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)

Specific binding of the Ca++ antagonist desmethoxyverapamil, (-)-[3H]D888, to cell membranes of equine portal vein smooth muscle was inhibited in a concentration-dependent manner by guanosine 5'-O-(gamma-thio)triphosphate and ATP but was little affected by guanosine 5'-O-(beta-thio)diphosphate, noradrenaline or phorbol 12-myristate 13-acetate ester. Inhibition constants for GTP and ATP were in the range of 0.1 to 0.3 mM. From Scatchard plots and dissociation kinetic experiments, it is proposed that D888 high affinity binding sites are transferred into low affinity sites. In intact strips of rat portal vein bathed in physiological solution, both noradrenalin and a combination of aluminum chloride and sodium fluoride inhibited (-)-[3H]D888 binding, whereas guanosine 5'-O-(gamma-thio)triphosphate was without effect. In strips pretreated with 1 microM prazosin or 10 micrograms/ml pertussis toxin (PTX) for 6 h, noradrenalin had no effect on specific (-)-[3H]D888 binding. In addition, inhibition of (-)-[3H]D888 binding in the presence of 3 microM noradrenalin was reversed in a concentration-dependent manner by prazosin but not by propranolol. Noradrenalin-induced contractions were inhibited in a concentration-dependent manner by D888. In strips preincubated with 10 micrograms/ml PTX for 6 h, the concentration-response curve was shifted to the left, indicating that removal of the PTX sensitive transduction pathway increased D888 affinity for its specific binding sites. These results show that (-)-[3H]D888 binding to Ca++ channels is changed by GTP analogs in a way that suggests that a PTX-sensitive guanine nucleotide-binding protein may directly interact with Ca++ channels in response to activation of alpha 1 adrenoceptors.
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PMID:Guanine nucleotide-binding proteins modulate desmethoxyverapamil binding to calcium channels in vascular smooth muscle. 165 17

In intact NIH 3T3 murine fibroblasts, prostaglandins (PGs) F2 alpha and E2 induce dose-dependent stimulation of inositol monophosphate generation. PGF2 alpha is greater than 50-fold more potent than PGE2 in eliciting this response. In streptolysin O-permeabilized NIH 3T3 cells, PGF2 alpha and PGE2 induced dose-dependent accumulations of inositol bis- and trisphosphates, which were dependent on the presence of the guanine nucleotide guanosine-5'-O-(3-thio)triphosphate (GTP gamma S) (10 microM). Pretreatment of cells for 16 hr with 100 nM PGF2 alpha resulted in a significant reduction of not only subsequent PGF2 alpha- and PGE2-induced but also GTP gamma S-induced stimulation of inositol phosphate formation in permeabilized cells. PGF2 alpha-induced accumulation of inositol phosphates was partially inhibited by pretreatment with pertussis toxin (1 microgram/ml, 4 hr). The inhibition by pertussis toxin was small but was not related to cyclic AMP formation, because forskolin, which activates adenylate cyclase, did not mimic pertussis toxin-induced inhibition. In the same cell line, PGF2 alpha and PGE2 induced a dose-dependent accumulation of cAMP and a dose-dependent potentiation of 0.5 microM forskolin-stimulated cAMP formation. PGF2 alpha and PGE2 were almost equipotent in eliciting both responses. However, PGF2 alpha was less efficacious than PGE2 and, in the presence of forskolin, PGF2 alpha at 10 microM induced an inhibitory effect on cAMP accumulation. Such inhibition may be related to PGF2 alpha-mediated phospholipase C activation and subsequent stimulation of protein kinase C, because the phorbol ester phorbol 12-myristate-13-acetate, which directly activates protein kinase C, also inhibited forskolin- and PGE2-induced cAMP accumulation. Pretreatment with PGF2 alpha for 16 hr did not reduce subsequent stimulation of cAMP accumulation by PGF2 alpha or PGE2. The results indicate that in NIH 3T3 cells two receptors for PGs are present, one that couples to adenylate cyclase, probably through Gs, and does not exhibit selectivity between PGF2 alpha and PGE2 and a second receptor that couples to phospholipase C through a guanine nucleotide-binding protein that is not sensitive to pertussis toxin pretreatment. The latter shows at least 40-fold selectivity towards PGF2 alpha over PGE2. Because long treatment with PGF2 alpha resulted in desensitization of the GTP gamma S-induced response, it is possible that long exposure to PGF2 alpha may down-regulate the guanine nucleotide-binding involved in phospholipase C signal transduction.
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PMID:Prostaglandin receptors in NIH 3T3 cells: coupling of one receptor to adenylate cyclase and of a second receptor to phospholipase C. 165 2

