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. Desensitization of the myocardial beta-adrenergic signal transduction pathway is an important mechanism which is involved in the progression of hypertensive heart disease. The aim of the present study was to evaluate the differential effects of chronic pharmacotherapy with an angiotensin converting enzyme (ACE)-inhibitor, an AT1-receptor antagonist and a direct vasodilator on blood pressure, cardiac hypertrophy and the beta-adrenergic signal transduction. Therefore, transgenic TG(mREN2)27 (TG) rats overexpressing the mouse renin gene were used. This strain is characterized by the development of fulminant hypertension with cardiac hypertrophy. 2. Seven week old heterozygous TG(mREN2)27 rats were treated for 11 weeks with the AT1-receptor antagonist losartan (10 mg kg[-1]), the ACE-inhibitor quinapril (15 mg kg[-1]) and the direct vasodilator hydralazine (30 mg kg[-1]). Untreated TG and normotensive Sprague-Dawley rats (SD) served as controls. 3. TG(mREN2)27-rats were characterized by arterial hypertension (TG 194+/-3.2 mmHg vs SD 136+/-2.9 mmHg systolic blood pressure), increased left ventricular weights (TG 4.3+/-0.3 vs SD 3.0+/-0.1 mg g(-1) body weight), decreased myocardial neuropeptide Y (NPY) concentrations (TG 1143+/-108 vs SD 1953+/-134 pg g(-1) wet weight), reduced beta-adrenoceptor densities (TG 51.1+/-1.9 vs SD 63.4+/-3.7 fmol mg[-1]) as assessed by [125I]-cyanopindolol binding studies, and increased Gi(alpha)-activities (TG 4151+/-181 vs SD 3169+/-130 densitometric units) as assessed by pertussis toxin catalyzed [32P]-ADP-ribosylation. Downregulation of beta-adrenoceptors and increased Gi(alpha) were accompanied by significantly reduced isoprenaline-, Gpp(NH)p- and forskolin-stimulated adenylyl cyclase activity. Catalyst activity as determined by forskolin plus Mn2+ co-stimulation of adenylyl cyclase did not differ between TG(mREN2)27- and SD control-rats. 4. Losartan and quinapril significantly restored systolic blood pressures, left ventricular weights, beta-adrenoceptor densities, myocardial neuropeptide Y-concentrations, adenylyl cyclase activities and Gi(alpha)-activities towards the values in Sprague-Dawley-controls. No differences were observed between the effects of quinapril- and losartan-treatment. In contrast, hydralazine had only minor effects on blood pressure reduction, regression of left ventricular hypertrophy and neuroeffector defects in TG(mREN2)27. 5. In conclusion, direct vasodilatation is not able to overcome the pathophysiological alterations in TG caused by transgene overexpression. In contrast, ACE-inhibitors and AT1-receptor antagonists, which inhibit the renin angiotensin system, equally exert beneficial effects on blood pressure, myocardial hypertrophy and neuroeffector mechanisms. Modulation of the sympathetic tone and resensitization of the beta-adrenergic signal transduction system may contribute to the special effectiveness of these drugs in the treatment of the hypertensive cardiomyopathy.
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PMID:Effects of quinapril, losartan and hydralazine on cardiac hypertrophy and beta-adrenergic neuroeffector mechanisms in transgenic (mREN2)27 rats. 950 80

We have investigated at the single-cell level how the human LH receptor mediates a dose-responsive increase in intracellular free calcium-ion concentrations ([Ca2+]i). In human embryonic kidney cells (293 cells) stably transfected with the full-length human LH receptor cDNA. Intact dimeric LH, but not LH beta- or alpha-subunits, evoked specific [Ca2+]i signals. High-resolution fluorescence (fura-2) video-microscopy demonstrated cell-to-cell variability in [Ca2+]i signaling responses in individual cells, viz., an all-or-none spike (9%), spike-and-plateau (25%), or plateau (52%) types of temporal signal. Oscillatory [Ca2+]i responses were observed in 12-14% of LH-stimulated cells unrelated to LH concentration. The LH dose-response originated by higher concentrations of LH recruiting more individually responding cells (rather than altering [Ca2+]i signal amplitude), and eliciting a [Ca2+]i rise more rapidly, i.e., at reduced latency. Cobalt did not abolish the LH-stimulated [Ca2+]i spike-and-plateau response, but decreased the percentage of cells with a plateau pattern. Quench experiments demonstrated influx of Mn2+ following the [Ca2+]i spike, thus directly documenting divalent cation inflow during the plateau phase. Adenylyl-cyclase activation with forskolin or treatment with a cAMP analog failed to elicit the biphasic [Ca2+]i response, and pertussis toxin (PTX) did not alter LH-stimulated [Ca2+]i signaling. However, overnight preincubation with LH reduced the percentage of [Ca2+]i-responding cells following re-exposure to LH to 5.7% (vs 72% in control), suggesting LH-induced desensitization of the LH-receptor directed [Ca2+]i signal. In summary, the present studies of human LH receptor signal transduction at the single-cell level show that increasing concentrations of LH achieve a dose-dependent intracellular Ca2+ signaling response by recruiting an increasing number of [Ca2+]i-responding cells, while concomitantly decreasing the temporal latency of the biphasic [Ca2+]i signal without altering the amplitude of its spike phase. Prolonged exposure to LH appears to desensitize the LH receptor-driven [Ca2+]i signal.
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PMID:Recruitment of individually (all-or-none) responding cells, rather than amplitude enhancement, is the single-cell mechanism subserving the dose-responsive activation of intracellular calcium second messenger signaling by the human luteinizing-hormone receptor. 954 48

