose-dependent manner. Likewise, GDP beta S inhibited NOx (NO2 + NO3) production for the 1st h. However, inhibition was not detectable between 1 and 3 h. Pertussis toxin (PTx) had no effect on the shear response at any time point. The burst in NO production caused by a change in shear stress appears to be dependent on a PTx-refractory G protein. Sustained shear-mediated production is independent of G protein activation.
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PMID:Role of G proteins in shear stress-mediated nitric oxide production by endothelial cells. 794 4

Involvement of a cyclic GMP pathway in signal transduction stimulated by endothelins (ETs) and sarafotoxins (SRTXs) was explored using rat cerebellar slices. These peptides activated the same receptor binding sites (ET-1 and SRTX-b at the picomolar sites; ET-3 and SRTX-c at the nanomolar sites) to produce cyclic GMP, but their signaling pathways differed. The endothelins (ET-1 and ET-3) were found to signal via nitric oxide formation and to involve pertussis toxin-sensitive G-protein(s). The SRTXs (b and c), while also stimulating cyclic GMP production, did so via a pathway which is not L-arginine-dependent, i.e., carbon monoxide formation, and did not involve pertussis-toxin-sensitive G-protein(s). This is the first demonstration that the signaling pathways of endothelins and sarafotoxins may differ, even though they share the same binding sites.
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PMID:Cyclic GMP formation in rat cerebellar slices is stimulated by endothelins via nitric oxide formation and by sarafotoxins via formation of carbon monoxide. 799 93

Pentoxifylline (1-(5-oxohexyl)-3,7-dimethylxanthine) is a metylxanthine derivative used in the treatment of peripheral arterial disease. In isolated rat mesenteric resistance vessels mounted on an isometric myograph and precontracted with noradrenaline (5 microM), pentoxifylline (0.1 microM-10 mM) and aminophylline (0.1 microM-10 mM) evoked concentration-dependent relaxations. The resistance vessels were more sensitive to pentoxifylline, i.e., the concentration of the agonist evoking 50% relaxation (EC50 value) was 105 +/- 15 microM for pentoxifylline vs. 200 +/- 20 microM for aminophylline (P < 0.01). The vasorelaxant response to pentoxifylline was attenuated by mechanical removal of the endothelium, or by inhibition of the endothelial production of nitric oxide with NG-nitro-L-arginine. Inhibition of cyclooxygenase metabolism with indomethacin did not influence the response to pentoxifylline significantly, but was associated with an increased sensitivity to aminophylline. Furthermore, the vasorelaxation of resistance vessels elicited by pentoxifylline was diminished after incubation with tetraethylammonium, a nonselective K+ channel blocker, and pertussis toxin, an inhibitor of certain G-proteins. In contrast, the vasorelaxation elicited by aminophylline was generally enhanced by these experimental manipulations. The results indicate that the vasorelaxant properties of pentoxifylline and aminophylline in resistance vessels are mediated primarily at the level of the vascular smooth muscle cell, but that the mechanisms of the two agonists partly differ. Endothelial-derived factors (e.g., nitric oxide) contribute to the response to pentoxifylline, and may, through other mechanisms, attenuate the vasorelaxation elicited by aminophylline.
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PMID:In vitro studies on responses to pentoxifylline and aminophylline of rat mesenteric resistance vessels. 800 31

This study was done to determine whether abnormal receptor-dependent release of endothelium-derived relaxing factor (EDRF) might be caused by G-protein dysfunction. Dogs were exposed to global myocardial ischemia (45 minutes, induced by aortic cross-clamping) followed by reperfusion (60 minutes) while on cardiopulmonary bypass, and coronary arteries were then studied in vitro in organ chamber experiments. After reperfusion, endothelium-dependent relaxation to the receptor-dependent agonists adenosine diphosphate and acetyl-choline was significantly impaired as well as to sodium fluoride, which acts on a pertussis toxin-sensitive G-protein. In contrast, endothelium-dependent relaxations to the receptor-independent agonists A23187 and phospholipase C were normal. Furthermore, endothelium-dependent relaxation to poly-L-arginine (molecular weight, 139,200), which appears to induce endothelium-dependent relaxation of the canine coronary artery by a nonnitric oxide pathway, was unaffected by ischemia and reperfusion. These experiments suggest that global myocardial ischemia and reperfusion selectively impair receptor-mediated release of EDRF (nitric oxide) but that the ability of the endothelial cell to produce EDRF or generate endothelium-dependent relaxation to nonnitric oxide-dependent agonists remains intact. We hypothesize that coronary reperfusion injury leads to G-protein dysfunction in the endothelium.
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PMID:Impaired endothelium-dependent relaxation after coronary reperfusion injury: evidence for G-protein dysfunction. 801 Aug 1


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