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. G protein betagamma subunits activate the acetylcholine-induced potassium current IK,ACh. There is no evidence of specificity at the level of the betagamma subunits. Therefore all G protein-coupled receptors in atrial myocytes should be able to activate IK,ACh. Paradoxically, it is often stated that isoprenaline does not activate IK,ACh. Rationales to explain this negative result include insufficient concentrations of Gs in the atrium or restricted access of Gs-derived betagamma subunits to the IK,ACh channel. We took advantage of a non-specific increase in Gs that results after infection with adenovirus. 2. Adenoviral infection unmasked a 1 microM isoprenaline-induced IK,ACh which was prevented by propranolol. Isoprenaline occasionally activated IK,ACh in uninfected and freshly dissociated atrial myocytes but the effect was larger and more consistent in infected myocytes. 3. Pertussis toxin pretreatment (100 ng ml-1 overnight) did not block the effect of isoprenaline. The effect of isoprenaline became persistent if cells were pretreated with cholera toxin (200 ng nl-1). 4. Signal transduction events distal to adenylyl cyclase were not involved in isoprenaline-induced IK,ACh. Forskolin (10 microM) did not activate IK,ACh. Inhibition of adenylyl cyclase with cytoplasmic application of 300 microM 2'-deoxyadenosine 3'-monophosphate did not prevent the activation of IK,ACh by isoprenaline. 5. Cytoplasmic application of a betagamma binding peptide derived from the C terminus of beta-adrenergic receptor kinase 1 (50 microM) prevented the effect of isoprenaline on IK,ACh. The peptide did not prevent the stimulation of the L-type calcium current by isoprenaline. 6. The results indicate that beta-adrenoceptors can activate IK,ACh in atrial myocytes through the release of betagamma subunits from Gs.
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PMID:Isoprenaline can activate the acetylcholine-induced K+ current in canine atrial myocytes via Gs-derived betagamma subunits. 985 23

We investigated the involvement of muscarinic M1 receptors in the regulation of action potentials, and its modulation by adrenergic signaling and its change by aging in mouse isolated right atria using a conventional glass microelectrode technique. In adult mice, acetylcholine (ACh) (3-10 microM) reduced the maximum upstroke velocity of action potential (Vmax) followed by an increase. In electrically driven atria, similar effects of ACh on Vmax were observed. McN-A-343 (100-300 microM), a M1 agonist, reduced Vmax, while M2 agonist oxotremorine (0.1-0.3 microM), increased it. Isoproterenol (3 nM), antagonized ACh- and McN-A-343-induced reduction of Vmax, and potentiated the ACh- and oxotremorine-induced increase. The effects of isoproterenol were mimicked by cholera toxin, a Gs-protein activator, and forskolin, a direct activator of adenylyl cyclase. H-89, a selective protein kinase-A inhibitor, abolished the antagonism by isoproterenol of ACh-induced reduction in Vmax. Calphostin C, a selective protein kinase-C inhibitor, but not pertussis toxin attenuated ACh-induced reduction in Vmax. These results show that 1) ACh-induced reduction of Vmax and its subsequent increase are mediated by the activation of muscarinic M1 and M2 receptors, respectively, 2) the M1 and M2 subtypes may exert a balancing action on each other, and 3) the beta-adrenergic activation antagonizes M1-mediated effects, and enhances M2-mediated effects, on Vmax. In young mice, ACh (5-10 microM) increased Vmax, which was abolished by AF-DX 116 (0.3 microM), a M2 antagonist. In aged mice, ACh did not affect Vmax up to a concentration of 10 microM. The present findings may be of importance in the occurrence of cardiac disfunction in aging.
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PMID:[The involvement of muscarinic M1 receptor in the regulation of action potentials in mouse isolated right atria]. 1019 Jan 49