During Ca2+-activated C- current oscillations a mechanical deformation of the Xenopus laevis oocyte by a fluid stream evokes transient inward currents of high amplitude (stream evoked inward current, Ii,st). This current can be observed either in native or RNA-injected oocytes expressing ligand-controlled ion channels from rat brain. Ii,st reversed at the equilibrium potential of chloride and was blocked by 9-anthracene carboxylic acid (2 mM). Power spectral analysis of the oscillations did not reveal a correlation between the features of the oscillations and the amplitude of Ii,st. Antagonists of stretch-activated cation channels [gadolinium (100 microM) and lanthanum (1mM)] did not block Ii,st. Calcium channel blockers [cobalt and manganese (10 mM)] did not inhibited Ii,st and Ii,st could also be elicited in calcium-free medium. Preloading oocytes with pertussis toxin (PTX) for 17 h prevented current oscillations and Ii,st caffeine (10 mM), an antagonist of the liberation of calcium from intracellular stores, inhibited Ii,st. Our results proride evidence for modulation of the mechanosensitivity of chloride currents by activation of intracellular second messenger cascades.
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PMID:Characterization of ion currents elicited by a stream of fluid during spontaneous and ligand-induced chloride current oscillation in Xenopus laevis oocytes. 956 Apr 46

Guanine nucleotide regulatory proteins (G-proteins) play an important role in the onset and progression of malignancy. We hypothesized that alterations in inhibitory G-protein (Gi) expression and/or function may contribute to cellular invasion and formation of hepatocellular carcinoma (HCC). H4IIE hepatoma cells were inoculated directly into the liver parenchyma of ACI strain rats, and membranes were prepared from HCC livers and adjacent nonneoplastic livers 12 days following the initial inoculation. Expression of inhibitory Gialpha proteins was determined by Western blot analysis and changes in the functional activity of these proteins confirmed by pertussis toxin catalyzed ADP ribosylation and adenylyl cyclase activity. Inhibitory Gialpha1, Gialpha1/2, and Gialpha3 protein expression was significantly elevated in HCC when compared to adjacent nonneoplastic liver and sham-operated hepatic tissue. Pertussis toxin catalyzed ADP ribosylation of Gialpha substrates was significantly enhanced in HCC concomitant with increased basal and stimulated adenylyl cyclase activity following uncoupling of Gi-proteins with manganese ions. The role of Gi-proteins in cellular proliferation was confirmed using cultured H4IIE cells and normal hepatocytes. In quiescent H4IIE cells, mastoparan (Gialpha activator) increased [3H] thymidine incorporation and cell growth in a dose-dependent manner, whereas both pertussis toxin (a Gi-protein inhibitor) and 8-bromo-cAMP inhibited mitogenesis. In contrast, in isolated cultured hepatocytes, mastoparan inhibited [3H] thymidine incorporation, while pertussis toxin and 8-bromo-cAMP were mitogenic. We conclude that HCC is associated with marked changes in Gialpha-protein expression in vivo and in vitro, direct activation of which leads to increased mitogenesis in H4IIE cells in vitro.
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PMID:Altered expression of inhibitory guanine nucleotide regulatory proteins (Gi-proteins) in experimental hepatocellular carcinoma. 957 74

