Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the expression of the gene fragments encoding the enzymatically active portion of three bacterial cytotoxins: exotoxin A (ETA) of Pseudomonas aeruginosa, and pertussis toxin (PT) and adenylate cyclase toxin (CYA) of Bordetella pertussis, in sensitive mammalian target cells. Expression of active ETA and CYA was lethal to the producing cells and stable transfectants of Cos-1 cells containing the corresponding genes could not be obtained. The expression of the PTS1 subunit was tolerated by the producing mammalian cells. Since PT is cytotoxic because of ADP-ribosylation of G-proteins, we assume that the endogenously expressed PTS1 may not find the cellular target G proteins or PTS1 alone may not be sufficient for ADP-ribosylation of these proteins in vivo.
Mol Microbiol 1992 Sep
PMID:Expression of bacterial cytotoxin genes in mammalian target cells. 144 74

The basis for the hypersensitive response of glycogen phosphorylase to epinephrine stimulation was investigated in adult rat cardiomyocytes isolated from normal and alloxan-diabetic animals. To assess potential G-protein involvement in the response, normal and diabetic derived myocytes were incubated with either cholera or pertussis toxin prior to hormonal stimulation. Pretreatment of cardiomyocytes with cholera toxin resulted in a potentiated response to epinephrine stimulation whereas pertussis toxin did not affect the activation of this signaling pathway. To determine if the enhanced response of phosphorylase activation resulted from an alteration in adenylate cyclase activation, the cells were challenged with forskolin. After 3 hr in primary culture, diabetic cardiomyocytes exhibited a hypersensitive response to forskolin stimulation relative to normal cells. However, after 24 hr in culture, both normal and diabetic myocytes responded identically to forskolin challenge. The present data suggest that a cholera toxin sensitive G-protein mediates the hypersensitive response of glycogen phosphorylase to catecholamine stimulation in diabetic cardiomyocytes and this response which is present in alloxan-diabetic cells and is induced in vitro in normal cardiomyocytes is primarily due to a defect at a post-receptor site.
Mol Cell Biochem 1992 Nov 04
PMID:Post-receptor defect accounts for phosphorylase hypersensitivity in cultured diabetic cardiomyocytes. 148 Jan 65

Previous studies from our laboratory have suggested that diabetes-associated central nervous system abnormalities are characterized by progressive alterations of neurotransmitters and of transductional Gi/Go proteins. In this study, we have further characterized these abnormalities in the striatum of alloxan-diabetic rats by means of adenosine 5'-diphosphate (ADP)-ribosylation, and Western and Northern blotting techniques. Fourteen weeks after diabetes induction, pertussis-toxin (PTX) catalyzed ADP-ribosylation of Gi/Go proteins was markedly reduced in diabetic animals, as shown by a clear decrease of 32P-ADPribose incorporation into G protein alpha subunits. In agreement with our previous pharmacological studies that showed a reduction of Gi-mediated modulation of adenylate cyclase activity only at this stage of diabetes, no changes in PTX-mediated ADP-ribosylation were observed earlier (5-wk diabetes). Immunoblotting studies performed by using antibodies selectively raised against Gi-2, Go, and Gs proteins did not reveal any differences between control and diabetic animals at any stage of diabetes. Similarly, the mRNAs corresponding to the alpha subunits of Gi-2, Go, and Gs proteins did not show any marked changes in chronic diabetic rats with respect to control animals. It is therefore concluded that diabetes is associated with development of a time-related alteration of cerebral Gi/Go proteins and that this defect is not owing to gross changes in either content of G proteins or mRNA level, but probably reflects modifications of G protein's structure or physiological status affecting the coupling with membrane effector systems and the sensitivity to PTX.
Mol Chem Neuropathol 1992 Dec
PMID:Diabetes-induced alterations of central nervous system G proteins. ADP-ribosylation, immunoreactivity, and gene-expression studies in rat striatum. 149 84

Inhibition of insulin secretion from rat islets of Langerhans is known to involve at least one pertussis toxin-sensitive guanine-nucleotide binding (G) protein. We have used antisera raised against unique antigenic determinants of different members of the family of pertussis toxin-sensitive G proteins to identify these proteins in rat islets. Antiserum SG1, which recognizes both Gi1 and Gi2, reacted with an islet protein having an approximate Mr of 40,000. Antiserum I1C (Gi1 specific) failed to recognize any islet proteins, suggesting that Gi2 is present in much greater amounts than Gi1. Indeed, Gi1 levels were below the detection limit of a sensitive immunogold/silver-staining method, indicating that it may be absent from the cells of rat islets. Two different antisera were used to identify Go-like G proteins in rat islet homogenates. Both antisera reacted with a protein band which, under appropriate conditions, could be resolved to reveal two separate proteins of Mr 39-40,000. Thus, at least two molecular forms of Go are present in rat islets. Subcellular fractionation indicated that all three G proteins identified in this study (Gi2 and two forms of Go) are localized to islet membranes. No immunoreactivity could be detected in the cytosolic fraction.
J Mol Endocrinol 1992 Apr
PMID:Immunological characterization of the guanine-nucleotide binding proteins Gi and Go in rat islets of Langerhans. 151 16