We investigated the effects of R(-)-1-(benzo[b]thiophen-5-yl)-2-[2-(N,N-diethylamino)ethoxy]ethan ol hydrochloride (T-588), a novel cognitive enhancer, on trimeric GTP-binding proteins (G proteins) and cyclic AMP accumulation in rat cerebral cortex. T-588 (0.1-1.0 mM) inhibited the ADP-ribosylation of alpha subunit of Gs in a concentration-dependent manner. Auto-ADP-ribosylation of CTX was not inhibited by T-588. The stimulatory effect of guanosine 5'-(3-O-thio)triphosphate (GTPgammaS) on CTX-catalyzed ADP-ribosylation was attenuated by adding T-588 in assay mixture. ADP-ribosylation of Gi/Go by pertussis toxin was slightly inhibited by T-588. Isoproterenol-stimulated cyclic AMP accumulation was inhibited by adding 3 mM T-588 to rat cerebral cortical slices. Next, we investigated the effects of isoproterenol and T-588 on GTPgammaS binding. Membranes were first incubated with or without isoproterenol and T-588 in the presence of 0.2mM GTPgammaS, then cholate extract preparations were prepared from the washed membranes. Interestingly, the [32P]ADP-ribosylation of G(s alpha) was enhanced not only by isoproterenol but also by T-588. Although the obtained results are apparently inconsistent, T-588 seems to interact with G proteins, specifically Gs.
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PMID:Effects of T-588, a novel cognitive enhancer, on ADP-ribosylation of G(s alpha) by cholera toxin and cyclic AMP accumulation in rat cerebral cortex. 1021 74

ADP-ribosyl cyclase activities in cultured rat astrocytes were examined by using TLC for separation of enzymatic products. A relatively high rate of [3H]cyclic ADP-ribose production converted from [3H]NAD+ by ADP-ribosyl cyclase (2.015+/-0.554 nmol/min/mg of protein) was detected in the crude membrane fraction of astrocytes, which contained approximately 50% of the total cyclase activity in astrocytes. The formation rate of [3H]ADP-ribose from cyclic ADP-ribose by cyclic ADP-ribose hydrolase and/or from NAD+ by NAD glycohydrolase was low and enriched in the cytosolic fraction. Although NAD+ in the extracellular medium was metabolized to cyclic ADP-ribose by incubating cultures of intact astrocytes, the presence of Triton X-100 in the medium for permeabilizing cells increased cyclic ADP-ribose production three times as much. Isoproterenol and GTP increased [3H]cyclic ADP-ribose formation in crude membrane-associated cyclase activity. This isoproterenol-induced stimulation of membrane-associated ADP-ribosyl cyclase activity was confirmed by cyclic GDP-ribose formation fluorometrically. This stimulatory action was blocked by prior treatment of cells with cholera toxin but not with pertussis toxin. These results suggest that ADP-ribosyl cyclase in astrocytes has both extracellular and intracellular actions and that signals of beta-adrenergic stimulation are transduced to membrane-bound ADP-ribosyl cyclase via G proteins within cell surface membranes of astrocytes.
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PMID:Membrane-bound form of ADP-ribosyl cyclase in rat cortical astrocytes in culture. 1064 18

Targeted cardiac overexpression of the alpha-subunit of the heterotrimeric G protein G(q) in transgenic mice evokes hypertrophy and depressed stimulation of cardiac inotropy and chronotropy by beta-adrenergic receptor (betaAR) agonists in vivo, which is a hallmark of many forms of experimental and human heart failure. The molecular basis of this betaAR dysfunction was explored in transgenic mice overexpressing G(alphaq) approximately 5-fold over background. Isoproterenol-stimulated adenylyl cyclase activities in myocardial membranes were significantly depressed in G(alphaq) mice compared with nontransgenic controls (19.7 +/- 2.6 versus 43.7 +/- 5. 6 pmol/min/mg) without a decrease in betaAR expression levels. Functional coupling of both betaAR subtypes was impaired. Similarly, in whole-cell patch-clamp studies, betaAR stimulation of L-type Ca(2+) channel currents was depressed approximately 75% in the G(alphaq) mice. Cardiac betaAR from these mice showed decreased formation of the active high-affinity conformation (R(H) = 29% versus 62% for nontransgenic littermates), confirming a receptor-G(s)-coupling defect. Of the three candidate kinases that might impose this uncoupling by receptor phosphorylation (protein kinase A, betaAR kinase, protein kinase C), only protein kinase C activity was elevated in G(alphaq) mouse hearts. Type V adenylyl cyclase was decreased approximately 45% in these mice, consistent with decreased basal, NaF, and forskolin-stimulated enzyme activities. Although cellular G(s) levels were unaltered, G(i2) and G(i3) were increased in G(alphaq) mice. Pertussis toxin treatment of isolated G(alphaq) myocytes resulted in an improvement in betaAR, but not that of forskolin or NaF, stimulation of adenylyl cyclase. Thus three distinct mechanisms contribute to impaired betaAR function by in vivo G(q) signaling cross-talk in myocytes. Because many elements of hypertrophy and/or failure in cellular and animal models can be initiated by increased G(alphaq) signaling, the current work may be broadly applicable to interfaces whereby modification of heart failure might be considered.
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PMID:Mechanisms of impaired beta-adrenergic receptor signaling in G(alphaq)-mediated cardiac hypertrophy and ventricular dysfunction. 1064 37