alpha 2-Adrenergic receptor (alpha 2-AR) responses are mediated by the pertussis toxin-sensitive guanine nucleotide-binding protein (G protein) Gi. Because all three known Gi subtypes are inactivated by pertussis toxin, it has been difficult to determine which of the subtypes are involved in alpha 2-AR responses. In order to investigate alpha 2-AR/Gi coupling, we performed binding and adenylyl cyclase experiments in membranes from CHO-K1 cells transfected with the human alpha 2A-AR. Antisera directed against the carboxyl-terminal region of the Gi1/Gi2 or the Gi3 proteins were used to determine which subtypes were important for high affinity agonist binding and inhibition of adenylyl cyclase. The CHO-K1 cell membranes exhibited immunoreactivity at an apparent molecular mass of 40-41 kDa for both Gi1/Gi2 and Gi3 antisera. Western blot analysis, using purified bovine brain G proteins for comparison, demonstrated that the transfected CHO-K1 cells possess Gi2 and Gi3. High affinity guanosine 5'-(beta,gamma-imido) triphosphate-sensitive binding of the alpha 2-AR agonists [3H]bromoxidine and p-[125I]iodoclonidine ([125I]PIC) was reduced by 30-50% by either the Gi1/Gi2 or Gi3 antiserum. Bromoxidine (1 microM) and PIC (1 microM) inhibited membrane adenylyl cyclase by 34 and 27%, respectively. Gi3 antiserum reduced the inhibition by 26% and 67% for bromoxidine and PIC, respectively. The Gi1/Gi2 antiserum reduced the inhibition by 56% and 63% for bromoxidine and PIC, respectively. Furthermore, when both antisera were used together, there was a complete reversal of alpha 2-AR-mediated inhibition. These observations provide evidence of alpha 2A-AR coupling to at least two subtypes of Gi proteins and the first evidence of functional involvement of Gi3 in the inhibition of adenylyl cyclase.
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PMID:Multiple Gi protein subtypes regulate a single effector mechanism. 165 6

Pretreatment of 1321N1 human astrocytoma cells with phorbol 12-myristate-13-acetate or other activators of protein kinase C led to 2.5- to 5-fold increases (sensitization) in subsequent stimulation by forskolin of intracellular cyclic AMP accumulation. These compounds caused much smaller or no increases in receptor-mediated stimulation of cyclic AMP accumulation induced by isoproterenol and by prostaglandin E1. Carbachol and histamine, agonists acting at receptors coupled to polyphosphoinositide turnover in these cells, induced less sensitization of subsequent stimulation by forskolin but greater sensitization of stimulation by isoproterenol and by prostaglandin E1. The specificities of various analogs of phorbol 12-myristate-13-acetate, for induction of sensitization of forskolin stimulation were consistent with involvement of protein kinase C. The effects of protein kinase inhibitors and of down-regulation of protein kinase C activity also indicated involvement of protein kinase C in sensitization of forskolin stimulation, although additional mechanisms are likely to be involved in sensitization of isoproterenol stimulation. Neither pertussis toxin pretreatment nor inclusion of isobutylmethylxanthine during assays of cyclic AMP accumulation were able to prevent or mimic these sensitization phenomena, suggesting that the primary site of modification responsible for sensitization is neither the inhibitory guanine nucleotide-binding protein nor cyclic AMP phosphodiesterase. Sensitization was only observed in assays with intact cells. These results, together with those from our previous study describing protein kinase C-mediated desensitization of broken cell adenylate cyclase activity, indicate that activation of protein kinase C leads to multiple changes in the receptor-stimulated adenylate cyclase signal transduction pathway of these cells.
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PMID:Protein kinase C activators sensitize cyclic AMP accumulation by intact 1321N1 human astrocytoma cells. 168 54

