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)

Attempts were made to identify prostaglandin (PG) receptors in rat myometrium, according to the differential rank order of potencies displayed by the natural PGs and their analogues, both at the level of second messenger generation and contraction. In estrogen-treated rat myometrium, PGs [iloprost = PGI2 greater than PGE2 much greater than 16,16-dimethyl (DM)-PGE2; sulprostone = misoprostol = 0] induced adenosine 3',5'-cyclic monophosphate generation, indicating the contribution of a PGI2 receptor. The generation of inositol phosphates was stimulated by PGs (PGF2 alpha greater than PGD2 much greater than PGE2 = DM-PGE2 much greater than iloprost greater than sulprostone = misoprostol = 0), reflecting a PGF2 alpha-receptor-mediated process, which was insensitive to pertussis toxin (PTX). Contractions caused by PGF2 alpha were closely correlated to PGF2 alpha-receptor activation associated with the phospholipase C pathway. By contrast, contractions evoked by PGE2, equally mimicked by sulprostone and misoprostol, were abolished by PTX and were independent of phospholipase C activation. In the pregnant myometrium (day 21), the latter PGE-receptor-mediated mechanism also contributed to contractions caused by PGE2 (less than microM concn). Phospholipase C activation was coupled not only to PGF2 alpha but also to PGE receptors and could be correlated with contractions induced by PGF2 alpha and PGE2 greater than microM concn). All PGs tested were coupled to inhibitory G protein-mediated adenylate cyclase inhibition, displaying an equipotency that did not allow characterization of the inhibitory PG receptors.
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PMID:Diverse prostaglandin receptors activate distinct signal transduction pathways in rat myometrium. 163 81

The making and sealing of a tight junction (TJ) requires cell-cell contacts and Ca2+, and can be gauged through the development of transepithelial electrical resistance (TER) and the accumulation of ZO-1 peptide at the cell borders. We observe that pertussis toxin increases TER, while AIF3 and carbamil choline (carbachol) inhibit it, and 5-guanylylimidodiphosphate (GTPTs) blocks the development of a cell border pattern of ZO-1, suggesting that G-proteins are involved. Phospholipase C (PLC) and protein kinase C (PKC) probably participate in these processes since (i) activation of PLC by thyrotropin-1 releasing hormone increases TER, and its inhibition by neomycin blocks the development of this resistance; (ii) 1,2-dioctanoylglycerol, an activator of PKC, stimulates TER development, while polymyxin B and 1-(5-isoquinoline sulfonyl)-2-methyl-piperazine dihydrochloride (H7), which inhibit this enzyme, abolish TER. Addition of 3-isobutyl-1-methyl-xanthine, dB-cAMP or forskolin do not enhance the value of TER, but have just the opposite effect. Trifluoperazine and calmidazoline inhibit TER development, suggesting that calmodulin (CaM) also plays a role in junction formation. These results indicate that junction formation may be controlled by a network of reactions where G-proteins, phospholipase C, adenylate cyclase, protein kinase C and CaM are involved.
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PMID:Assembly and sealing of tight junctions: possible participation of G-proteins, phospholipase C, protein kinase C and calmodulin. 192 Mar 85

When cultured in the presence of fetal calf serum, arterial smooth muscle cells from spontaneously hypertensive rats (SHR) proliferate more rapidly and are more numerous at confluency than cells from normotensive Wistar-Kyoto (WKY) animals. The phenomenon has been demonstrated in several laboratories but its molecular origin remains unclear. On the other hand phospholipase C activation and c-fos transcription are early events able to trigger cell mitosis. Therefore, the enhancement of inositol phosphates formation induced in SHR cells by various vasoactive agents and growth factors suggests that this enzyme might be implicated in the abnormal proliferation triggered by serum. In this case a unique molecular abnormality would be responsible for both arterial hypercontractility and dystrophy encountered in hypertension. In order to test this hypothesis we have compared DNA replication, phospholipase C activation, and c-jun and c-fos nuclear protooncogene transcriptions stimulated by fetal calf serum (FCS), vasoactive agents (angiotensin II and vasopressin), and epithelial growth factor (EGF) in SHR and WKY rat cells. The results obtained with these various agonists tested under the same experimental conditions confirm that the classical pathogenic diagram: (PLC hyperactivation----increase in c-fos transcription----enhanced cell proliferation) may apply to the action of vasoactive agents which are only slightly mitogenic on SHR cells, but not to the very important effect of fetal calf serum. Indeed, FCS stimulated inositol phosphate formation and c-jun and c-fos transcription, but none of these parameters was enhanced in SHR cells. Phospholipase C activation may exert some control upon DNA replication, as its partial inhibition by pertussis toxin coincided with an equivalent decrease in thymidine incorporation. It is, however, not absolutely required for the onset of DNA replication in aortic smooth muscle cells, as shown by the results obtained with EGF under the same experimental conditions. An abnormal molecular reaction different from PLC activation is therefore responsible for the enhanced proliferation of cultured SHR aortic smooth muscle cells, and several cell alterations may concur to the formation of the hypertensive arteriopathy.
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PMID:Hyperactivation of phospholipase C does not support the enhanced proliferation of aortic smooth muscle cells from spontaneously hypertensive rats. 193 Aug 47

