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. Inhibitory modualtion of the three Ca2+ channel current components by neurotransmitters was studied using the whole-cell patch-clamp method in a mammalian cell line, NG108-15. 2. In cells differentiated with dibutyryl cyclic AMP, both the low-voltage-activated current (ILVA) and omega CgTX-sensitive high-voltage-activated current (I omega CgTX) could be inhibited by [D-phen2, D-phen5]enkephalin, acetylcholine and noradrenaline. In contrast, differentiation with prostaglandin E1 and theophylline eliminated the agonist-induced inhibition of ILVA, but enhanced that of I omega CgTX. The DHP-sensitive high-voltage-activated current was unaffected by the transmitters in most of the cells. 3. The inhibition was prevented by pre-treatment of cells with pertussis toxin, suggesting involvement of a G-protein. Long treatment of the cells with phorbol ester did not prevent the inhibition. 4. The inhibition was always partial: the maximal inhibition was 40% for ILVA and 70% for I omega CgTX. 5. The inhibition of ILVA and I omega CgTX was relieved during depolarization. Half-maximal relief of inhibition of I omega CgTX was attained at 0 mV, irrespective of agonist concentration. 6. The kinetics of removal and re-establishment of inhibition were voltage dependent. Both processes were single exponentials and had identical time constants at a given membrane potential. Time constants were 124 ms at -40 mV, 160 ms at 0 mV and 8 ms at 60 mV, at any agonist concentration. 7. Time courses of tail currents were unaltered by the inhibition. 8. The inhibition of the omega CgTX-sensitive Ca2+ channel can be described as a shift in gating modes; with an additional voltage-dependent gating state activated by the agonists. The voltage-dependent properties of this modulation allow inhibition of Ca2+ channel to be overcome by high-frequency trains of action potentials.
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PMID:Voltage- and time-dependent inhibition of neuronal calcium channels by a GTP-binding protein in a mammalian cell line. 135 Jun 37

Three major subtypes of glutamate receptors that are coupled to cation channels--N-methyl-D-aspartate (NMDA), kainate, and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors--are known as ionotropic receptors in the mammalian CNS. Recently, an additional subtype that is coupled to GTP binding proteins and stimulates (or inhibits) metabolism of phosphoinositides has been proposed as a metabotropic receptor. Incubation of dispersed hippocampal cells from adult rats with glutamate or NMDA decreased forskolin-stimulated cyclic AMP (cAMP) accumulation; half-maximal effects were obtained with 5.6 +/- 2.2 and 6.4 +/- 2.3 microM, respectively. Kainate and quisqualate were less potent. The effect of glutamate was antagonized by 2,3-diaminopropionate and 2-amino-5-phosphonovalerate, NMDA/glutamate receptor antagonists, but not by 0.5 microM Joro spider toxin, a specific blocker of the AMPA receptor. The inhibitory effect of glutamate on cAMP formation was not blocked by 2 microM tetrodotoxin or by the absence of Ca2+. In hippocampal membranes, glutamate, similar to carbachol, inhibited adenylate cyclase activity in a GTP-dependent manner. These findings suggest that the glutamate inhibition of adenylate cyclase is direct and is not due to a result of the release of other neurotransmitters. The effect of glutamate on cAMP accumulation was observed in an assay medium containing 0.7 mM MgCl2, which is known to inhibit both ionotropic NMDA receptor/channels in the hippocampus and metabotropic NMDA receptors in the cerebellum. The inhibitory effect of glutamate was abolished by pertussis toxin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glutamate inhibits adenylate cyclase activity in dispersed rat hippocampal cells directly via an N-methyl-D-aspartate-like metabotropic receptor. 135 90