1. We used large conductance Ca2+-activated K+ (BKCa) channel activity as a probe to characterize the inhibitory/stimulatory G protein (Gi/Gs) signalling pathways in intact cells from pregnant (PM) and non-pregnant (NPM) myometrium. 2. Isoprenaline (10 microM) enhanced the outward current (Iout) in PM cells and inhibited Iout in NPM cells. Additional application of the alpha2-adrenoceptor (alpha2-AR) agonist clonidine (10 microM) further enhanced the isoprenaline-modulated Iout in PM cells but partially antagonized Iout in NPM cells. Clonidine alone did not affect Iout. The specific cAMP kinase (PKA) inhibitor H-89 (1 microM) abolished the effects of isoprenaline and clonidine. The specific BKCa channel blocker iberiotoxin (0.1 microM) inhibited Iout by approximately 80 %; the residual current was insensitive to isoprenaline. 3. Inhibition of Gi activity by either pertussis toxin or the GTPase activating protein RGS16 abolished inhibitory as well as stimulatory effects of clonidine on Iout. 4. Transducin-alpha, a scavenger of Gi betagamma dimers, converted the stimulatory action of clonidine on Iout into an inhibitory effect. Free transducin-betagamma enhanced both the stimulatory and the inhibitory effects of isoprenaline on Iout. 5. The results demonstrate that BKCa channel activity is a sensitive probe to follow adenylyl cyclase-cAMP-PKA signalling in myometrial smooth muscle cells. Both Gialpha-mediated inhibition and Gibetagamma-mediated stimulation can occur in the same cell, irrespective of pregnancy. It is speculated that the coupling between alpha2-AR and Gi proteins is more efficient during pregnancy and that Gibetagamma at high levels simply override the inhibitory action of Gi alpha.
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PMID:Pregnancy switches adrenergic signal transduction in rat and human uterine myocytes as probed by BKCa channel activity. 1076 16

Brain natriuretic peptide (BNP) gene expression and chronic activation of the sympathetic nervous system are characteristics of the development of heart failure. We studied the role of the beta-adrenergic signaling pathway in regulation of the human BNP (hBNP) promoter. An hBNP promoter (-1818 to +100) coupled to a luciferase reporter gene was transferred into neonatal cardiac myocytes, and luciferase activity was measured as an index of promoter activity. Isoproterenol (ISO), forskolin, and cAMP stimulated the promoter, and the beta(2)-antagonist ICI 118,551 abrogated the effect of ISO. In contrast, the protein kinase A (PKA) inhibitor H-89 failed to block the action of cAMP and ISO. Pertussis toxin (PT), which inactivates Galpha(i), inhibited ISO- and cAMP-stimulated hBNP promoter activity. The Src tyrosine kinase inhibitor PP1 and a dominant-negative mutant of the small G protein Rac also abolished the effect of ISO and cAMP. Finally, we studied the involvement of M-CAT-like binding sites in basal and inducible regulation of the hBNP promoter. Mutation of these elements decreased basal and cAMP-induced activity. These data suggest that beta-adrenergic regulation of hBNP is PKA independent, involves a Galpha(i)-activated pathway, and targets regulatory elements in the proximal BNP promoter.
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PMID:Isoproterenol and cAMP regulation of the human brain natriuretic peptide gene involves Src and Rac. 1082 15

Basal contractility and responses to beta-adrenoceptor activation are compromised in hearts from rats with chronic portal vein stenosis. Here we report the effect of partial ligation of the portal vein on myocardial G protein expression, beta-adrenoceptor-G protein coupling, and excitation-contraction coupling (ECC). Contractility (dT/dt) was reduced 30-50% in right and left ventricles, but the rate of relaxation (-dT/dt) was unaffected. Isoproterenol-induced positive inotropism was diminished, but there was no difference in ED(50). The concentration-dependent increase in -dT/dt was unaffected. G(s)alpha and G(i)alpha expression, cholera toxin- and pertussis toxin-induced ADP-ribosylation, and formation of the agonist-receptor-G(s) complex were unaffected by portal vein stenosis. Of the components of ECC examined, the caffeine-sensitive sarcoplasmic reticulum Ca(2+) pool was reduced 35%, although the Ca(2+) uptake and release processes were unchanged; the apparent density of L-type Ca(2+) channels decreased 60% with no change in affinity; the dihydropyridine Ca(2+) channel agonist BAY K 8644 produced relative changes in dT/dt that were similar in both groups, suggesting normal function in the remaining Ca(2+) channels; and Na(+)/Ca(2+) exchange was reduced 50% in the portal vein stenosis group. These data suggest that the effect of portal vein stenosis on the myocardium is the result of alterations to ECC.
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PMID:Cardiac excitation-contraction coupling in the portal hypertensive rat. 1089 44