The alpha subunit of the guanine nucleotide-binding protein Go ("o" for other) is believed to mediate signal transduction between a variety of receptors and effectors. cDNA clones encoding two forms of Go alpha subunit were isolated from a mouse brain library. These two forms, which we call GoA alpha and GoB alpha, appear to be the products of alternative splicing. GoA alpha differs from GoB alpha over the C-terminal third of the deduced protein sequence. Both forms are predicted to be substrates for ADP-ribosylation by pertussis toxin. GoA alpha transcripts are present in a variety of tissues but are most abundant in brain. The GoB alpha transcript is expressed at highest levels in brain and testis. It is possible that GoA alpha and GoB alpha have different functions.
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PMID:Alternative splicing produces transcripts encoding two forms of the alpha subunit of GTP-binding protein Go. 169 81

We find that half of the pertussis toxin-sensitive guanine nucleotide-binding protein (G protein) in the squid (Loligo pealei) giant axon is cytoplasmic and that this species of G protein is intermediate in size between the two forms present in axolemma. This G protein is transported toward synaptic terminals at 44 mm/day. Moreover, these data are consistent with there being two additional steps leading to the maturation of G proteins: (i) association with and transport on intracellular organelles and (ii) modification at the time of transfer to the plasmalemma resulting in a molecular weight shift. Since the other two components of G protein-mediated signal transduction pathways, receptors and effector enzymes, are known to be delivered to the synaptic terminals by fast axonal transport, our findings introduce the possibility that these three macromolecules are assembled as a complex in the cell body and delivered together to the plasma membrane of the axon and synaptic terminals.
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PMID:Pertussis toxin-sensitive G proteins are transported toward synaptic terminals by fast axonal transport. 170 7

Exposure of 1321N1 human astrocytoma cells to fresh medium containing fetal bovine serum induced a marked increase in the subsequent ability of isoproterenol and forskolin to stimulate cAMP accumulation in intact cells, compared with cells exposed to fresh medium without serum. This "sensitization" of cAMP accumulation by serum was dose dependent, occurred rapidly, was maintained in the continuing presence of serum, and reversed rapidly upon removal of serum. Preliminary characterization of the sensitizing factor(s) in serum has been performed, but the factor(s) remain to be identified. Sensitization appeared to result from an increase in maximal response and not from changes in the potency of isoproterenol or forskolin. The protein kinase C inhibitor staurosporine inhibited serum-induced sensitization. Furthermore, down-regulation of protein kinase C almost completely eliminated the subsequent ability of serum to induce sensitization, indicating involvement of protein kinase C in the serum effect. Pretreatment of cells with pertussis toxin also markedly reduced subsequent sensitization induced by serum, suggesting involvement of a pertussis toxin-sensitive guanine nucleotide-binding protein in the pathway for serum-induced sensitization. The rate of cAMP degradation was not changed in sensitized cells, but some increase in adenylyl cyclase activity was retained in broken cell preparations from sensitized cells, suggesting increased synthesis of cAMP by adenylyl cyclase as the mechanism for sensitization.
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PMID:Serum-induced sensitization of cyclic AMP accumulation in 1321N1 human astrocytoma cells. 170 72

