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)

Guanine nucleotide-binding proteins (G proteins) are critically important mediators of many signal-transduction systems. Several important sites regulating stimulus-secretion coupling and release of insulin from pancreatic beta-cells are modulated by G proteins. Gs mediates increases in intracellular cAMP associated with hormone-induced stimulation of insulin secretin. Gi mediates decreases in intracellular cAMP caused by inhibitors of insulin secretion, e.g., epinephrine, somatostatin, prostaglandin E2, and galanin. G proteins also regulate ion channels, phospholipases, and distal sites in exocytosis. Cholera and pertussis toxins irreversibly ADP ribosylate G proteins and are important tools that can be used both to manipulate G-protein-dependent modulators of insulin secretion and detect and quantify G proteins by electrophoretic techniques. The stage is set to pursue these initial observations in greater depth and ascertain whether G-protein research will provide important new insights into normal and abnormal regulation of insulin secretion.
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PMID:G proteins and modulation of insulin secretion. 190 7

Extracellular ATP and UTP produced a rapid accumulation of inositol phosphates in human airway epithelial cells (CF/T43). The order of agonist potencies for a series of nucleotide analogues differed markedly from that of the classically described P2x- or P2y-purinergic receptors. UTP was the most potent agonist and was fully efficacious; ATP and adenosine-5'-O-(3-thiotriphosphate) were also full agonists. In contrast, 2-methylthio-ATP, adenosine-5'-O-(2-thiodiphosphate) and alpha,beta-methylene-ATP were without effect. ADP and UDP had little or no effect at concentrations as high as 100 microM, and deoxyribose and dideoxyribose compounds were inactive. The effects of ATP and UTP were not additive, whereas bradykinin- or histamine-stimulated inositol phosphate production was additive with the effects of ATP or UTP. Preincubation of cells with either UTP or ATP resulted in a parallel loss of responsiveness to both agonists. Desensitization was specific for the response to nucleotides, because no ATP- or UTP-induced effect on the response to histamine or bradykinin was observed. Pertussis toxin treatment of CF/T43 cells produced a 30-40% decrease in the response to ATP or UTP, which correlated with the ADP-ribosylation of 41- and 43-kDa proteins. Bradykinin and histamine responses were not modified by pertussis toxin. Guanine nucleotides had little effect on the inositol phosphate response in intact CF/T43 cells at concentrations below 100 microM. However, in streptolysin-O-permeabilized cells GTP-gamma S produced a concentration-dependence activation of inositol phosphate formation. UTP or ATP had little effect in permeabilized cells in the absence of guanine nucleotides but markedly increased inositol phosphate formation in the presence of guanine nucleotides. Taken together, these results suggest that UTP and ATP activate a 5'-nucleotide receptor on CF/T43 cells that is distinct from the classically defined P2x- and P2y-purinergic receptors. Activation of phospholipase C by this receptor involves, at least in part, a guanine nucleotide-binding regulatory protein.
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PMID:Evidence that UTP and ATP regulate phospholipase C through a common extracellular 5'-nucleotide receptor in human airway epithelial cells. 194 36

The vascular tree and the mesangium in the glomerulus respond to various hormones, growth factors, and autonomic signals, leading to generation of second messengers and regulation of ion channels. Guanine nucleotide regulatory proteins (G proteins) mediate these effects in other systems. Glomerular G proteins were studied by immunoblotting and immunohistochemical techniques. Glomeruli were isolated from bovine kidney cortex by differential sieving. Glomerular proteins were resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and nitrocellulose transfers were immunoblotted with antibodies to G proteins. G alpha,common antiserum (P-960) recognized proteins with a molecular mass of 41 to 45 kDa. Antibodies against peptide sequences specific to Gi alpha and Go alpha demonstrated Gi alpha, 1/3 (molecular mass, 39 to 41 kDa), Gi alpha 2 (molecular mass, 40 kDa), and Go alpha (molecular mass, 39 kDa). Presence of these proteins was further confirmed by pertussis toxin-catalyzed ADP ribosylation of protein(s) with a molecular mass of 39 to 41 kDa in the glomeruli. Immunohistochemical staining of frozen sections from bovine kidney cortex revealed the presence of Gi alpha 2 in capillary loop distribution in glomeruli and interstitium, but Gi,1/3 or Go could not be demonstrated. The pattern of immunofluorescence with Gi alpha 2 antiserum suggested localization of Gi alpha 2 to the endothelium in glomerular and interstitial vasculature. The novel finding of Go in glomeruli requires localization of Go to specific cells and determination of its role in glomerular physiology. In conclusion, these studies demonstrate that bovine kidney glomeruli express alpha subunits of pertussis toxin-sensitive GTP-binding proteins Gi,1/3, Gi,2 and Go.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification and localization of pertussis toxin-sensitive GTP-binding proteins in bovine kidney glomeruli. 195 30