Angiotensin II (AT) receptor subtypes (AT1, selectively displaced by DuP 753, and AT2, selectively displaced by PD123177 and CGP42112A) were characterized by quantitative autoradiography after incubation with the AT agonist 125I-Sar1-AT, in specific brain nuclei of young (2-week-old) rats. Binding to AT1 receptors was sensitive (decreased affinity) to incubation in the presence of guanosine 5'-O-(3-thio)triphosphate (GTP gamma S). Only the AT1 receptors in the paraventricular nucleus were sensitive to pertussis toxin, indicating the possibility of the existence of AT1 receptor subtypes. The sensitivity of AT2 receptors to GTP gamma S was heterogeneous. In the ventral thalamic and medial geniculate nuclei and in the locus coeruleus, binding to AT2 receptors was sensitive to GTP gamma S and to pertussis toxin pretreatment. Conversely, in the inferior olive, binding was insensitive to GTP gamma S and to pertussis toxin pretreatment. We propose the nomenclature of AT2A receptors for those receptors sensitive to guanine nucleotides and pertussis toxin and that of AT2B receptors for those showing no sensitivity to guanine nucleotides or pertussis toxin treatment.
Mol Pharmacol 1992 Feb
PMID:Heterogeneity of angiotensin II AT2 receptors in the rat brain. 153 9

Guanine nucleotide-binding regulatory proteins play key intermediary roles in regulating zona pellucida-mediated acrosomal exocytosis in mouse and bull sperm. Since human sperm possess a Gi-like protein and undergo the acrosome reaction in response to the human zona pellucida, we investigated whether this G protein plays a regulatory role in this exocytotic process. Zonae pellucidae isolated from eggs that had been inseminated but had shown no signs of fertilization after retrieval for in vitro fertilization and embryo transfer were pooled into groups of greater than or equal to 50 in order to reduce variability in biological responses due to the possible presence of ZP that had undergone modifications associated with the polyspermy block. Acid-solubilized zonae pellucidae were incubated with capacitated sperm, and the sperm then assessed for the acrosome reaction using both the P. sativum agglutinin and chlortetracycline fluorescence assays; both assays gave similar results. Sperm incubated with solubilized zonae pellucidae at a final concentration of 2, 4, or 6 ZP/microliter underwent acrosomal exocytosis to a similar extent as compared with A-23187. Sperm were incubated with 1 microgram/ml pertussis toxin during capacitation to functionally inactivate the Gi-like protein. Pertussis toxin treatment of sperm did not affect sperm motility and the ability of the cells to bind to structurally intact zonae pellucidae. Pertussis toxin, however, completely inhibited the percentage acrosome reactions induced by solubilized zonae pellucidae. By contrast, the A-23187-induced acrosome reaction was insensitive to PT treatment. Pertussis toxin inhibition of the zona pellucida-induced acrosome reaction occurred in a concentration-dependent manner with maximal effects observed at 100 ng/ml PT.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Reprod Dev 1992 Jan
PMID:A guanine nucleotide-binding regulatory protein in human sperm mediates acrosomal exocytosis induced by the human zona pellucida. 156 31

Mammalian sperm possess a guanine nucleotide-binding regulatory protein (G protein), with properties similar to Gi, that appears to be involved in the signal transduction pathway required for zona pellucida (ZP)-mediated acrosomal exocytosis. Mouse sperm treated with pertussis toxin (PT), a toxin that functionally inactivates Gi proteins, bind to the ZP of mouse eggs but are inhibited from undergoing acrosomal exocytosis. We have measured high-affinity GTPase activity and GTP gamma [35S] binding in mouse sperm homogenates incubated in the absence and presence of ZP glycoproteins isolated from either ovulated eggs or from ovarian homogenates to determine whether this extracellular matrix can activate the sperm-associated Gi protein. An increase in GTP hydrolysis (approximately 50% over basal activity) and GTP gamma [35S] binding (approximately 25-60% over basal activity) is observed when sperm homogenates are incubated in the presence of solubilized ZP glycoproteins, and the increase in GTPase activity is dependent on the concentration of ZP added to the homogenates. Accompanying this increase is a reduction in the ability of PT to catalyze in vitro [32P]ADP-ribosylation of a Mr = 41,000 sperm Gi protein, suggesting that the increase in GTPase activity and GTP gamma [35S] binding is associated with the activation of a PT-sensitive sperm G protein(s). The ability of the ZP to stimulate high-affinity GTPase activity in these homogenates appears to be dependent on the capacitation state of the sperm from which the homogenates are prepared. These data suggest that a component(s) of the ZP may function in a manner similar to that of other ligands by binding to a sperm surface-associated receptor and subsequently activating a G protein coupled to an intracellular signal transduction cascade(s) required for induction of acrosomal exocytosis.
Mol Reprod Dev 1992 Apr
PMID:Activation of a G protein in mouse sperm by the zona pellucida, an egg-associated extracellular matrix. 157 Nov 63

