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)

Adenylyl cyclases are under positive and negative control by guanine nucleotides and hormones. Stimulatory responses are mediated by a guanine nucleotide- and Mg-binding regulatory component (Ns), a protein that has been purified to homogeneity. Inhibitory responses have been hypothesized to be mediated by an analogous regulatory component (Ni) distinct from Ns, but definitive proof for this is lacking and these effects may result from modulation of Ns activity. Recently, Bordetella pertussis toxin has been shown to ADP-ribosylate a peptide that is not part of Ns, and this coincides with attenuation of hormonal inhibition of adenylyl cyclase. We show here that cyc- S49 cells contain a substrate for ADP-ribosylation by pertussis toxin and that the toxin alters GTP dependent inhibition of cyc- adenyl cyclase activity. As cyc- S49 cells do not contain Ns by several criteria, we conclude that Ni is a distinct and separate regulatory component of adenylyl cyclase.
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PMID:Stimulation and inhibition of adenylyl cyclases mediated by distinct regulatory proteins. 630 Jun 94

Previous investigations have shown that the adhesion of T. cruzi plasma membrane vesicles (PMV) to monolayers of host cell myoblasts and to immobilized heart muscle sarcolemma membranes (PAM) on polyacrylamide beads is mediated by the interaction of T. cruzi attachment sites with the muscarinic cholinergic and beta-adrenergic receptors of the host cell membrane. It has also been shown that this interaction is blunted by the specific antagonists of the mammalian receptors atropine and propranol, respectively. In the studies reported here, PAM also rapidly attached to swimming T. cruzi trypomastigotes in a complex, concentration-dependent fashion and binding isotherms showed that the equilibrium between free and bound PAM is rapidly reached within 2 minutes of incubation in physiologically balanced salt solutions. In this time frame, trypomastigote cAMP levels are significantly reduced from steady state values within 30 seconds of the addition of PAM in a buffer system containing a diesterase inhibitor. Maximal attenuation of cAMP levels was measured between 1 and 2 minutes of the addition of PAM to T. cruzi trypomastigotes. The degree of cAMP level attenuation was reduced by blocking PAM attachment with either atropine or propranol. On the basis of these results we propose that a likely pathway for the negative parasite signal generated upon adhesion of host muscle cell membranes to the surface of the flagellates is from the parasite's surface attachment sites directly to a Pertussis toxin sensitive inhibitory protein Gi, thereby blunting adenyl cyclase activity and cAMP formation.
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PMID:Attenuation of parasite cAMP levels in T. cruzi-host cell membrane interactions in vitro. 753 43

In a search for new alpha-subunits of trimeric GTP-binding proteins in human platelets, we prepared leucocyte-free platelet concentrates and analyzed total RNA for areas homologous to known alpha-subunits. RT-PCR based on two degenerate primers revealed the expected band of 495 base pairs and an additional band of 540 base pairs reflecting the alternative splice product of Gs alpha. Following subcloning in pGEM-T vector and sequencing, we identified the alpha-subunits Gi alpha-2 and Gs alpha-S of the regulating GTP-binding proteins of adenyl cyclase as well as Gz alpha whose function is unknown, confirming earlier immunological identification. In addition, we identified Gs alpha-L (differing from Gs alpha-S by an insertion of 45 base pairs), G16 alpha, (a member of the pertussis toxin insensitive Gq-family), and two new variants of both Gs alpha-S and Gs alpha-L each containing a C-A-G triplet. With G16 we have identified another candidate for pertussis-toxin insensitive signal transduction in platelets. The C-A-G containing sequences of Gs alpha lead to an insertion of a Ser-residue, which results in the consensus sequence of a phosphorylation site for protein kinase C (Ser-X-Lys), making these variants candidates for protein kinase C-sensitive cyclic AMP formation.
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PMID:Identification of alpha-subunits of trimeric GTP-binding proteins in human platelets by RT-PCR. 754 94