We investigated whether selective beta(1)-adrenoceptor stimulation causes hypertrophic growth on isolated ventricular cardiomyocytes from adult rat. As parameters for the induction of hypertrophic growth, the increases of [(14)C]phenylalanine incorporation, protein and RNA mass, and cell size were determined. Isoproterenol (Iso, 10 microM) alone had no growth effect. In the presence of the beta(2)-adrenoceptor antagonist ICI-118551 (ICI, 10 microM), Iso caused an increase in [(14)C]phenylalanine incorporation, protein and RNA mass, cell volume, and cross-sectional area. We showed for phenylalanine incorporation that the growth effect of Iso+ICI could be antagonized by beta(1)-adrenoceptor blockade with atenolol (10 microM) or metoprolol (10 microM), indicating that it was caused by selective beta(1)-adrenoceptor stimulation. The growth response to Iso+ICI was accompanied by an increase in ornithine decarboxylase (ODC) activity and expression. Inhibition of ODC by the ODC antagonist difluoromethylornithine (1 mM) attenuated this hypertrophic response, indicating that ODC induction is causally involved. The growth response to Iso+ICI was found to be cAMP independent but was sensitive to genistein (100 microM) or rapamycin (0.1 microM). The reaction was enhanced in the presence of pertussis toxin (10 microM). We conclude that selective beta(1)-adrenoceptor stimulation causes hypertrophic growth of ventricular cardiomyocytes by a mechanism that is independent of cAMP but dependent on a tyrosine kinase and ODC.
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PMID:Hypertrophic effect of selective beta(1)-adrenoceptor stimulation on ventricular cardiomyocytes from adult rat. 1091 16

Parathyroid hormone (PTH) sensitive adenylyl cyclase activity (ACA) in SaOS-2 cells varies as a function of cell passage. In early passage (EP) cells (< 6), ACA in response to PTH and forskolin (FOR) was relatively low and equivalent, whereas in late passage (LP) cells (> 22), PTH exceeded FOR dependent ACA. Potential biochemical mechanisms for this passage dependent change in ACA were considered. In EP, prolonged exposure to pertussis toxin (PT) markedly enhanced ACA activity in response to PTH, Isoproterenol and Gpp(NH)p, whereas ACA in response to FOR was decreased. In contrast, the identical treatment of LP with PT diminished all ACA in response to PTH, Gpp(NH)p, and FOR. The dose dependent effects of PT on subsequent [(32)P]ADP-ribosylation of its substrates, GTPase activity, as well as FOR-dependent ACA, were equivalent in EP and LP. The relative amounts of G(alpha)i and G(alpha)s proteins, as determined both by Western blot, PT and cholera toxin (CT) dependent [(32)P]ADP-ribosylation, were quantitatively similar in EP and LP. Western blot levels of G(alpha)s and G(alpha)i proteins were not influenced by prior exposure to PT. Both PT and CT dependent [(32)P]ADP-ribosylation were dose-dependently decreased following exposure to PT. However, the PT-dependent decline in CT-dependent [(32)P]ADP-ribosylation occurred with enhanced sensitivity in LP. The protein synthesis inhibitor cycloheximide partially reversed the PT associated decrease in FOR dependent ACA in EP. In contrast, cycloheximide completely reversed the PT associated decrease in FOR and as well as PTH dependent ACA in LP. G(alpha)s activity, revealed by cyc(-) reconstitution, was not altered either by cell passage or exposure to PT. The results suggest that the coupling between the components of the complex may be pivotally important in the differential responsiveness of early and late passage SaOS-2 cells to PTH.
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PMID:PTH-dependent adenylyl cyclase activation in SaOS-2 cells: passage dependent effects on G protein interactions. 1220 75


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