Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pertussis toxin (PTX) ADP-ribosylates alpha subunits of GTP-binding proteins (G proteins) when they are in association with beta gamma dimers, and free alpha subunits are thought not to be substrates under standard assay conditions. We now report the rather unexpected discovery that synthetic peptides encompassing the last 10-20 amino acids of alpha subunits of PTX-sensitive G proteins are substrates for PTX by themselves and in the absence of beta gamma dimers. As determined for G13, the Km of PTX for the 20-amino acid carboxyl-terminal peptide is 10-fold higher than that for the trimeric G protein. Interestingly, PTX ADP-ribosylates the free full length alpha 13 subunit with a Km not different from that of the trimer but with a Vmax that is only 1% of that with which it ADP-ribosylates the trimer. It follows that the primary role of beta gamma dimers in ADP-ribosylation of G proteins is one of increasing the Vmax of the reaction without affecting the Km of the substrate for the toxin. Mutant peptides lacking the ADP-ribose acceptor site act as competitive inhibitors.
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PMID:Peptide inhibitors of ADP-ribosylation by pertussis toxin are substrates with affinities comparable to those of the trimeric GTP-binding proteins. 143 50

An antiserum (13CB) was generated against a synthetic peptide, HDNLKQLMLQ, which is predicted to represent the C-terminal decapeptide of the alpha subunit of the novel G-protein, G13. Competitive ELISA indicated that the antiserum reacted with this peptide but that it showed minimal ability to recognize peptides which represent the equivalent regions of the pertussis toxin-insensitive G-proteins, Gq + G11, G12, G15 + G16, GL1 (also called G14) as Gz, and well as other G-proteins. Immunoblots of human platelet membranes with antiserum 13CB identified a single 43-kDa polypeptide, and while this immunoreactivity was abolished by the presence of the cognate peptide it was not modified by the presence of peptides corresponding to the equivalent region of other G-proteins. Immunoreactivity corresponding to G13 alpha was detected in a range of cell types with human platelets having the highest levels of this polypeptide.
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PMID:Immunological identification of the alpha subunit of G13, a novel guanine nucleotide binding protein. 155 27

The human leukaemic cell line K562 is a pluripotent stem cell with the potential to mature along a megakaryocytic or erythroid line. In these cells, thrombin and U46619 (9,11-dideoxy-9 alpha, 11 alpha-methanoepoxy prostaglandin F2 alpha), a thromboxane A2 analogue, increased intracellular Ca2+ in a rapid and concentration-dependent manner. The peak transient observed with both thrombin and U46619 was preserved upon stimulation in the absence of extracellular calcium and blunted with phorbol myristate acetate, suggestive of activation of phospholipase C. Short-term treatment with leupeptin abolished the calcium response to thrombin, but did not alter that to U46619. Both pertussis toxin (PT) and DMSO pretreatment inhibited thrombin- but not U46619-stimulated intracellular calcium elevation, indicating that these agonists signal through different G-proteins. Western blot analysis of crude membranes from K562 cells revealed the presence of G12 alpha and G13 alpha; the other known PT-substrates, Gi1 alpha and G0 alpha, were not detected. Consistent with this observation, ADP-ribosylation experiments revealed the presence of two PT substrates which co-migrated with human erythrocyte G12 alpha and G13 alpha. An antibody raised against Gq/11 alpha, a subfamily of G-protein alpha subunits unmodified by PT, specifically recognized 42 kDa protein(s) in K562 cells. PCR amplification of reverse-transcribed K562 RNA followed by DNA sequencing showed that these cells express messages for both Gq alpha and G11 alpha. Treatment of K562 cells with DMSO reduced the levels of thrombin receptor mRNA, without simultaneous changes in the expression of G12 alpha and G13 alpha. We have thus identified Ca(2+)-mobilizing agonists and related G-proteins in K562 cells, together with changes induced by DMSO in this signalling pathway.
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PMID:Ca2+ signalling in K562 human erythroleukaemia cells: effect of dimethyl sulphoxide and role of G-proteins in thrombin- and thromboxane A2-activated pathways. 749 5