Guanine nucleotide-binding proteins (G proteins) are key components in membrane signal transduction that may play an important role in testis function. The present study is the first description of cell-specific differences in the contents of G protein alpha-subunits and their mRNAs in isolated rat testicular cells (pachytene spermatocytes, round spermatids, Sertoli cells, peritubular cells). By using Western blot techniques G1-3 alpha was shown to be the only pertussis toxin (PTX) substrate present in all the testicular cells examined. Surprisingly, we observed a lack of immunoreactive Gi-1 alpha/Gi-2 alpha protein in pachytene spermatocytes and round spermatids in spite of significant levels of the corresponding mRNAs as revealed by Northern analysis. No immunoreactive Gs alpha was detected in germ cells, in agreement with previous findings that the hormone-sensitive adenylyl cyclase is absent in these cell types. Peritubular cells and Sertoli cells contained no Go alpha, whereas high levels of both immunoreactive protein and mRNA were found in pachytene spermatocytes. This indicates that the Go protein may play a role at this stage of spermatogenesis. The stimulation of phospholipase C (PLC) in germ cell membranes by 5'-guanylyl imidophosphate indicates that PTX-sensitive PLC activation may be mediated by Go alpha or Gi-3 alpha.
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PMID:Cell-specific expression of guanine nucleotide-binding proteins in rat testicular cells. 175 30

The effects of pertussis toxin (PT) on the growth and dimethylsulfoxide (Me2SO4)-induced differentiation of the HL-60 human promyelocytic leukemia cell line were tested. Cell growth was quantified by direct cell counts. Cell differentiation was estimated by measuring the expression of myeloid-specific cell-surface antigens (Mo-1 and fMet-Leu-Phe [fMLP] receptors), the ability of the cells to produce superoxide anions on stimulation with fMLP, the calcium ionophore A23187 and phorbol 12-myristate 13-acetate (PMA), and by monitoring the level of expression of messenger RNA (mRNA) for tumor necrosis factor alpha (TNF alpha). By itself, PT did not affect the proliferation of HL-60 cells in serum-containing medium. In contrast, PT (but not its B-oligomer) dose-dependently inhibited the Me2SO4-induced expression of Mo-1, fMLP receptors, and the oxidative responses to the chemotactic factor and to A23187, but not to PMA. The addition of Me2SO4 induced a significant increase in the steady-state levels of TNF alpha mRNA, and this effect was strongly inhibited by PT. Finally, the bacterial toxin did not reverse the block of cell division that follows the addition of Me2SO4. These results provide evidence for the involvement of a PT substrate (presumably a guanine nucleotide-binding protein) in the regulation of the maturation of the excitation-response coupling sequence in human myeloid cell precursors and show that the regulation of cell division and maturation of HL-60 cells are under distinct sets of control mechanisms.
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PMID:Pertussis toxin selectively interferes with the responses of the HL-60 human promyelocytic cell line to dimethylsulfoxide. 182 51

This study characterized the rapid desensitization induced by arginine vasopressin (AVP) in vascular smooth muscle cells (VSMC) in culture. The Ca2+ mobilization response and, in some experiments, the intracellular pH changes were used as a probe for the desensitization phenomenon. In VSMC, AVP desensitization was homologous, concentration dependent, and occurred in less than 30 s. The desensitization was complete with 10(-7) M AVP. Receptor occupancy was a critical factor in the maintenance of desensitization, since complete hormone washing by acid glycine buffer produced an earlier (less than 5 min) recovery of the cell response, whereas partial hormone washing with saline (pH 7.4) required 15 min to produce any significant recovery. Protein kinase C activation was a significant mechanism in AVP desensitization, because protein kinase C downregulation inhibited the desensitization phenomenon. Receptor internalization was, however, not important for the desensitization phenomenon, since it still occurred at 4 degrees C. Treatment with pertussis toxin did not affect the Ca2+ mobilization response but decreased the AVP-mediated intracellular alkalinization, therefore suggesting that a Gi or Go protein may be involved in some but not all the aspects of the AVP signal transduction and the desensitization phenomena.
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PMID:Mechanisms of rapid desensitization to arginine vasopressin in vascular smooth muscle cells. 182 52


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