Exposure of cardiomyocytes from chicken embryos for 3 days to the beta-adrenoceptor agonist, isoproterenol, lead to a down-regulation of beta-adrenoceptors by about 70% and to a decrease in isoproterenol-stimulated adenylyl cyclase activity by about 40% (homologous desensitization). In addition, the isoproterenol treatment induced an increase in the level of muscarinic acetylcholine receptors by about 30% and an increase in pertussis toxin-catalyzed ADP-ribosylation of two about 40 kDa proteins, most probably alpha-subunits of the inhibitory G-protein (Gi), by about a factor of two (heterologous desensitization). The purpose of the present study was to characterize the role of beta-adrenoceptor-dependent and -independent mechanisms in heterologous desensitization of adenylyl cyclase. Therefore, the effect of pretreatment with the beta-adrenoceptor antagonist, propranolol, with the partial agonists, celiprolol and xamoterol, and with the beta-adrenoceptor-independent adenylyl cyclase activators, prostaglandin E1 and forskolin, on beta-adrenoceptors, muscarinic acetylcholine receptors and pertussis-toxin-catalyzed ADP-ribosylation of G-protein alpha-subunits was studied. Pretreatment of the cardiomyocytes for 3 days with xamoterol or celiprolol, but not with propranolol, induced a small decrease in beta-adrenoceptor number and in isoproterenol-stimulated adenylyl cyclase activity by about 15-20%. Exposure to prostaglandin E1 and forskolin lead to a more pronounced decrease in beta-adrenoceptor binding and in isoproterenol-mediated adenylyl cyclase stimulation by about 40-60% (heterologous desensitization). An increase in the level of muscarinic acetylcholine receptors, similar to that induced by isoproterenol exposure, was only observed after pretreatment with the partial agonists, celiprolol and xamoterol, but not after pretreatment with the beta-adrenoceptor-independent agonists, prostaglandin E1 and forskolin, nor after pretreatment with propranolol. In contrast, prostaglandin E1 and forskolin exposure lead to a similar increase in pertussis toxin-catalyzed ADP-ribosylation of about 40 kDa G-proteins as isoproterenol exposure whereas treatment with propranolol, celiprolol and xamoterol had no or only a very small effect on pertussis toxin substrates. In summary, the data suggest that, similar as shown for homologous desensitization, cyclic AMP-dependent and -independent mechanisms are also involved in heterologous desensitization of adenylyl cyclase stimulation. The beta-adrenoceptor-induced upregulation of muscarinic acetylcholine receptors and of the alpha-subunits of pertussis toxin-sensitive G-proteins, most probably of Gi, seem to be mediated via distinct pathways.
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PMID:Distinct pathways for beta-adrenoceptor-induced up-regulation of muscarinic acetylcholine receptors and inhibitory G-protein alpha-subunits in chicken cardiomyocytes. 135 32

Thyroid stimulating hormone (TSH) and other substances increase adenylate cyclase (AC) activity and growth of normal and neoplastic thyroid tissue. Factors that inhibit cAMP may provide targeted therapy to tumors dependent on cAMP for growth. Somatostatin has been reported to inhibit the growth of gastrinomas and carcinoid tumors. We therefore studied the effects of somatostatin on basal, TSH, pertussis toxin, and forskolin stimulated adenylate cyclase activity in normal and neoplastic thyroid tissue from 19 patients. Adenylate cyclase (AC) activity was determined by the conversion of alpha 32P-ATP to 32P-cAMP in pmoles/mg protein/30 minutes in an 8000 x g particulate fraction rich in thyroid plasma membranes. TSH (300 mU/ml) and forskolin (100 mM) (a diterpine that directly stimulates the catalytic unit of AC) increased AC activity in normal and neoplastic thyroid tissue. The AC stimulation was greater in the neoplasms (p less than 0.01). Somatostatin (5 x 10(-6)M) decreased basal and TSH stimulated AC activity below basal levels in both normal and neoplastic thyroid tissue (including papillary, follicular, and medullary carcinomas). The inhibition of AC by somatostatin was greater in neoplastic tissue (p less than 0.025). Pertussis toxin (which blocks the inhibitory guanyl nucleotide regulatory protein) was able to partially reverse the effect of somatostatin. Somatostatin partially inhibited forskolin stimulated AC activity. Somatostatin inhibits basal and TSH stimulated AC activity in both normal and neoplastic human thyroid tissue, with a greater effect on neoplasms. These studies establish that somatostatin blocks a major regulator of thyroid growth and provides the rationale for the use of somatostatin analogs in the treatment of thyroid cancers.
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PMID:Effect of somatostatin on adenylate cyclase activity in normal and neoplastic thyroid tissue. 135 26