The Xenopus melatonin receptor was expressed in human embryonic kidney 293 cells and assayed for cAMP accumulation. In transfected 293 cells expressing the melatonin receptor, melatonin dose-dependently inhibited the endogenous adenylyl cyclases. In contrast, melatonin stimulated the accumulation of cAMP in cells co-expressing the type II adenylyl cyclase. Both the inhibitory and stimulatory responses to melatonin were mediated via Gi-like proteins as they were blocked by pertussis toxin. Upon co-transfection with the alpha subunit of Gz, the ability of melatonin to regulate both type II and the endogenous adenylyl cyclases became refractory to pertussis toxin, indicating that the melatonin receptor can also couple to Gz. However, other pertussis toxin-insensitive G proteins such as Gq, G12 and G13 were unable to interact with the melatonin receptor.
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PMID:Stimulation of cAMP accumulation by the cloned Xenopus melatonin receptor through Gi and Gz proteins. 755 53

Opioid receptors are multifunctional receptors that utilize G proteins for signal transduction. The cloned delta-opioid receptor has been shown recently to stimulate phospholipase C, as well as to inhibit or stimulate different isoforms of adenylyl cyclase. By using transient transfection studies, the ability of the cloned mu-opioid receptor to stimulate type II adenylyl cyclase was examined. Co-expression of the mu-opioid receptor with type II adenylyl cyclase in human embryonic kidney 293 cells allowed the mu-selective agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin, to stimulate cyclic AMP accumulation in a dose-dependent manner. The opioid-induced stimulation of type II adenylyl cyclase was mediated via pertussis toxin-sensitive Gi proteins, because it was abolished completely by the toxin. Possible coupling between the mu-opioid receptor and various G protein alpha subunits was examined in the type II adenylyl cyclase system. The opioid-induced response became pertussis toxin-insensitive and was enhanced significantly upon co-expression with the alpha subunit of Gz, whereas those of Gq, G12, or G13 inhibited the opioid response. When pertussis toxin-sensitive G protein alpha subunits were tested under similar conditions, all three forms of alpha i and both forms of alpha o were able to enhance the opioid response to various extents. Enhancement of type II adenylyl cyclase responses by the co-expression of alpha subunits reflects a functional coupling between alpha subunits and the mu-opioid receptor, because such potentiations were not observed with the constitutively activated alpha subunit mutants.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of type II adenylyl cyclase by the cloned mu-opioid receptor: coupling to multiple G proteins. 759 66

In neuroblastoma-glioma hybrid cells, bradykinin has dual modulatory effects on ion channels: it activates a K+ current as well as inhibits the voltage-dependent Ca2+ current (ICa,V). Both of these actions are mediated by pertussis toxin-insensitive G proteins. Antibodies raised against the homologous Gq and G11 proteins suppress only the activation of the K+ current; this suggested that at least two distinct G protein pathways transduce diverse effects of this transmitter. Here, we show that the inhibition of ICa,V by bradykinin is suppressed selectively by intracellular application of antibodies specific for G13. This novel G protein may play a general role in the inhibition of ICa,V by pathways resistant to pertussis toxin.
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PMID:The G protein G13 mediates inhibition of voltage-dependent calcium current by bradykinin. 794 58

The cDNAs of two putatively pertussis toxin-insensitive G-protein alpha-subunits, alpha 12 and alpha 13, were recently cloned. mRNA analyses based on the reverse transcriptase polymerase chain reaction indicated a widespread distribution of both mRNAs [Strathmann, M. P., and Simon, M. I. (1991) Proc. Natl. Acad. Sci. USA 88, 5582-5586]. Generating specific antibodies directed against internal and C-terminal peptide sequences, we identified alpha 12 protein in all and alpha 13 protein in most tissues and cell lines tested. No species differences were observed, indicating a high degree of identity between mammalian species. Strong immunoreactive signals of both proteins were obtained in neuronal cell membranes of various species. Our results support the hypothesis that G12 and G13 are involved in pertussis toxin-insensitive pathways of signal transduction common to most tissues.
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PMID:G12 and G13 alpha-subunits are immunochemically detectable in most membranes of various mammalian cells and tissues. 811 95