The possible involvement of a stimulatory guanosine triphosphate (GTP)-binding (G) protein in epidermal growth factor (EGF)-induced phosphoinositide hydrolysis has been investigated in permeabilized NIH-3T3 cells expressing the human EGF receptor. The mitogenic phospholipid lysophosphatidate (LPA), a potent inducer of phosphoinositide hydrolysis, was used as a control stimulus. In intact cells, pertussis toxin partially inhibits the LPA-induced formation of inositol phosphates, but has no effect on the response to EGF. In cells permeabilized with streptolysin-O, guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) dramatically increases the initial rate of inositol phosphate formation induced by LPA. In contrast, activation of phospholipase C (PLC) by EGF occurs in a GTP-independent manner. Guanine 5'-O-(2-thiodiphosphate) (GDP beta S) which keeps G proteins in their inactive state, blocks the stimulation by LPA and GTP gamma S, but fails to affect the EGF-induced response. Tyrosine-containing substrate peptides, when added to permeabilized cells, inhibit EGF-induced phosphoinositide hydrolysis without interfering with the response to LPA and GTP gamma S. These data suggest that the EGF receptor does not utilize an intermediary G protein to activate PLC and that receptor-mediated activation of effector systems can be inhibited by exogenous substrate peptides.
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PMID:Epidermal growth factor-induced phosphoinositide hydrolysis in permeabilized 3T3 cells: lack of guanosine triphosphate dependence and inhibition by tyrosine-containing peptides. 196 91

Guanine nucleotide binding proteins (G proteins) are regulatory molecules that couple membrane receptors to effector systems such as adenylate cyclase and phospholipase C. The alpha subunits of G proteins bind to guanosine 5'-diphosphate (GDP) in the unstimulated state and guanosine 5' triphosphate (GTP) in the active state. Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide), a specific inhibitor of inosine monophosphate (IMP) dehydrogenase, decreases guanylate synthesis from IMP in HL-60 promyelocytic leukemia cells and depletes intracellular guanine nucleotide pools. This study demonstrates that treatment of HL-60 cells with tiazofurin is associated with a fourfold increase in membrane binding sites for the nonhydrolyzable analogue GDP beta S. This increase in binding sites was associated with a 3.2-fold decrease in GDP beta S binding affinity. Similar findings were obtained with GTP gamma S. These effects of tiazofurin treatment on guanine nucleotide binding were also associated with decreased adenosine diphosphate-ribosylation of specific G protein substrates by cholera and pertussis toxin. The results further demonstrate that tiazofurin treatment results in inhibition of G protein-mediated transmembrane signaling mechanisms. In this regard, stimulation of adenylate cyclase by prostaglandin E2 was inhibited by over 50% in tiazofurin-treated cells. Furthermore, tiazofurin treatment resulted in inhibition of N-formylmethionylleucylphenylalanine-induced stimulation of phospholipase C. Taken together, these results indicate that tiazofurin acts at least in part by inhibiting the ability of G proteins to function as transducers of intracellular signals.
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PMID:Effects of tiazofurin on guanine nucleotide binding regulatory proteins in HL-60 cells. 196 38