Defective vasodilator function could be important in the pathogenesis and/or maintenance of the hypertensive state and the predisposition of the elderly to hypertension. Impaired beta-adrenergic-mediated vasodilation and reduced lymphocyte beta-adrenergic activation of adenyl cyclase have been demonstrated both in aging and with hypertension. The cellular mechanisms responsible for these alterations remain unclear. To determine if these defects may be due to alterations in guanine nucleotide regulatory proteins (G proteins) that link receptor activation with effector function, we assessed (1) human lymphocyte adenyl cyclase activity, (2) stimulatory G proteins by cholera toxin-mediated [32P]ADP ribosylation and, in hypertensive subjects, with alpha s-specific and beta-subunit antisera, and (3) inhibitory G proteins by pertussis toxin-mediated [32P]ADP ribosylation and, in older subjects, with alpha i,1,2- and beta-subunit-specific antisera. Lymphocytes from older subjects and from hypertensive subjects demonstrated a comparable reduction in isoproterenol-stimulated adenyl cyclase. However, aluminum fluoride-stimulated activity was reduced only in lymphocytes from hypertensive subjects. Furthermore, aluminum fluoride-stimulated activity was inversely correlated with mean arterial pressure. In lymphocytes from younger hypertensive subjects, cholera toxin-mediated labeling was significantly increased. In contrast, inhibitory G protein labeling by immunodetection was unaltered. In lymphocytes from older subjects, cholera toxin-mediated labeling was not altered; however, pertussis toxin-mediated labelling was significantly increased. In contrast, inhibitory G protein labeling by immunodetection was unaltered. Overall, the study suggests alterations of G protein function of adenyl cyclase is impaired. However, these defects are associated with divergent alterations in stimulatory and inhibitory G proteins.
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PMID:G protein alterations in hypertension and aging. 759 Oct 10

We have previously described a novel human B cell differentiation factor (BCDF), 446-BCDF, that is distinct biochemically and functionally from other cytokines. Since signal transduction pathways involved in human B cell differentiation have been incompletely studied and are poorly understood, we assessed the effects of 446-BCDF on various intracellular second messenger systems. After exposure of B cells to 446-BCDF, intracellular cAMP concentration started to decrease at 5 min and was significantly lower at 30 min and reached the lowest level at 4 hr. In most cases, cAMP concentrations returned toward baseline by 24 hr. A cAMP analog (dibutyryl cAMP), a stimulator of adenyl cyclase (forskolin), and phosphodiesterase inhibitors (aminophylline and IBMX) which inhibited the 446-BCDF-induced decrease in intracellular cAMP, inhibited 446-BCDF-induced B cell differentiation, suggesting that the fall in intracellular cAMP was a critical event in this process. To understand the mechanism involved in the reduction of cAMP, B cells were treated with pertussis toxin (PTX), a Gi protein inhibitor. Pertussis toxin blocked 446-BCDF-induced B cell differentiation as well, suggesting that 446-BCDF may function by stimulation of a Gi-linked receptor resulting in the inhibition of adenylate cyclase with a consequent reduction in cAMP. Other cytokines known to promote Ig secretion (IL2 and IL6) also caused a reduction in cAMP, suggesting that this pathway may be generally important in B cell differentiation. Taken together, these data suggest that at least one pathway of terminal maturation in B cells may involve the reduction of intracellular cAMP.
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PMID:B cell differentiation factor-induced B cell maturation: regulation via reduction in cAMP. 770 10

