UMLS:C0043167 - FACTA Search

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An adrenal cGMP-stimulated phosphodiesterase (cGS-PDE) has been shown to mediate atrial natriuretic peptide (ANP)-induced reductions in aldosterone secretion and cAMP levels in primary bovine glomerulosa cells. High concentrations of cGS-PDE have been localized to the zona glomerulosa cell layer of the adrenal cortex using biochemical and immunological techniques. Immunoblot analysis using an affinity-purified, isozyme-specific antiserum revealed a single band that comigrated with a purified cGS-PDE (105 kDa) (1) and that was most highly concentrated in the outermost 1-2 mm of the cortex, representing the capsule and zona glomerulosa regions. Greater than 90% of the overall phosphodiesterase activity present in tissue extracts prepared from these regions was immunoprecipitated using a solid-phase monoclonal antibody reagent, indicating the cGS-PDE as the predominant phosphodiesterase isozyme. Immunohistochemical staining experiments of frozen thin sections of intact adrenal tissue revealed that the cGS-PDE present in this region was localized in the glomerulosa cells themselves. The role of this isozyme as a mediator of ANP-induced decreases in intracellular cAMP concentrations and aldosterone production was tested in primary cultures of bovine adrenal glomerulosa cells. In cells stimulated by ACTH, ANP treatment produced dose-dependent reductions in aldosterone secretion and cellular cAMP content over the same concentration range. Increases in aldosterone production elicited by three cell-permeable cAMP derivatives (8-bromo-cAMP, 8-p-chlorophenylthio-cAMP, and N6-2'-O-dibutyryl-cAMP) were antagonized by ANP, indicating a site of action distal to adenylate cyclase for this hormone. Because the relative magnitude of the ANP effect differed depending upon the derivative used, the three derivatives were compared with respect to their relative rates of in vitro hydrolysis by adrenal cGS-PDE. A positive correlation between their rates of hydrolysis and the degree to which the steroidogenic response produced by these derivatives was antagonized by ANP was demonstrated, further suggesting an ANP-induced activation of the cGS-PDE as being responsible for this effect. The possible contribution of an additional pathway mediated by an inhibitory guanine nucleotide binding regulatory protein (Gi) acting on adenylate cyclase was tested by pretreatment of primary glomerulosa cells with pertussis toxin. Levels of pertussis toxin sufficient to inhibit subsequent in vitro ribosylation did not significantly alter the ANP effect on aldosterone production, although a partial reduction in the ANP effect on cAMP levels was observed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:High concentrations of a cGMP-stimulated phosphodiesterase mediate ANP-induced decreases in cAMP and steroidogenesis in adrenal glomerulosa cells. 184 62

The formation of the second messenger cyclic AMP (cAMP) is known to be coupled to its receptor via a guanine nucleotide regulatory protein, GS. Ca2+-mobilizing receptors stimulate the hydrolysis of phosphatidylinositol bisphosphate (PtdIns(4,5)P2), which generates two intracellular signals Ins(1,4,5)P3 and diacylglycerol. We review the evidence that this signalling system is also composed of three types of proteins: receptor, G-protein and effector. The G-protein that couples to the effector, polyphosphoinositide phosphodiesterase (PPI-PDE), is a novel G-protein, GP, which is a substrate for pertussis toxin in some cells (e.g. neutrophils and platelets) but not others (e.g. pancreatic acinar cells and GH3 cells). This implies that GP is not a single G-protein but encompasses a family of proteins that can activate PPI-PDE. We have also identified a role for another G-protein, GE, which is involved in the secretory process in mast cells and neutrophils. In this case, neither the receptor nor effector has been identified and the main evidence for proposing this second G-protein is based on the ability of guanine nucleotide analogues (e.g. GTP gamma S) to stimulate secretion independently of PPI-PDE activation.
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PMID:G-proteins, the inositol lipid signalling pathway, and secretion. 290 37

Alterations of receptor-G-protein-regulated adenylyl cyclase activity have been suggested to represent an important alteration leading to contractile dysfunction in the failing human heart. Recent experiments suggest that the beta 1-adrenoceptor (beta 1 AR) density and mRNA levels are reduced, while beta 2-adrenoceptors and stimulatory G-proteins are unchanged (mRNA and protein level). Functional assays demonstrated that the catalyst of the adenylyl cyclase is not different between failing and nonfailing myocardium. Inhibitory G-proteins are increased (pertussis toxin substrates, protein and mRNA) and correlate to the reduced inotropic effects of beta-adrenoceptor agonists and of cAMP-PDE inhibitors. Gi alpha-coupled m-cholinoceptors and A1-adrenergic receptors are unchanged in density and affinity. Stimulation of these receptors resulted in an unchanged antiadrenergic effect on force of contraction. In conclusion, a downregulation of beta 1 AR and an increase of Gi alpha have been observed as signal transduction alteration in failing human myocardium. These alterations are due to alterations of gene expression in the failing heart and are related to a defective regulation of force of contraction in heart failure.
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PMID:Alterations of beta-adrenoceptor-G-protein-regulated adenylyl cyclase in heart failure. 749 44