Guanine nucleotide-binding regulatory proteins, or G proteins, mediate the interaction of agonist receptors on the platelet surface with phospholipase C and adenylyl cyclase. To better understand this process, we have used several approaches to identify which G proteins are present in platelets, normal human megakaryocytes, and human erythroleukemia (HEL) cells, a leukemic cell line with megakaryocytic features. Because platelet and HEL cell responses to thrombin are inhibited by pertussis toxin, we have focused upon the members of the Gi family, whose alpha subunits can be ADP-ribosylated by that toxin. Western blots with antisera specific for Gi alpha demonstrated the presence in both platelets and HEL cells of the three best-described forms of this protein: Gi alpha 1, Gi alpha 2, and Gi alpha 3. Based upon immunoprecipitation studies with [35S]-methionine-labeled HEL cells, their relative abundance appears to be Gi alpha 2 much greater than Gi alpha 3 greater than Gi alpha 1. A HEL cell cDNA library screened with the Gi alpha antisera produced clones encoding Gi alpha 2 and Gi alpha 3 that had sequences similar to those reported from other sources. Gi alpha-specific probes created from these cDNA clones confirmed the presence of mRNA encoding Gi alpha 2 and Gi alpha 3 in both platelets (by Northern blotting) and megakaryocytes (by in situ hybridization). Thus the pertussis toxin substrates that have previously been detected in platelets and HEL cells are shown to be members of the Gi alpha family, all of which are candidates for interaction with receptors for thrombin and other agonists.
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PMID:Identification of the pertussis toxin-sensitive G proteins in platelets, megakaryocytes, and human erythroleukemia cells. 211 27

Guanine nucleotide binding proteins (G proteins) sensitive to pertussis toxin (PTX) mediate the muscarinic receptor responses in several tissues. Therefore, the present study sought to investigate whether smooth muscle contractions and/or endothelium-dependent relaxations in response to acetylcholine (ACh) and other agonists were sensitive to PTX. In endothelium-denuded rabbit pulmonary artery rings, ACh, clonidine and serotonin produced concentration-dependent contractions which were markedly inhibited in nominally Ca+(+)-free medium and abolished in the presence of ethylene glycol bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (0.2 mM). In endothelium-denuded arterial rings obtained from rabbits treated in vivo with PTX (5 micrograms/kg i.v., 5 days before sacrifice) maximum contractions to ACh, clonidine and serotonin were inhibited by 77, 67 and 35%, respectively. Contractions induced with KCl (10-40 mM) were also abolished in Ca+(+)-free medium, but they were not affected by PTX. Endothelium-dependent relaxations of phenylephrine-contracted pulmonary arteries in response to ACh adenosine triphosphate and substance P were also reduced or abolished upon removal of extracellular Ca++. However, the endothelium-dependent relaxations were not affected by PTX. These data demonstrate that contractions of pulmonary arterial smooth muscle cells after stimulation through muscarinic receptors, alpha adrenoceptors and serotonin receptors require the influx of extracellular Ca++. This receptor-stimulated Ca++ influx is likely to be regulated by a PTX-sensitive G protein. Also, the induction of release of relaxing factor from endothelial cells of the pulmonary artery via muscarinic, purinergic or substance P receptors requires extracellular Ca++. However, in these cells, a different mode of signal transduction, insensitive to PTX, seems to be involved.
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PMID:Pertussis toxin inhibits contractions but not endothelium-dependent relaxations of rabbit pulmonary artery in response to acetylcholine and other agonists. 215 2