Properties of marmot (Marmota flaviventris) myocardial beta-adrenergic receptor complex (beta-AR) were evaluated during hibernation (H), in summer (S) animals, and in animals aroused from hibernation (C). The results obtained for S and C animals were identical, and only the results for C animals are shown. In H-animal myocardial membrane preparations assayed at 37 degrees C, isoproterenol-dependent adenylate cyclase activity (ACA) was consistently higher, whereas the synergistic contribution of 5'-guanylylimidodiphosphate [Gpp(NH)p] in this reaction was reduced. When assayed at 10 degrees C, only the ACA in H animals responded to the combination of isoproterenol and Gpp(NH)p. In contrast, at 10 degrees C, ACA in response to Gpp(NH)p alone is essentially equal in H and C animals. Hibernation did not change myocardial beta-AR receptor density or affinity. In contrast, analysis of isoproterenol displacement of [125I]iodocyanopindolol revealed that the proportion of beta-AR in the high-affinity state was substantially greater in H than in C animals, and this relationship was retained even in the presence of Gpp-(NH)p. In an evaluation of the role of the GTP binding proteins that couple the beta-AR to the effector adenyl cyclase, we determined that there was no change in the cholera toxin- or pertussis toxin-dependent ADP ribosylation patterns. Immunochemical detection of the individual GTP binding proteins revealed no change in the levels of G alpha i1, G alpha i2, or G alpha i3. In contrast, we observed a hibernation-associated decrease in G alpha o associated with the plasma membrane-enriched particulate fraction. (ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adaptations of myocardial beta-adrenergic receptor complex in hibernating marmots. 828 87

Isolated elements of the beta-adrenergic/adenyl cyclase signal transduction system have been studied previously using purified membranes. We used cultured syncytiotrophoblast cells to identify components of this signalling system and the interactions which regulate syncytial adenyl cyclase. Generation of cyclic AMP (cAMP) was stimulated in these cells by both forskolin and isoproterenol but not by dopamine, adenosine, carbachol or prostaglandin E1. Synthesis was also stimulated by treatment with cholera toxin, indicating the involvement of the G-protein, Gs. Somatostatin inhibited isoproterenol- or forskolin-stimulated cAMP generation, an effect which could be blocked by pretreatment of the cells with pertussis toxin, demonstrating the mediation of somatostatin action by Gi. Furthermore, secretion of human chorionic gonadotrophin (hCG) was increased significantly by isoproterenol while somatostatin blocked the isoproterenol-stimulated release of hCG. These results clearly demonstrate that adenyl cyclase in syncytiotrophoblast is controlled by a stimulatory pathway operating through Gs and inhibitory pathway acting through Gi.
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PMID:Beta-adrenergic regulation of cyclic AMP synthesis in cultured human syncytiotrophoblast. 857 58

Effector coupling of somatostatin receptor subtypes sst1 and sst2 was examined in a reconstituted system. Forskolin-stimulated cyclic adenosine monophosphate (cAMP) formation was inhibited 66% by somatostatin (SRIF-14) in CHO cells expressing somatostatin receptor 1(sst1) (CHO-SR1), but not sst2, in a dose-dependent manner with an ED50 of 1 x 10(-9) mol/L SRIF-14. The inhibition was blocked by pertussis toxin (PTX), indicating that sst1 is coupled to adenylyl cyclase via PTX-sensitive Gi protein. In CHO cells, Gi alpha 2 and Gi alpha 3 mRNAs were detected. In adenylyl cyclase assays, 1 mumol/L SRIF-14 caused a 16% inhibition of forskolin-stimulated adenyly cyclase activity. Preincubation with Gi alpha 3, but not Gi alpha 1/Gi alpha 2, antiserum blocked this inhibition. By contrast, sst2 is coupled to adenylyl cyclase via Gi alpha 1. In cells expressing sst2 with Gi alpha 1(CHO-SR2G1), SRIF-14 significantly inhibited forskolin-stimulated cAMP formation by 53% and with an ED50 at 4 x 10(-9)mmol/L SRIF-14, which was completely blocked by PTX; ED50 values for sst1 and sst2 agree with the IC50 values in binding assays. In CHO-SR1, the rank of potency of agonists affecting adenyl cyclase was SRIF-14 = SRIF-28 > RC 160 > SMS 201-995. In CHO-SR2G1, the rank was RC-160 > SRIF-14 = SRIF-28 > SMS 201-995.
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PMID:Effector coupling of somatostatin receptor subtypes on human endocrine tumors. 876 78