We studied the effect of several compounds that influence different cell activation steps on platelet-activating factor (PAF)-induced basophil histamine secretion. Isobutylmethylxanthine (1-100 microM), dimaprit (1-100 microM) and dibutyryl adenosine 3',5'-cyclic phosphate (cAMP; 0.01-1 mM), that increase intracellular cAMP levels, concentration-dependently inhibited PAF-elicited histamine release. Rolipram (phosphodiesterase, PDE, isotype IV inhibitor; 0.1 nM-10 microM) potently inhibited histamine secretion activated by PAF, whereas SKF95654 (PDE III inhibitor; 0.01-10 microM) was ineffective. The kinase inhibitor, staurosporine (0.1-100 nM), enhanced PAF-induced basophil histamine release, whereas the G-protein inhibitor, pertussis toxin (1 microgram/ml), had an inhibitory effect. The specific lipoxygenase inhibitor, AA-861 (0.1-10 microM), inhibited PAF-activated histamine release, while the leukotriene A4 hydrolase inhibitor, bestatin (100 microM), had only a marginal effect. Finally, the Ca2+ channel entry blockers, verapamil (3-30 microM) and zinc (1.5-50 microM), inhibited PAF-induced histamine release. These results suggest that PAF is a unique secretagogue for human basophils unlike antigen, anti-IgE or univalent stimuli.
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PMID:Pharmacologic control of histamine release from human basophils induced by platelet-activating factor. 769 3

Treating rats with pertussis toxin (PTX) both elevated the adipocyte cAMP levels and impaired sensitivity and responsiveness to the antilipolytic effect of insulin in the presence of different beta-adrenergic agonists. However, in the presence of a fixed medium concentration of the degradable cAMP analogue, 8-bromo-cAMP, the effect of insulin was similar in PTX- and control cells. Elevating the cAMP levels in control cells either through different concentrations of the cAMP analogue or addition of adenosine deaminase impaired both insulin sensitivity and responsiveness to a similar extent as that seen in PTX-treated cells. The antilipolytic effect of insulin was exerted through the activation of the cGMP-inhibitable phosphodiesterase (cGI-PDE) as it was dose-dependently impaired by the specific cGI-PDE inhibitor OPC 3911. The results show the importance of the cellular cAMP levels in modulating insulin sensitivity and action. Gi plays a minor role, if any, for the signal transduction of the antilipolytic effect of insulin.
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PMID:Cellular cyclic AMP levels modulate insulin sensitivity and responsiveness--evidence against a significant role of Gi in insulin signal transduction. 821 2

Endothelin-1 (ET) and ATP mobilize Ca2+ in rat C6 glioma cells by stimulating phosphoinositide turnover. Both agents also inhibit adenylyl cyclase (AC) activity in C6 glioma cells. The goal of this study was to characterize the molecular mechanisms responsible for the inhibition of AC activity. The administration of either ET, ATP, A23187, or thapsigargin to cells simultaneously with isoproterenol for 5 min inhibited isoproterenol-stimulated cAMP synthesis by a maximum of 60%, 91%, 65%, and 68%, respectively. Pretreatment of cells with pertussis toxin (PTX) did not alter the inhibitory effects of A23187 or thapsigargin, whereas the inhibitory effects of ET or ATP were completely eliminated. Removal of extracellular Ca2+ and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'- tetraacetic acid acetoxymethyl ester treatment failed to affect the inhibition caused by ET or ATP, whereas the inhibition caused by A23187 or thapsigargin was completely eliminated in Ca(2+)-free medium and was attenuated by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester treatment. The inhibition by both receptor agonists in the earlier phase (30 sec) of the AC reaction was, however, reduced by using either Ca(2+)-free medium or PTX pretreatment. The administration of 3-isobutyl-1-methylxanthine or Ro 20-1724 suggested that the inhibitory effects of A23187 and thapsigargin were partially due to Ca(2+)-dependent stimulation of PDE activity. Short term treatment with phorbol-12-myristate-13-acetate (PMA) had no effect on isoproterenol-stimulated AC activity. However, the inhibition of cAMP induced by ET or ATP, but not by A23187 or thapsigargin, was diminished by PMA, suggesting that the receptor signal via Gi was blocked by PMA treatment. The antagonistic effect of PMA was blocked by staurosporine. All four agents still inhibited AC activity in cells that had been treated with PMA for 24 hr to deplete protein kinase C. ET produced an additional decrease in AC activity in cells that had been treated with a maximally effective concentration of A23187 or thapsigargin. The ET- or ATP-induced decrease in cAMP levels showed homologous desensitization. These results demonstrate that ETZ receptors and ATP receptors in C6 glioma cells inhibit AC activity primarily by interaction with a PTX-sensitive G(i) and partially by elevation of [Ca(2+)]. Protein kinase C activation is not responsible for agonist-induced inhibition of AC but appears to uncouple the G(i)/AC system activated by ET or ATP.
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PMID:Endothelin- and ATP-induced inhibition of adenylyl cyclase activity in C6 glioma cells: role of Gi and calcium. 834 Dec 70