To determine whether a cloned receptor coupled to pertussis toxin (PTx)-sensitive G-proteins can induce cell proliferation and oncogenic transformation, as observed for receptors that elicit PTx-insensitive enhancement of phosphatidyl inositol (PI)-specific phospholipase-C (PLC) activity, nontransformed murine BALB/c-3T3 cells were transfected with the rat serotonin-1A (5-HT1A) receptor. The 5-HT1A receptor is coupled to PTx-sensitive G-proteins to induce a cell-specific activation of PLC. While 1 microM 5-HT induced no change in PI turnover or cytosolic free calcium levels ([Ca2+]i) in receptor-negative nontransfected 3T3 cells, 5-HT induced a 2-fold increase in inositol trisphosphate accumulation and a 2.5-fold increase in [Ca2+]i in the 3T3-ZD8 clone, which expressed 0.6 +/- 0.2 pmol/mg protein of specific 5-HT1A binding sites. The stimulatory actions of 5-HT on PI turnover and [Ca2+]i in 3T3ZD8 cells displayed the pharmacology of the 5-HT1A receptor and were abolished by pretreatment with PTx. Thus, BALB/c-3T3 fibroblast cells express the PLC-linked pathway of the 5-HT1A receptor. Overnight treatment with 5-HT (1 microM) enhanced incorporation of [3H]thymidine into DNA extracted from serum-starved 3T3ZD-8 cells, an action that was also blocked by pretreatment with pertussis toxin. Long term (1-2 weeks) exposure to 5-HT in the medium led to phenotypic transformation of the cells, including the formation of foci with 1 microM 5-HT. These actions of 5-HT were not observed in untransformed 3T3 cells. We conclude that the PTx-sensitive PLC-linked pathway of the 5-HT1A receptor expressed in nontransformed BALB/c-3T3 cells, in concert with other serum-derived factors, predisposes the cells to enhanced proliferation and transformation.
Mol Endocrinol 1992 May
PMID:Conditional transformation mediated via a pertussis toxin-sensitive receptor signalling pathway. 160 83

We have examined the phosphorylation and protein kinase activity of p44 mitogen-activated protein kinase (p44mapk) in growth factor-stimulated hamster fibroblasts using a specific antiserum. The activity of p44mapk was stimulated both by receptor tyrosine kinases and G protein-coupled receptors. Detailed kinetics revealed that alpha-thrombin induces a biphasic activation of p44mapk in CCL39 cells: a rapid phase appearing at 5-10 min was followed by a late and sustained phase still elevated after 4 h. Inactivation of alpha-thrombin with hirudin after 30 sec, which prevented DNA synthesis, did not alter the early p44mapk response but completely abolished the late phase. Pretreatment of the cells with pertussis toxin, which inhibits by more than 95% alpha-thrombin-induced mitogenicity, resulted in the complete loss of late phase activity, while the early peak was partially attenuated. Treatment of CCL39 cells with basic fibroblast growth factor also induced a strong activation of p44mapk. Serotonin, which is not a mitogen by its own, had no effect on late phase p44mapk activity, but synergized with basic fibroblast growth factor to induce late kinase response and DNA synthesis. Both early and late phase activation of p44mapk were accompanied by tyrosine phosphorylation of the enzyme. Together, the results indicate that there is a very close correlation between the ability of a growth factor to induce late and sustained p44mapk activation and its mitogenic potential. Therefore, we propose that sustained p44mapk activation is an obligatory event for growth factor-induced cell cycle progression.
Mol Endocrinol 1992 May
PMID:Biphasic and synergistic activation of p44mapk (ERK1) by growth factors: correlation between late phase activation and mitogenicity. 160 90

Acute myocardial ischaemia frequently is complicated by ventricular tachyarrhythmias. These arrhythmias are in part due to an increased susceptibility of myocardial cells to adenylyl cyclase stimulation by catecholamines [1]. As adenylyl cyclase underlies an endogenous dual regulation by stimulatory and inhibitory receptor systems, adenylyl cyclase stimulation can be counteracted by the activation of receptors like the muscarinic M2 receptor [2]. Therefore, the effect of myocardial ischaemia on muscarinic receptor and "inhibitory" guanine nucleotide binding proteins (G(i)) mediated inhibition of adenylyl cyclase was studied. During 5 min of myocardial ischaemia, carbachol mediated inhibition of forskolin and isoproterenol stimulated adenylyl cyclase was reduced by 30% and 50%, respectively. Hormone independent inhibition of adenylyl cyclase by the nonhydrolyzable GTP-analogue guanosine 5'-[beta gamma-imido]triphosphate (Gpp(NH)p) was reduced by 46%. In contrast, the amount of G(i), as determined by pertussis toxin catalyzed ADP-ribosylation, remained constant during 15 min of ischaemia. The impaired function of muscarinic receptor linked signal transduction during early myocardial ischaemia could contribute to the occurrence of ischaemia induced tachyarrhythmias by a reduced ability to counteract adenylyl cyclase activation.
J Mol Cell Cardiol 1992 May
PMID:Reduced adenylyl cyclase inhibition by carbachol and GTP during acute myocardial ischaemia. 163 72


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>