The mitogenic effect of extracellular ATP on porcine aortic smooth muscle cells (SMC) was examined. Stimulation of [3H]thymidine incorporation by ATP was dose-dependent; the maximal effect was obtained at 100 microM. ATP acted synergistically with insulin, IGF-1, EGF, PDGF, and various other mitogens. Incorporation of [3H]thymidine was correlated with the fraction of [3H]thymidine-labeled nuclei and changes in cell counts. The stimulation of proliferation was also determined by measurement of cellular DNA using bisbenzamide and by following the increase of mitochondrial dehydrogenase protein. The effect of ATP was not due to hydrolysis to adenosine, which shows synergism with ATP. ATP acted as a competence factor. The mitogenic effect of ATP, but not adenosine, was further increased by lysophosphatidate, phosphatidic acid, or norepinephrine. The inhibitor of adenosine deaminase, EHNA, stimulated the effect of adenosine but not ATP. The adenosine receptor antagonist theophylline depressed adenosine-induced mitogenesis. ADP and the non-hydrolyzable analogue adenosine 5'-[beta, gamma-imido]triphosphate (AMP-PNP) were equally mitogenic. Thus extracellular ATP stimulated mitogenesis of SMC via P2Y purinoceptors. The mechanism of ATP acting as a mitogen in SMC was further explored. Extracellular ATP stimulated the release of [3H]arachidonic acid (AA) and prostaglandin E2 (PGE2) into the medium, and enhanced cAMP accumulation in a dose-dependent fashion similar to ATP-induced [3H]thymidine incorporation. Inhibitors of the arachidonic acid metabolism pathway, quinacrine and indomethacin, partially inhibited the mitogenic effect of ATP but not of adenosine. Pertussis toxin inhibited ATP-stimulated DNA synthesis, AA release, PGE2 formation, and cAMP accumulation. Down-regulation of protein kinase C (PKC) by long-term exposure to phorbol dibutyrate (PDBu) partially prevented stimulation of DNA synthesis and activation of the AA pathway by ATP. The PKC inhibitor, staurosporine, antagonized mitogenesis stimulated by ATP. No synergistic effect was found when PDBu and ATP were added together. Therefore, a dual mechanism, including both arachidonic acid metabolism and PKC, is involved in ATP-mediated mitogenesis in SMC. In addition, ATP acted synergistically with angiotensin II, phospholipase C, serotonin, or carbachol to stimulate DNA synthesis. Finally, the possible physiological significance of ATP as a mitogen in SMC was further studied. The effect of endothelin and heparin, which are released from endothelial cells, on ATP-dependent mitogenesis was investigated. Extracellular ATP acted synergistically with endothelin to stimulate a greater extent of [3H]thymidine incorporation than was seen with PDGF plus endothelin. Heparin, believed to have a regulatory role, partially inhibited the stimulation of DNA synthesis caused both by ATP and PDGF.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Extracellular ATP and ADP stimulate proliferation of porcine aortic smooth muscle cells. 135 98

The effects of neuropeptide Y (NPY) on pineal gland cyclic AMP (cAMP) accumulation were investigated using dispersed pinealocytes from rats. NPY inhibited the intracellular cAMP accumulation stimulated by isoproterenol and norepinephrine in a dose-dependent manner during a 10-min incubation of pinealocytes. NPY (1 x 10(-7) M) also inhibited vasoactive intestinal peptide (VIP)- and cholera toxin-induced cAMP accumulation. The inhibitory effect of NPY on isoproterenol-induced cAMP accumulation was completely abolished by a 5-h pretreatment of pinealocytes with 1 microgram/ml of pertussis toxin (PT). These results suggest that NPY participates in modulation of cAMP production in the rat pineal gland through PT-sensitive G protein. Yohimbine, an alpha 2-adrenergic antagonist, blocked NPY inhibition of isoproterenol-stimulated cAMP accumulation. On the other hand, the alpha 2-adrenergic agonist clonidine by itself did not affect cAMP accumulation stimulated by isoproterenol but significantly potentiated NPY action. The present study demonstrates that NPY inhibits beta-adrenergic or VIPergic stimulation of the pineal gland cAMP accumulation. The inhibitory effect of NPY is mediated through PT-sensitive G protein. Our results also suggest that NPY exerts its action to affect alpha 2-adrenoceptor function.
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PMID:Neuropeptide Y inhibits beta-adrenergic agonist- and vasoactive intestinal peptide-induced cyclic AMP accumulation in rat pinealocytes through pertussis toxin-sensitive G protein. 135 17

Vasopressin (VP) stimulates insulin secretion and inositol phosphate (InsP) production in clonal hamster beta cells (HIT) via a cyclic AMP-independent V1-receptor-mediated signal-transduction pathway. Somatostatin (SRIF) inhibited VP-stimulated insulin secretion, and the effects of SRIF were abolished by pretreatment with pertussis toxin. The Ca(2+)-channel blockers verapamil and nifedipine also inhibited VP-stimulated insulin secretion during 20 min incubations, but verapamil was ineffective at 2 min, and the effects of SRIF and nifedipine together were not addictive. SRIF failed to inhibit further the attenuated insulin response to VP in Ca(2+)-free medium. VP-stimulated InsP production was also inhibited by SRIF in a pertussis-toxin-sensitive manner. Whereas VP-stimulated insulin secretion was almost completely inhibited by SRIF at an equimolar concentration, VP-stimulated InsP production was much less sensitive to inhibition by SRIF, even at a 100-fold excess concentration. VP increased cytosolic Ca2+ in HIT cells loaded with fura 2, the fluorescent Ca2+ indicator. The increase was biphasic, with an initial rapid spike increase followed by a prolonged second phase. Both SRIF, at a concentration which inhibited VP-stimulated insulin secretion but not InsP production, and verapamil failed to inhibit the rapid spike increase in intracellular Ca2+, but did inhibit the second phase. We conclude that VP induces biphasic changes in cytosolic Ca2+, secondary to mobilization of intracellular Ca2+ and influx of extracellular Ca2+. SRIF inhibits insulin secretion by interrupting influx of extracellular Ca2+, likely by inhibiting Gi-subunit activity. Inhibition of VP-stimulated phosphoinositide hydrolysis, which is also pertussis-toxin-sensitive, may represent an additional mechanism of action of SRIF.
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PMID:Somatostatin inhibits vasopressin-stimulated phosphoinositide hydrolysis and influx of extracellular calcium in clonal hamster beta (HIT) cells. 136 25