1. We sought to reconstitute and characterize G-protein linked phosphatidyl-D-inositol 4,5-bisphosphate (PIP2)-directed phospholipase C (PLC) isoform activity in pig aortic vascular smooth muscle. 2. Six soluble PLC isoforms, namely gamma 1, delta 1 and beta 1 to beta 4 were partially separated by heparin affinity chromatography and were identified by Western blotting using specific antibodies. 3. In separate experiments, PLC activity was measured in the eluted fractions. Four of the partially resolved PLC isoforms gamma 1, beta 4, beta 2 and beta 1, showed corresponding activity using exogenous [3H]-PIP2 as substrate. 4. The isolated soluble PLC isoforms were reconstituted with receptors and guanyl nucleotide regulatory proteins (G-proteins) by addition of plasma membranes, the phospholipids which had been prelabelled with [3H]-myo-inositol. When so reconstituted PLC beta 2, beta 3 and beta 4 were inhibited (40 +/- 9, 47 +/- 12 and 40 +/- 5% respectively n = 12, +/-s.e.mean and each P < 0.05) by the addition of 1 mM guanosine 5'[beta gamma-imido]triphosphate (p[NH]ppG). 5. By contrast, when plasma membranes were preincubated with pertussis toxin to inhibit the activity of G-protein subunits G alpha i/alpha o the activities of PLC beta 2, beta 3 and beta 4 were stimulated (46 +/- 11, 31 +/- 9 and 37 +/- 8% respectively, n = 12, +/- s.e.mean and each P < 0.05) by the addition of p[NH]ppG. 6. Using well resolved fractions containing only PLC beta 3, time-dependent activity in the presence of p[NH]ppG was measurable only with membranes pretreated with pertussis toxin. 7. PLC beta 3 activity, measured with pertussis pretreated membranes, showed a dose-dependent increase in the presence of p[NH]ppG or guanosine 5'-[gamma-thio]triphosphate (GTP[S]). This increase with 10 microM p[NH]ppG or GTP[S] 10% +/- 4 and 12% +/- 5 respectively (both P < 0.05 vs control without GTP analogue +/- s.e.mean, n = 10) was abolished by 50 microM guanosine 5'-[beta-thio]diphosphate (GDP[S]) which also reduced constitutive PLC beta 3 activity by 9% +/- 4. 8. G-protein antibodies were used to neutralize PLC activity. Antibody to G alpha q/alpha 11, added to membrane fractions pretreated with pertussis toxin and assayed with GTP[S], reduced PLC beta 3 activity by 21% +/- 6 P < 0.02, n = 6, but was without effect on non-pertussis pretreated membranes. Antibodies to G alpha i1/alpha i2 had no effect. Antibodies to G-protein beta subunits had no effect on PLC beta 3 activity with pertussis pretreated preparations but activity without pertussis pretreatment was increased by 30% +/- 10, P < 0.03, n = 6. All results were expressed as % change from controls containing rabbit IgG. 9. In conclusion, pig aortic vascular smooth muscle contains six PLC isoforms. Activation of pertussis sensitive G-protein by GTP analogues results in inhibition of PLC beta 3 activity from liberated G-protein beta gamma subunits. Stimulation of PLC beta 3 activity is associated with a G-protein of the G alpha q family acting through the alpha subunit. The results suggest that the G-protein linked PLC beta isoforms in vascular smooth muscle demonstrate dual regulation by an inhibitory pertussis-sensitive pathway and a stimulatory G-protein of the G alpha q family, which is the case for PLC beta 3. This dual regulation is analogous to that of adenyl cyclase.
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PMID:Phospholipase C isoforms in vascular smooth muscle and their regulation by G-proteins. 879 75

We report two infants less than 2 months of age who died of Bordetella pertussis infection: one of primary B. pertussis infection and the other of secondary bronchopneumonia. We describe histopathologic findings in the lung, including transmission and immunoelectron microscopy, studies showing close association between B. pertussis organisms and ciliated cells. A novel finding in both cases was striking dilatation and inspissation of proteinaceous material in pancreatic ducts, reminiscent of changes described in cystic fibrosis. The possible mechanism for these changes may be related to cellular and molecular actions of pertussis toxin-a powerful inhibitor of G proteins and adenyl cyclase important in cellular signal transduction.
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PMID:Fatal Bordetella pertussis infection: report of two cases with novel pathologic findings. 902 61


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