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. Inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase by simvastatin leads to inhibition of both cell growth and Na+/H+ antiport activity. The effect of simvastatin on intracellular pH and Na+/H+ antiport activity was therefore studied on an adherent cell line, the SV40-virus-transformed MRC5 human fibroblast. 2. Simvastatin led to a dose-dependent decrease in intracellular pH, attributed to a reduction in Na+/H+ exchange, together with a rounding of cell shape. Mevalonate (1 mmol/l) prevented these effects of simvastatin, and when added after inhibition of the antiport by simvastatin, reversed these changes within 1-2h. 3. The phenomenon of mevalonate reversal of antiport inhibition by simvastatin was not sensitive to cycloheximide, indicating its post-translational nature. This was also consistent with the short period of incubation with mevalonate leading to reversal of antiport inhibition (1-2 h). These changes in intracellular pH regulation were not due to alterations in cell cholesterol content. 4. A variety of inhibitors of post-translational processes, such as N-linked glycosylation (tunicamycin), phosphorylation (staurosporine), isoprenylation (farnesol, limonene), and of pertussis-toxin-sensitive G-proteins or calmodulin (W7), had no effect on the reversal by mevalonate of simvastatin-induced changes in Na+/H+ antiport activity. 5. N-Ethylmaleimide (50 mumol/l for 5 min) prevented mevalonate reversing the effects of simvastatin, suggesting the importance of thiol groups in the phenomenon of reversal of the inhibition of Na+/H+ antiport activity by simvastatin. Furthermore, concurrent incubation of simvastatin-treated cells with dithiothreitol (1 mmol/l) and N-ethylmaleimide restored the ability of mevalonate to reverse the inhibitory effects of simvastatin on Na+H+ antiport activity.
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PMID:Simvastatin and intracellular pH regulation by the Na+/H+ antiport of SV40-virus-transformed human MRC5 fibroblasts. 839 20

Whole cell recordings were used to investigate the effects of adenosine and several of its analogues on voltage-activated calcium currents (VACC) of myenteric and submucosal neurons. Electrophysiological and pharmacological properties of the soma VACC recorded in myenteric neurons indicate that they are carried through N-type calcium channels, similar to those of the submucosal neurons and to those of the calcium conductance that mediates acetylcholine release at the submucosal ganglia. Adenosinergic compounds inhibited, in a concentration-response and in a voltage-dependent manner, VACC in neurons from both enteric plexuses. The pharmacological profile of the receptors that mediate this effect was similar to that of the receptors involved in presynaptic inhibition in enteric neurons and likely of the A1 subtype. The effects of 2-chloroadenosine (CADO) on VACC were prevented by pretreatment with pertussis toxin (PTX), became irreversible with guanosine 5'-O-(3-thiotriphosphate) (inside the pipette), and were abolished with N-ethylmaleimide (NEM; known to uncouple receptors from G protein complexes). Intracellular recordings were used to further evaluate presynaptic effects of adenosine at the submucosal plexus. Adenosinergic compounds reduced the amplitude of fast excitatory postsynaptic potentials (EPSPs) by acting at nerve terminals. This effect was insensitive to PTX and staurosporine (a protein kinase inhibitor) but was abolished by NEM. CADO effects on EPSPs were not reversed by increasing the extracellular calcium concentration. In conclusion, activation of A1 adenosine receptors inhibits VACC via PTX-sensitive G proteins in myenteric and submucosal neurons. Reduction of cholinergic transmission also involves A1 adenosine receptors and appears to involve the activation of PTX-insensitive G proteins.
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PMID:Cellular mechanisms underlying adenosine actions on cholinergic transmission in enteric neurons. 876 55