The present study elucidated the precise mechanism of 5-hydroxytryptamine (5-HT)-induced increase of intracellular Ca2+ concentration ([Ca2+]i) in cultured vascular smooth muscle cells isolated from rat aortic media. [Ca2+]i was measured using fluorescent Ca2+ indicator, fura-2. 5-HT caused a dose-dependent increase in [Ca2+]i, which was completely inhibited by ketanserin. alpha-Methyl-5-HT had an equipotent effect to 5-HT. Diltiazem at 10 microM partially suppressed the 5-HT-induced increase in [Ca2+]i. 5-HT also augmented Mn2+ influx, when monitored by Mn2+ quenching of fura-2 fluorescence. When extracellular Ca2+ (1.3 mM) was removed, a decrease in resting level and a small, transient increase in [Ca2+]i were observed. 5-HT stimulation also induced an increase in the production of inositol triphosphate. 5-HT-induced increase in [Ca2+]i was significantly, but partially inhibited by staurosporin and H-7. Phorbol 12-myristate 13-acetate induced an increase in [Ca2+]i, which was abolished by removal of extracellular Ca2+. 5-HT-induced increase in [Ca2+]i was not affected by the pretreatment with pertussis toxin (PTX), and was not accompanied by a change in cyclic AMP content. These results suggest that, in cultured rat aortic smooth muscle cells, 5-HT increases [Ca2+]i via 5-HT2 receptor subtype by inducing influx of extracellular Ca2+ partially through L-type voltage-dependent Ca2+ channel, as well as by mobilizing Ca2+ from its intracellular stores. Activation of protein kinase C may be positively involved in the regulatory mechanism of Ca2+ influx, but PTX-sensitive G protein and cyclic AMP seem to be not involved.
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PMID:Effect of 5-hydroxytryptamine on intracellular calcium dynamics in cultured rat vascular smooth muscle cells. 959 25

Muscarinic receptor regulation of guanine nucleotide turnover on Gi/Go proteins in ventricular sarcolemma was investigated. In the absence of a muscarinic receptor (MR) agonist, GTP bound to background sites with a Kapp value of 60 nM and a Bmax of 50 pmol/mg. The addition of the MR agonist, carbachol, further increased GTP binding by 50 pmol/mg to sites with the same Kapp value of 60 nM. Pertussis toxin treatment reduced GTP binding to carbachol-regulated and background binding sites, thus identifying both sites as Gi/Go. The identity of the carbachol-regulated GTP binding sites was further confirmed by demonstrating that carbachol stimulated GTP binding and inhibited adenylyl cyclase with an EC50 value of 200 nM. Background and carbachol-regulated guanine nucleotide binding sites bound GDP with a Kapp value of 150 nM. However, maximal background GDP binding was 50 pmol/mg, whereas maximal carbachol-regulated GDP binding was only 12-15 pmol/mg. In sarcolemma preloaded with [3H]GDP, carbachol-regulated [3H]GDP release was strictly dependent on the presence of guanine nucleotides. The Kapp values for GTP and GDP to support carbachol-regulated [3H]GDP release were 60 nM and 150 nM, respectively. Guanosine 5'-O-(3-thiotriphosphate) (GDPbetaS) facilitated carbachol-regulated [3H]GDP release with a Kapp value of 2 microM. However, GTP was two times more efficacious than GDP or GDPbetaS in facilitating carbachol-regulated [3H]GDP release. Mn2+ also stimulated [3H]GDP release from carbachol-regulated sites by a mechanism not requiring guanine nucleotides. These studies indicate that two pools of muscarinic receptors, carbachol regulated and spontaneously active, regulate guanine nucleotide turnover on pertussis toxin sensitive Gi/Go. These studies further suggest that guanine nucleotide binding provides the signal to stimulate GDP release from receptor activated Gi/Go proteins. A quaternary mechanism involving G-protein interactions may be necessary to promote guanine nucleotide exchange on Gi/Go.
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PMID:Regulation of guanine nucleotide turnover on Gi/Go by agonist-stimulated and spontaneously active muscarinic receptors in cardiac membranes. 988 28

The sphingosine derivatives sphingosylphosphorylcholine (SPC) and sphingosine-1-phosphate (S1P) caused a similar elevation of the intracellular Ca2+ concentration ([Ca2+]i) in an immortalized airway epithelial cell line (CFNP9o-) incubated in Ca(2+)-free medium. The maximal effect was obtained with 2 microM SPC and 0.1 microM S1P and was sensitive to pre-incubation with pertussis toxin, indicating the involvement of a Gi/G(o) type of G protein. In Ca2+ containing medium, [Ca2+]i elevation by SPC was significantly higher than that by S1P, due to the fact that SPC was able to stimulate Mn2+ entry, whereas S1P was ineffective. SPC, but not S1P, caused a dose-dependent production of total inositol phosphates. Conversely, S1P, but not SPC, increased the level of phosphatidic acid. These findings suggest the presence of two distinct receptors, specific for SPC and S1P, respectively. Depletion of intracellular Ca2+ stores by SPC makes cells unable to respond to a subsequent addition of S1P. Conversely, cells do respond to SPC after a challenge with S1P, suggesting that the two receptors likely share one or more intracellular signalling component(s).
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PMID:Sphingosylphosphorylcholine and sphingosine-1-phosphate mobilize cytosolic calcium through different mechanisms in human airway epithelial cells. 992 30