Incubation of the C6 cells with 10 microM idazoxan (an alpha 2-adrenoceptor antagonist and putative antidepressant) for 5 days in vitro resulted in a 23% reduction of beta-adrenoceptor number and a 37% decrease in isoproterenol-induced cyclic AMP accumulation. In contrast, post-receptor stimulated cyclic AMP accumulation (by the use of forskolin or cholera toxin) was unaffected. The desensitization of the beta-adrenoceptor was accompanied by an increase in the KL/KH ratio for this receptor. Chronic in vitro treatment of C6 glioma cells with idazoxan did not significantly affect cholera or pertussis toxin catalyzed ribosylation of Gs and Gi/Go in these cells. Similarly, idazoxan did not alter either the basal levels of protein kinase C (PKC) alpha, or its cytoplasm to membrane translocation. These results suggest that idazoxan may have direct postsynaptic effects, the site of which may be at the level of receptor/G protein interaction.
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PMID:Idazoxan down-regulates beta-adrenoceptors on C6 glioma cells in vitro. 136 12

The muscarinic stimulation of adenylate cyclase activity in rat olfactory bulb was characterized, with the aim of elucidating the nature of the molecular mechanism involved. Carbachol (CCh) stimulated the enzyme activity in either crude or purified cell membrane preparations and increased cyclic AMP accumulation in miniprisms of olfactory bulb. The CCh stimulation of adenylate cyclase activity displayed a fast onset and was rapidly reversed by addition of atropine. The stimulation was associated with an increase in the apparent Vmax of the enzyme, with no change in the Km for Mg-ATP. The affinity of the enzyme for Mg2+ was enhanced by CCh. The muscarinic effect required GTP at concentrations higher than those needed for enzyme stimulation with either l-isoproterenol or vasoactive intestinal peptide. Moreover, contrary to the beta-adrenergic stimulation, the muscarinic effect disappeared when guanosine 5'-O-(3'-thiotriphosphate) was substituted for GTP. In vivo treatment of olfactory bulbs with pertussis toxin completely prevented the muscarinic stimulation of adenylate cyclase, whereas cholera toxin was without effect. These results indicate that in rat olfactory bulb muscarinic receptors increase adenylate cyclase activity by interacting with a pertussis toxin-sensitive GTP-binding protein different from the stimulatory GTP-binding protein.
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PMID:Properties of muscarinic-stimulated adenylate cyclase activity in rat olfactory bulb. 137 77

Fully-differentiated mouse 3T3-L1 fibroblasts accumulate large amounts of lipid at 7-10 days after induction by insulin or by dexamethasone and a methyl xanthine. G proteins mediate transmembrane signalling from a diverse group of cell-surface receptors to effector units that include phospholipase C, adenylyl cyclase and ion channels. They are also targets of regulation themselves. 3T3-L1 fibroblasts display marked changes in levels of G protein when induced to differentiate to adipocytes. Here we show that cholera toxin, which ADP-ribosylates and activates the G protein subunit Gs alpha, blocks the induction of differentiation, whereas increasing intracellular cyclic AMP directly with the dibutyryl analogue or indirectly with pertussis toxin or forskolin does not affect differentiation. Oligodeoxynucleotides antisense to the sequence encoding Gs alpha accelerate differentiation markedly. The time course of adipogenesis declined from 7-10 days in controls to roughly 3 days in cultures treated with antisense-Gs alpha oligodeoxynucleotides, whereas oligodeoxynucleotides, antisense to Gi alpha 1, Gi alpha 3, and sense and missense to Gs alpha, had no such effect. Antisense-Gs alpha alone induced differentiation by day 7, indicating that Gs alpha activity modulates differentiation in 3T3-L1 cells, acting in a new role which is independent of increased intracellular cAMP.
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PMID:Antisense oligodeoxynucleotides to GS protein alpha-subunit sequence accelerate differentiation of fibroblasts to adipocytes. 137 45


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