The effect of adenosine analogues on glucagon-stimulated cyclic AMP accumulation in rat hepatocytes was explored. N6-Cyclopentyladenosine (CPA), 5'-N-ethylcarboxamidoadenosine and N6-(R-phenylisopropyl)adenosine inhibited in a dose-dependent manner the cyclic AMP accumulation induced by glucagon. This effect seems to be mediated through A1 adenosine receptors. Pertussis toxin completely abolished the effect of CPA on glucagon-stimulated cyclic AMP accumulation in whole cells which suggested that a pertussis-toxin-sensitive G-protein was involved. On the other hand, this action of adenosine analogues on glucagon-induced cyclic AMP accumulation was reverted by the selective low-Km cyclic AMP-phosphodiesterase inhibitor Ro 20-1724. Analysis of cyclic AMP-phosphodiesterase activity in purified hepatocyte plasma membranes showed that glucagon in the presence of GTP inhibited basal PDE activity by 45% and that CPA reverted this inhibition in dose-dependent manner. In membranes derived from pertussis-toxin-treated rats, we observed no inhibition of cyclic AMP-phosphodiesterase activity by glucagon in the absence or presence of CPA. Our results indicate that in hepatocyte plasma membranes, stimulation of adenylate cyclase activity and inhibition of a low-Km cyclic AMP phosphodiesterase activity are co-ordinately regulated by glucagon, and that A1 adenosine receptors can inhibit glucagon-stimulated cyclic AMP accumulation by blocking glucagon's effect on phosphodiesterase activity.
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PMID:Cross-talk between glucagon- and adenosine-mediated signalling systems in rat hepatocytes: effects on cyclic AMP-phosphodiesterase activity. 855 17

The cGMP phosphodiesterase from retinal rods (PDE-6) is an alphabetagamma2 heterotetramer. The alpha and beta subunits contain catalytic sites for cGMP hydrolysis, whereas the gamma subunits serve as a protein inhibitor of the enzyme. Visual excitation of photoreceptors enables the activated GTP-bound form of the G-protein transducin to remove the inhibitory action of the gamma subunit, thereby triggering PDE-6 activation. The type 5 phosphodiesterase (PDE-5) isoform shares a number of similar characteristics with PDE-6, including binding of cGMP to noncatalytic sites, the cyclic nucleotide specificity, and inhibitor sensitivities. Although the functional role of PDE-5 remains unclear, it has been shown to be activated by protein kinase A (PKA) (Burns, F., Rodger, I. W. & Pyne, N. J. (1992) Biochem. J. 283, 487-491). Here we report that both the recombinant gamma subunit and a peptide corresponding to amino acids 24-46 in this protein inhibited the activation of PDE-5 by PKA. Furthermore, immunoblotting airway smooth muscle membranes with a specific antibody against amino acids 24-46 of the PDE-6 gamma subunit identified two major immunoreactive small molecular mass proteins of 14 and 18 kDa (p14 and p18). These appear to form a complex with PDE-5, because PDE activity was immunoprecipitated using antibody against the PDE-6 gamma subunit. p14 and p18 were also substrates for phosphorylation by a unidentified kinase that was stimulated by a pertussis toxin-sensitive G-protein. Phosphorylation of p14/p18 in membranes treated with guanine nucleotides correlated with a concurrent reduction in the activation of PDE-5 by PKA. We suggest that p14 and p18 share an epitope common to PDE-6 gamma and that this region may interact with PDE-5 to prevent its activation by PKA.
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PMID:The regulation of the cGMP-binding cGMP phosphodiesterase by proteins that are immunologically related to gamma subunit of the photoreceptor cGMP phosphodiesterase. 921 82