1. The involvement of G proteins in the transduction pathway that links muscarinic receptors to the low-threshold voltage-dependent sodium current (INa,M) was studied in neurones from intact sympathetic prevertebral ganglia using the whole-cell configuration of the patch-clamp technique. Experiments were performed in the presence of the nicotinic receptor antagonists hexamethonium (50 microM) and d-tubocurarine (50 microM). 2. INa,M was activated by either bath-applying muscarinic agonists or stimulating the preganglionic splanchnic nerves. Synaptically and agonist-mediated INa,M did not display significant run-down or changes in their properties in cells tested, irrespective of whether the pipette solutions contained GTP. 3. Dialysis of sympathetic neurones with GDP beta S (500-750 microM) decreased the amplitude of INa,M by approximately 65% compared with control neurones within 30 min. 4. In the absence of muscarinic receptor stimulation, intracellular dialysis with GTP gamma S (500 microM) for 10 min slowly and slightly (20-25%) activated INa,M. GTP gamma S dialysis markedly slowed down the decay of INa,M after its transient activation with carbachol pulses (10-20 s) or nerve stimulation (3-5 s). The INa,M activation became fully irreversible 2.9 min after the start of GTP gamma S dialysis. Dialysing cells with the G protein activator AIF4-led to a rapid but transient activation of INa,M. 5. Synaptically and agonist-evoked INa,M were not affected in ganglia treated with 0.5-1 microgram ml-1 pertussis toxin (PTX) for 7-24 h at 37 degrees C. Control experiments showed that this treatment severely reduced the PTX-sensitive inhibition of N-type calcium currents induced by carbachol (CCh) and noradrenaline. Application of NEM (N-ethylmaleimide) for 2 min depressed the INa,M evoked in response to bath-applied CCh by only 27%. 6. Incubating ganglia with 5-10 micrograms ml-1 of cholera toxin for 7 h had no effect on the carbachol-induced INa,M but greatly potentiated (approximately 250%) the synaptically evoked INa,M, presumably via a presynaptic mechanism. 7. These results show that the coupling between muscarinic receptors and NaM channels is mediated by pertussis toxin- and cholera toxin-insensitive G proteins, possibly of the Gq/11 or G12 class.
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PMID:Exotoxin-insensitive G proteins mediate synaptically evoked muscarinic sodium current in rabbit sympathetic neurones. 905 75

The effect of guanine nucleotide-binding protein (G protein) modifiers on the binding of the adenosine A2A receptor agonist 2-[4-(2-p-carboxyethyl[3H])phenyl-amino]-5'-N-ethylcarboxamidoadenosine ([3H]CGS 21680) and of the adenosine A1 receptor agonist [3H]R-phenylisopropyladenosine ([3H]R-PIA) to rat cortical and striatal membranes was studied. Guanosine 5'-(beta,gamma-imido)triphosphate (1-300 microM), which uncouples all G proteins, more effectively inhibited [3H]CGS 21680 (30 nM) binding in the cortex than [3H]R-PIA (2 nM) binding to cortical or striatal membranes or [3H]CGS 21680 (30 nM) binding in the striatum. N-Ethylmaleimide (1-300 microM) or pertussis toxin (1-100 microg/ml), which uncouple G(i)/G(o) protein-coupled receptors, more effectively inhibited [3H]R-PIA binding to cortical or striatal membranes and [3H]CGS 21680 binding in the cortex than [3H]CGS 21680 binding in the striatum. Cholera toxin (2.5-250 microg/ml), which uncouples G(S) protein-coupled receptors, more effectively inhibited [3H]CGS 21680 binding in the striatum than [3H]CGS 21680 binding in the cortex and less effectively inhibited [3H]R-PIA binding to cortical or striatal membranes. Treatment of solubilised cortical membranes with pertussis toxin (50 microg/ml) decreased [3H]CGS 21680 (30-100 nM) binding which almost fully recovered after reconstitution with G(i)/G(o) proteins. The K(i) for displacement of [2-3H]-(4{2-[7-amino-2-(2-furyl)(1,2,4)triazolo(2,3-a)(1,3,5)triazin+ ++-5-ylamino]ethyl}phenol) ([3H]ZM 241385, 1nM) by CGS 21680 was 110 nM (95%CI: 98-122 nM) in non-treated, 230 (167-292) nM in pertussis toxin (25 microg/ml)-treated and 222 (150-295) nM in cholera toxin (50 microg/ml)-treated cortical membranes; in contrast, the K(i) for displacement of [3H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo(4,3-e)-1,2,4-triazol o(1,5-c)pyrimidine ([3H]SCH 58261, 1 nM) by CGS 21680 was 74 (57-91) nM in non-treated, 71 (44-100) nM in pertussis toxin-treated and 147 (100-193) nM in cholera toxin-treated cortical membranes. Finally, CGS 21680 displaced monophasically the binding of the A1 antagonist, [3H]8-cyclopentyl-1,3-dipropylxanthine (2 nM), and the A1 agonist, [3H]R-PIA (2 nM), in 2 or 10 mM Mg(2+)-medium, either at 25 degrees C or 37 degrees C, in cortical or striatal membranes. These results indicate that CGS 21680 does not bind to A1 receptors and that limbic CGS 21680 binding sites differ from striatal-like A2A receptors since they couple to G(i)/G(o) proteins, as well as to G(s) proteins.
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PMID:G protein coupling of CGS 21680 binding sites in the rat hippocampus and cortex is different from that of adenosine A1 and striatal A2A receptors. 1034 28