Muscarinic acetylcholine receptors were identified by the specific binding of [H](-)quinuclidinylbenzilate [( 3H](-)QNB) and [3H]oxotremorine-M [( 3H]Oxo-M), to membranes isolated from the sino-atrial (SA) node and right atrium (RA) of bovine heart. The density of [3H](-)QNB binding sites was greater in the SA node compared to the RA. Specific [3H](-)QNB binding was saturable and occurred to a single population of binding sites in both regions. The binding of antagonists, as assessed by competition with [3H](-)QNB, also occurred to a single population of sites; the binding affinities of all antagonists were similar in either region. Agonist competition curves, except for McN-A-343, were complex and computer analyses indicated that agonists bound to at least two populations of binding sites that differed in affinity. The proportion of high-affinity agonist binding sites was consistently greater in the SA nodal, relative to the RA membranes, while the affinity of the high-affinity agonist binding sites to a given agonist was essentially similar in either region. The high-affinity binding of [3H]Oxo-M was saturable and occurred to a single population of sites. The maximal binding of [3H]Oxo-M in the SA nodal membranes was higher than in the RA membranes. Guanine nucleotides and N-ethylmaleimide (NEM) markedly decreased [3H]Oxo-M binding; NEM did not appear to influence guanine nucleotide-dependent decrease in [3H]Oxo-M binding. Phospholipase A2 decreased both [3H](-)QNB and [3H]Oxo-M specific binding, the latter being affected to a greater extent. Phospholipase C also decreased [3H](-)QNB and [3H]Oxo-M binding, although to a lesser degree compared to phospholipase A2. Either lipase, however, increased the guanine nucleotide-sensitive agonist binding. Analysis of [3H](-)QNB binding to microsomal subfractions showed that binding sites were enriched in the light plasma membrane fractions that were also enriched in pertussis toxin sensitive guanine nucleotide binding proteins.
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PMID:Muscarinic acetylcholine receptors in the sino-atrial node and right atrium of bovine heart. 225 3

Guanine nucleotide binding (G) proteins couple a variety of receptors to ionic channels. Until recently the pathway was thought to be indirect via cytoplasmic second messengers; now the heterotrimeric G proteins are known to act directly on K+ and Ca2+ channels. Here we summarize recent developments concerning this widespread mechanism which we call G protein gating of ion channels. A specific pertussis toxin-sensitive G protein called Gk, purified from human red blood cells, activates a unique K+ channel and Gk, or a similar G protein, couples this channel to muscarinic atrial receptors. The alpha-subunit (alpha k) at less than 10 pM mediates the effects, and alpha k also activates K+ channels directly in neurosecretory cells. The G protein stimulatory to adenylyl cyclase, Gs, gates directly through its alpha-subunit, specific Ca2+ channels in heart and skeletal muscle T tubules. Hence, one G protein can have two distinct effectors.
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PMID:Direct G protein gating of ion channels. 245 Apr 76

Guanine nucleotides and pertussis toxin were used to test for the involvement of a guanine nucleotide binding protein in the vasopressin V1 receptor-mediated stimulation of protein kinase C activity in Swiss 3T3 cells. Addition of vasopressin in the presence of [gamma-32P]ATP and digitonin caused a marked and rapid increase (8 +/- 1-fold after 1 min) in the phosphorylation of an Mr = 80,000 cellular protein (80K), a specific marker for protein kinase C activation. This phosphorylation was selectively blocked by the V1 receptor antagonist Pmp1-0-Me-Tyr2 [Arg8] vasopressin, indicating that the effect was mediated through the vasopressin V1 receptor. Down regulation of protein kinase C by prior prolonged pretreatment of intact cells with phorbol 12,13-dibutyrate (PBt2) blocked the ability of vasopressin to stimulate the phosphorylation of 80K in digitonin-permeabilized cells. Addition of a submaximal concentration of vasopressin together with the GTP analogue GTP-gamma-S caused a synergistic stimulation of 80K phosphorylation. The GDP analogue GDP-beta-S caused a 50% inhibition of the phosphorylation of 80K induced by a saturating concentration of vasopressin and shifted the vasopressin dose-response curve to the right. GDP-beta-S had no effect on the dose-response for the stimulation of 80K phosphorylation induced by PBt2. Prior incubation of intact quiescent cultures of Swiss 3T3 cells with pertussis toxin did not impair either vasopressin-induced increase in cytosolic [Ca2+] or activation of protein kinase C. These findings provide functional evidence for the involvement of a pertussis toxin-insesitive G protein in the vasopressin V1 receptor-mediated stimulation of protein kinase C in Swiss 3T3 cells.
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PMID:Vasopressin rapidly stimulates protein kinase C in digitonin-permeabilized Swiss 3T3 cells: involvement of a pertussis toxin-insensitive guanine nucleotide binding protein. 253 Feb 40

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