Acetylcholine (ACh)-induced contraction of esophageal circular smooth muscle cells was inhibited by the M2 muscarinic antagonist methoctramine. In lower esophageal sphincter (LES) cells contraction was inhibited by the M3 antagonist p-fluoro-hexa-hydro-sila-difenidol (pF-HSD). Pertussis toxin (PTX) reduced ACh-induced contraction of esophageal but not of LES cells, which suggested that different receptor-linked G proteins are involved. Antibodies against G13 antagonized contraction of esophageal cells and G9-G11 antibodies antagonized contraction of LES cells. The phosphatidylinositol-specific phospholipase C (PLC) inhibitors, U-73122 and neomycin, reduced ACh-induced contraction of LES but not of esophageal cells. Conversely, propranolol and p-chloromercuribenzoic acid (pCMB), which inhibit a phosphatidylcholine-specific phospholipase D (PLD)-dependent pathway, reduced contraction of esophageal but not of LES muscle cells. At 1 and 5 sec after the administration of ACh (10(-5) M), inositol 1,4,5-trisphosphate (IP3) increased only in LES muscle, which suggested that contraction results from PLC-induced IP3 production in the LES but not in the esophagus. The IP3 receptor antagonist heparin, and depletion of intracellular Ca++ stores by thapsigargin or A23187, inhibited ACh-induced contraction of LES but not of esophageal muscle. It was concluded that ACh-induced esophageal contraction depends preferentially on M2 receptors, a PTX-sensitive G13 protein, phosphatidylcholine-specific PLD and production of diacylglycerol (DAG) and is independent of IP3 formation and the release of intracellular Ca++. Conversely, LES contraction is mediated through M3 receptors, a PTX-insensitive G9-G11 protein, activation of PLC, IP3 formation and the release of intracellular Ca++.
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PMID:Distinct muscarinic receptors, G proteins and phospholipases in esophageal and lower esophageal sphincter circular muscle. 826 81

Thyrotropin is the primary hormone that, via one heptahelical receptor, regulates thyroid cell functions such as secretion, specific gene expression, and growth. In human thyroid, thyrotropin receptor activation leads to stimulation of the adenylyl cyclase and phospholipase C cascades. However, the G proteins involved in thyrotropin receptor action have been only partially defined. In membranes of human thyroid gland, we immunologically identified alpha subunits of the G proteins Gs short, Gs long, Gi1, Gi2, Gi3, G(o) (Go2 and another form of Go, presumably Go1), Gq, G11, G12, and G13. Activation of the thyrotropin (TSH) receptor by bovine TSH led to increased incorporation of the photoreactive GTP analogue [alpha-32P]GTP azidoanilide into immunoprecipitated alpha subunits of all G proteins detected in thyroid membranes. This effect was receptor-dependent and not due to direct G protein stimulation because it was mimicked by TSH receptor-stimulating antibodies of patients suffering from Grave disease and was abolished by a receptor-blocking antiserum from a patient with autoimmune hypothyroidism. The TSH-induced activation of individual G proteins occurred with EC50 values of 5-50 milliunits/ml, indicating that the activated TSH receptor coupled with similar potency to different G proteins. When human thyroid slices were pretreated with pertussis toxin, the TSH receptor-mediated accumulation of cAMP increased by approximately 35% with TSH at 1 milliunits/ml, indicating that the TSH receptor coupled to Gs and G(i). Taken together, these findings show that, at least in human thyroid membranes, in which the protein is expressed at its physiological levels, the TSH receptor resembles a naturally occurring example of a general G protein-activating receptor.
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PMID:The human thyrotropin receptor: a heptahelical receptor capable of stimulating members of all four G protein families. 855 86

Hormones that interact with seven-transmembrane spanning receptors, generally considered to be involved in acute signaling functions, also induce longer term effects on gene expression and cell growth. These genetic and proliferative effects can be induced by activation of receptors that signal through heterotrimeric GTP-binding proteins (G-proteins) of the Gq family, pertussis toxin-sensitive Gi/Go proteins, Gs, or G12/G13. Numerous growth-promoting G protein-coupled receptors activate the low molecular weight G-protein Ras and stimulate mitogen-activated protein kinase. Recent data suggest that c-Jun NH2-terminal kinase is also activated, possibly through interaction with low molecular weight G-proteins of the Rho family. Because G protein-coupled receptors lack intrinsic tyrosine kinase activity, the mechanisms by which heterotrimeric G-proteins couple to these kinase cascades remain to be elucidated. By analogy to growth factor receptors, G protein-coupled receptors may access these kinase cascades through binding of adapter proteins or recruitment of cytosolic tyrosine kinases. It is likely that interactions between multiple signaling pathways are required for G protein-coupled receptors to propagate signals to the nucleus.
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PMID:G protein-coupled receptors and signaling pathways regulating growth responses. 863 91


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