The aim of the present paper is to evaluate the modulation of phosphatidate phosphohydrolase (PAPase) and diacylglyceride lipase (DGL) activities in bovine rod outer segment (ROS) under dark and light conditions and to evaluate the role of transducin (T) in this phenomenon. In dark-adapted ROS membranes exposed to light, PAPase activity is inhibited by 20% with respect to the activity found under dark conditions. To determine whether the retinal G protein, T, participates in the regulation of PAPase activity in these membranes, the effects of GTPgammaS and GDPbetaS on enzyme activity were examined. Under dark conditions in the presence of GTPgammaS, which stabilizes T in its active form (Talpha + Tbetagamma), enzyme activity was inhibited and approached control values under light conditions. GDPbetaS, on the other hand, which stabilizes the inactive state of T (Talphabetagamma), stimulated PAPase activity by 36% with respect to control light conditions. ADP-ribosylation by cholera and pertussis toxin was also studied. In ADP-rybosilated ROS membranes with pertussis toxin under dark conditions, PAPase activity was 36% higher than the activity found under control light conditions. ADP-ribosylation by CTx, on the other hand, inhibited PAPase activity by 22%, with respect to dark control conditions, mimicking light effect. The effects of GTPgammaS and GDPbetaS and conditions of ADP-ribosylation by PTx and CTx on DGL activity were similar to those of PAPase activities. Based on NEM sensitivity we have also demonstrated that the PAPase present in ROS is the PAP 2 isoform. Our findings therefore suggest that light inhibition of PAP 2 in ROS is a transducin-mediated mechanism.
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PMID:Effect of light on phosphatidate phosphohydrolase activity of retina rod outer segments: the role of transducin. 1089 48

The median preoptic (MnPO) nucleus, a key CNS site for hydromineral and cardiovascular homeostasis, receives a dense norepinephrine innervation from brainstem autonomic centers. Since norepinephrine is known to influence neuronal excitability by modulating calcium channel function, we applied whole cell patch clamp techniques to study calcium currents in 116 dissociated MnPO neurons, including 30 cells identified by a retrograde label as projecting to the hypothalamic paraventricular nucleus. Norepinephrine (3-50 microM) suppressed high-voltage-activated calcium currents (HVA I(Ca)) in 80% of cells, selectively blockable by yohimbine and mimicked by UK14,304 and clonidine. The norepinephrine effect was relieved by strong prior depolarization, indicating a voltage-dependent component. Intracellular GTP-gamma-S blocked the effect. Blockade by extracellular NEM suggested involvement of pertussis-toxin sensitive G-proteins. Based on pharmacological properties, these HVA I(Ca)s had the following composition: 40-45% N-type (blockable by omega-conotoxin GVIA); 20-25% L-type (blockable by nimodipine); 15-20% P/Q-type (blockable by omega-agatoxin IVA). Since approximately 75% of the norepinephrine effect was blockable with omega-conotoxin GVIA, we conclude that postsynaptic alpha(2) adrenoceptors preferentially suppress N-type calcium channels, revealing a novel mechanism whereby norepinephrine can modulate excitability in MnPO neurons.
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PMID:Norepinephrine acts via alpha(2) adrenergic receptors to suppress N-type calcium channels in dissociated rat median preoptic nucleus neurons. 1154 67