For most, if not all, organisms, iron (Fe) is an essential element. In response to the nutritional requirement for Fe, bacteria evolved complex systems to acquire the element from the environment. The genes encoding these systems are often coordinately regulated in response to the Fe concentration. Recent investigations revealed that Bordetella avium, a respiratory pathogen of birds, expressed a number of Fe-regulated genes (T. D. Connell, A. Dickenson, A. J. Martone, K. T. Militello, M. J. Filiatraut, M. L. Hayman, and J. Pitula, Infect. Immun. 66:3597-3605, 1998). By using manganese selection on an engineered strain of B. avium that carried an Fe-regulated alkaline phosphatase reporter gene, a mutant was obtained that was affected in expression of Fe-regulated genes. To determine if Fe-dependent regulation in B. avium was mediated by a fur-like gene, a fragment of the B. avium chromosome, corresponding to the fur locus of B. pertussis, was cloned by PCR. Sequencing revealed that the fragment from B. avium encoded a polypeptide with 92% identity to the Fur protein of B. pertussis. In vivo experiments showed that the cloned gene complemented H1780, a fur mutant of Escherichia coli. Southern hybridizations and PCRs demonstrated that the manganese mutant had a deletion of 2 to 3 kbp of nucleotide sequence in the region located immediately 5' of the fur open reading frame. A spontaneous PCR-derived mutant of the B. avium fur gene was isolated that encoded a Fur protein in which a histidine was substituted for an arginine at amino acid position 18 (R18H). Genetic analysis showed that the R18H mutant gene when cloned into a low-copy-number vector did not complement the fur mutation in H1780. However, the R18H mutant gene was able to complement the fur mutation when cloned into a high-copy-number vector. The cloned wild-type fur gene will be useful as a genetic tool to identify Fur-regulated genes in the B. avium chromosome.
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PMID:Genetic characterization of wild-type and mutant fur genes of Bordetella avium. 1033 37

Pretreatment of mouse brain membranes with arachidonic acid (AA) and related unsaturated fatty acids at 30 degrees C for 10 min decreased basal activity and isoproterenol/guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S)- and forskolin-stimulated activities of adenylyl cyclase to a level less than 5% of control. The presence of the carboxyl group on the fatty acids was essential for the inhibition, because no such inhibition was found with ethyl arachidonate or AA attached to diacylglycerols and phospholipids. The AA-mediated inhibition was observed when the activity was measured in the presence of Mn2+ or forskolin and was insensitive to pertussis toxin or guanosine 5'-O-(2-thiodiphosphate) (GDPbetaS), indicating a mechanism independent of GTP-binding proteins. In addition, the fact that stimulators of the adenylyl cyclase catalytic unit, ATP, GTP gamma S and forskolin, when present during pretreatment, attenuate the inhibitory effect of AA may suggest that the catalytic unit is a target of AA. Bovine serum albumin suppressed the inhibition when present in the mixtures for pretreatment, but could not restore the adenylyl cyclase activity that had been reduced by AA, indicating an irreversible inhibition by AA. The effect of AA was found to be additive to P-site-mediated inhibition. The present study suggests the existence of another mechanism of regulation of adenylyl cyclase by unsaturated fatty acids.
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PMID:Inhibition of adenylyl cyclase activity in brain membrane fractions by arachidonic acid and related unsaturated fatty acids. 1137 Jun 73

We investigated the effect of manganese on the morphology of cultured rat cortical astrocytes. Astrocytes exhibited flattened, polygonal morphology in the absence of stimulation, and differentiated into process-bearing stellate cells following exposure to MnCl(2). MnCl(2)-induced stellation was a reversible process, which depended on the presence of extracellular free manganese. MnCl(2)-induced stellation did not stop with the introduction of pertussis toxin, PD98059, SB203580, phorbol 12-myristat 13-acetate, SQ22536, or LY83583. Alternatively, MnCl(2)-induced stellation did stop when exposed to colchicine and sodium orthovanadate, suggesting the involvement of the cytoskeletal elements and orthovanadate-sensitive protein tyrosine phosphatase. MnCl(2) might function as a factor regulating astrocyte morphology.
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PMID:Manganese stimulates stellation of cultured rat cortical astrocytes. 1174 2


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