Phospholipase C (specific for inositol lipids) is known to be present both in membranes and cytosol. Receptor-mediated activation of this enzyme occurs via a guanine nucleotide regulatory protein (G-protein), designated Gp. We have compared the stimulation of this enzyme by fMet-Leu-Phe via the G-protein in HL60 membranes and in permeabilised cells. fMet-Leu-Phe stimulated phospholipase C in membranes at 2 min and the response was dependent on exogenously added GTP. GTP alone also stimulated phospholipase C activity such that at 10 min the response to fMet-Leu-Phe was minimal. In comparison, the response to fMet-Leu-Phe in permeabilised cells was greater in extent but did not require added GTP. However, it was antagonized by GDP analogues (GDP[beta S] greater than GDP greater than dGDP) and by pertussis toxin pretreatment, indicating that fMet-Leu-Phe-stimulated phospholipase C activity was also mediated via Gp. GTP and its analogue GTP[gamma S] also stimulated phospholipase C and their effects were strictly additive to the stimulation obtained with fMet-Leu-Phe. Such additivity was also observed when two receptor-directed agonists, fMet-Leu-Phe and ATP, were used to stimulate intact cells. It is concluded that (a) the size of the response with fMet-Leu-Phe in membranes is limited by the loss of a component, possibly phospholipase C, and (b) stoichiometry and physical organisation of multiple species of G-proteins and/or phospholipases C may explain the independent nature of phospholipase C activation by fMet-Leu-Phe, ATP and guanine nucleotides.
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PMID:Characterization of fMet-Leu-Phe-stimulated phospholipase C in streptolysin-O-permeabilised cells. 201 14

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

Activation of vascular smooth muscle by angiotensin II results in the phospholipase C-mediated generation of two second messengers, inositol trisphosphate (IP3) and diacylglycerol (DG). IP3 is responsible for mobilizing calcium from endoplasmic reticulum whereas DG activates protein kinase C and ultimately Na+/H+ exchange, leading to intracellular alkalinization. The IP3/calcium signal is transient, most likely serving to initiate calcium-mediated events leading to contraction, and is attenuated by activation of protein kinase C. DG formation/protein kinase C activation is sustained and may be enhanced by the concurrent intracellular alkalinization. The delay in induction of the sustained response appears to be related to cellular processing of the angiotensin II-receptor complex. Phospholipase C activity is also modulated by a cholera toxin-sensitive, pertussis toxin-insensitive guanine nucleotide regulatory protein. This guanine nucleotide regulatory protein, movement of the receptor-ligand complex, and the signals generated by the two second messengers, IP3 and DG, interact in a complex manner to cause an integrated response of vascular smooth muscle to angiotensin II stimulation.
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PMID:Angiotensin II stimulation of vascular smooth muscle cells. Secondary signalling mechanisms. 267 2

Many hormones, neurotransmitters, and secretagogues act by increasing the intracellular free Ca2+ concentration in target cells. The initial event following binding of agonists to specific receptors in the plasma membrane involves a receptor-mediated activation of a guanosine nucleotide-binding protein (G protein), which induces a Ca2+-independent activation of phospholipase C. This novel, presently uncharacterized G protein is inactivated by pertussis toxin-catalyzed adenosine 5'-diphosphate ribosylation in some but not all cell types. Phospholipase C catalyzes the breakdown of inositol lipids, notably phosphatidylinositol 4,5-bisphosphate, with the production of inositol phosphates and 1,2-diacylglycerol. Inositol 1,4,5-trisphosphate (IP3) is responsible for a rapid mobilization of intracellular Ca2+ by activating Ca2+ efflux from a subpopulation of the endoplasmic reticulum. The properties of this process are consistent with its being a ligand-activated ion channel with electrogenic Ca2+ efflux being charge-compensated by K+ influx. Sustained hormonal responses require extracellular Ca2+ and a prolonged elevation of the cytosolic free Ca2+. This is brought about by hormone-mediated changes of Ca2+ flux across the plasma membrane involving both an inhibition of Ca2+ efflux and an activation of Ca2+ influx. This review summarizes recent findings concerning the role of G proteins in receptor coupling to phospholipase C; the regulation of enzymes of phosphoinositide metabolism; the evidence for IP3 being a Ca2+-mobilizing second messenger and its mechanism of action; the formation of new inositol phosphates and their possible significance; the relation of intracellular Ca2+ mobilization and plasma membrane Ca2+ fluxes to the kinetics of the hormone-induced cytosolic free Ca2+ transient; and the possible roles of protein kinase C in influencing the hormone-mediated functional response.
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PMID:Role of inositol lipid breakdown in the generation of intracellular signals. State of the art lecture. 301 67