Effects of 5-hydroxytryptamine (5-HT) on inhibitory synaptic transmission in the rat dorsolateral septal nucleus (DLSN) were examined by conventional intracellular and voltage-clamp recording methods. 5-HT (1-30 microM) depressed the monosynaptic fast IPSC evoked by local stimulation of the DLSN in the presence of DNQX, AP5 and CGP 55845A. CP 93129, a selective 5-HT1B receptor agonist, depressed the fast IPSC. The 5-HT-induced depression of the fast IPSC was attenuated by SB 216641, a selective antagonist for 5-HT1B receptors. 5-HT did not change the inward currents mediated by GABAA receptors, suggesting that 5-HT presynaptically inhibited the fast IPSC. 5-HT and CP 93129 depressed the frequency of miniature fast IPSPs (mIPSPs) without changing their amplitudes. Neither a selective protein kinase A inhibitor, H-89, nor a selective protein kinase C inhibitor, calphostin C, blocked the 5-HT-induced depression of the fast IPSC. N-Ethylmaleimide (NEM) blocked the 5-HT-induced depression of the evoked IPSC. These results suggest that activation of presynaptic 5-HT1B receptors depresses the release of GABA via a pertussis toxin (PTX)-sensitive G-protein in the rat DLSN.
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PMID:5-Hydroxytryptamine 1B receptors mediate presynaptic inhibition of monosynaptic IPSC in the rat dorsolateral septal nucleus. 1515 69

The effect of the sulfhydryl alkylating agent N-ethylmaleimide on the modulation of potassium-evoked [(3)H]noradrenaline release via inhibitory presynaptic receptors was studied using synaptosomes from rabbit hippocampus. Dose-response curves for the ?(2)-adrenoceptor agonist clonidine, the preferential ?-opioid receptor agonist ethylketocyclazocine and the A(1)-adenosine receptor agonist (?)phenylisopropyladenosine were compared to the effects of these agonists after pretreatment of [(3)H]noradrenaline loaded synaptosomes with N-ethylmaleimide (2 ?M) for 15 min. The inhibitory effects of all three agonists were attenuated to the same extent in a non-competitive manner after pretreatment with N-ethylmaleimide. Pertussis toxin-catalyzed [(32)P]ADP-ribosylation of synaptosomal proteins after purification of synaptosomes on a discontinuous Percoll gradient revealed the presence of three toxin-sensitive G proteins with apparent molecular weights of the ?-subunits between 41 and 39 kDa. N-Ethylmaleimide treatment of synaptosomes prior to pertussis toxin-catalyzed [(32)P]ADP-ribosylation reduced the incorporation of radioactivity into the toxin substrates to an extent comparable to the invalidation of agonist-induced inhibition of [(3)H]noradrenaline release. The quantitative agreement of the effects of N-ethylmaleimide on the modulation of [(3)H]noradrenaline release and on pertussis toxin-catalyzed [(32)P]ADP-ribosylation lends support to the proposal that inhibitory receptors on noradrenergic terminals in rabbit hippocampus are coupled to pertussis toxin-sensitive G proteins. The observation that the extent of functional antagonism after N-ethylmaleimide pretreatment was the same for all three agonists investigated is compatible with the existence of a common step in the signal transduction mechanism of the three pharmacologically different receptors, presumably on the level of a common G protein.
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PMID:Involvement of N-ethylmaleimide-sensitive G proteins in the modulation of evoked [(3)H]noradrenaline release from rabbit hippocampus synaptosomes. 2050 15


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