1. We have previously shown that nitric oxide (NO) production is essential for cholinergic inhibition of the beta-adrenergic stimulated L-type calcium current (ICa-L) in rabbit pacemaker (sino-atrial node (SAN)) cells. The present experiments demonstrate the presence of constitutive nitric oxide synthase (cNOS) in SAN cells, and characterize the NO-mediated cholinergic response. 2. Immunohistochemical staining, using an antibody prepared against endothelial cNOS, demonstrated that this enzyme was present in single myocytes obtained from the SAN. 3. The activation of cNOS is known to be Ca2+ and calmodulin dependent. Strongly buffering intracellular Ca2+ with the membrane-permeable chelator BAPTA-AM (10 microM) significantly reduced (and in some cases abolished) the attenuation of ICa-L by the muscarinic agonist carbamylcholine (CCh). In contrast, the CCh-induced activation of an outward K+ current, IK,ACh, was unaffected by buffering of [Ca2+]i. The calmodulin inhibitor 48/80 (20 microM) also abolished the attenuation of ICa-L by CCh, with no change in the activation of IK,ACh. 4. Neither thapsigargin nor ryanodine (5-10 microM), agents which deplete intracellular Ca2+ stores, significantly changed the attenuation of ICa-L by CCh. 5. Pertussis toxin (PTX) completely abolished both the inhibitory action of CCh on ICa-L and the activation of IK,ACh. This establishes that a PTX-sensitive GTP-binding protein links the muscarinic receptor to NO synthase activation in SAN cells. 6. Our hypothesis is that NO leads to activation of a cyclic GMP (cGMP)-activated phosphodiesterase (PDE II) as a mechanism for enhanced cyclic AMP breakdown and ICa-L attenuation. This was supported by showing that a specific inhibitor of PDE II, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), blocks the effect of CCh on ICa-L, but not on IK,ACh. Using reverse transcriptase-polymerase chain reaction techniques, we have established that PDE II is the dominant cyclic nucleotide phosphodiesterase isoform in SAN cells.
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PMID:Characteristics of nitric oxide-mediated cholinergic modulation of calcium current in rabbit sino-atrial node. 959 96

The gut hormone, glucagon-like peptide-1 (GLP-1), which is secreted in nanomolar amounts in response to nutrients in the intestinal lumen, exerts cAMP/protein kinase A-mediated insulinotropic actions in target endocrine tissues, but its actions in heart cells are unknown. GLP-1 (10 nmol/L) increased intracellular cAMP (from 5.7+/-0.5 to 13.1+/-0.12 pmol/mg protein) in rat cardiac myocytes. The effects of cAMP-doubling concentrations of both GLP-1 and isoproterenol (ISO, 10 nmol/L) on contraction amplitude, intracellular Ca(2+) transient (CaT), and pH(i) in indo-1 and seminaphthorhodafluor (SNARF)-1 loaded myocytes were compared. Whereas ISO caused a characteristic increase (above baseline) in contraction amplitude (160+/-34%) and CaT (70+/-5%), GLP-1 induced a significant decrease in contraction amplitude (-27+/-5%) with no change in the CaT after 20 minutes. Neither pertussis toxin treatment nor exposure to the cGMP-stimulated phosphodiesterase (PDE2) inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine or the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine nor the phosphatase inhibitors okadaic acid or calyculin A unmasked an ISO-mimicking response of GLP-1. In SNARF-1-loaded myocytes, however, both ISO and GLP-1 caused an intracellular acidosis (DeltapH(i) -0.09+/-0.02 and -0.08+/-0.03, respectively). The specific GLP-1 antagonist exendin 9-39 and the cAMP inhibitory analog Rp-8CPT-cAMPS inhibited both the GLP-1-induced intracellular acidosis and the negative contractile effect. We conclude that in contrast to beta-adrenergic signaling, GLP-1 increases cAMP but fails to augment contraction, suggesting the existence of functionally distinct adenylyl cyclase/cAMP/protein kinase A compartments, possibly determined by unique receptor signaling microdomains that are not controlled by pertussis toxin-sensitive G proteins or by enhanced local PDE or phosphatase activation. Furthermore, GLP-1 elicits a cAMP-dependent modest negative inotropic effect produced by a decrease in myofilament-Ca(2+) responsiveness probably resulting from intracellular acidification.
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PMID:Glucagon-like peptide-1 increases cAMP but fails to augment contraction in adult rat cardiac myocytes. 1153 95

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