It has recently been shown in this laboratory that permeabilization of human platelets with 15-25 micrograms/ml saponin allows ADP-ribosylation by pertussis toxin of the alpha i-subunit of Gi (Ni), a guanine nucleotide-binding regulatory protein. The same assay conditions have been used to determine phospholipase C in permeabilized platelets. Guanosine 5'-O-thiotriphosphate- (GTP[gamma S]-) activated phospholipase C in permeabilized platelets whose inositol phospholipids were prelabeled with [3H]inositol. Phospholipase C activity was measured by [3H]polyphosphoinositide decreases and formation of [3H]inositol bisphosphate and [3H]inositol trisphosphate. Prostacyclin, cyclic AMP or pretreatment of permeabilized platelets with pertussis toxin did not alter this effect under conditions in which the alpha i-subunit was effectively ADP-ribosylated by pertussis toxin. This information indicated that ADP-ribosylation of Gi-protein was not directly related to activation or inhibition of platelet phospholipase C by GTP [gamma S]. Thrombin also activated phospholipase C in permeabilized platelets and, surprisingly, this action was enhanced by pertussis toxin pretreatment. This indicates that ADP-ribosylation of Gi-protein facilitates the action of thrombin on phospholipase C.
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PMID:Effect of pertussis toxin on the phosphodiesteratic cleavage of the polyphosphoinositides by guanosine 5'-O-thiotriphosphate and thrombin in permeabilized human platelets. 302 Dec 35

Tumour necrosis factor (TNF) is an important mediator of endotoxin-induced vascular collapse and other inflammatory reactions. Eicosanoids have been implicated in the pathogeensis of these responses. In order to explore further the potential interactions between TNF and eicosanoid metabolism in eliciting vascular responses, we studied the effects of TNF on the bovine endothelial cell line CPAE. TNF induced cellular retraction observed by light microscope. This morphological change was monitored by the passage of iodinated protein A between adjacent cells and by release of [3H]arachidonic acid metabolites from cells. Both the morphological and functional responses were abrogated by inhibition of eicosanoid synthesis with BW755c. The release of [3H]arachidonic acid metabolites appeared to be mediated by a transient increase in phospholipase A2 activity. Phospholipase C activity was not affected by TNF. The maximal increase in phospholipase A2 activity occurred at 5 min following the addition of TNF. Phospholipase A2 activation, [3H]arachidonic acid-metabolite synthesis and passage of iodinated protein A, required both RNA and protein synthesis and were associated with an increase in the synthesis of a recently described phospholipase A2-activating protein. The Bordetella pertussis toxin, islet-activating protein, also inhibited the increase in phospholipase A2 activity, the release of [3H]arachidonic acid metabolites and the passage of iodinated protein A, suggesting that the TNF receptor-ligand interaction resulting in cellular retraction, phospholipase A2 activation and eicosanoid synthesis, is coupled through the Ni guanine nucleotide regulatory protein in these cells.
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PMID:Tumour necrosis factor (cachectin) induces phospholipase A2 activity and synthesis of a phospholipase A2-activating protein in endothelial cells. 312 74

U-937 cells differentiated by exposure to dibutyryl cyclic AMP respond to complement fragment C5a with a marked increase in cytoskeletal F-actin, which can be detected by fluorescence-activated cell sorting (f.a.c.s.) analysis of their rhodamine phalloidin-stained cytoskeletons. The C5a-induced increase in F-actin content can be prevented by prior exposure of the cells to cytochalasin B and pertussis toxin. It is insensitive to removal of extra cellular Ca2+, to cholera toxin or to neomycin. Phorbol myristate acetate (PMA), an activator of protein kinase C, does not induce actin polymerization in the differentiated cells. Both C5a and PMA stimulate superoxide production. The action of C5a on superoxide formation is also inhibited by neomycin, a phospholipase inhibitor. These results suggest that the cytoskeletal response to C5a requires activation of a G protein, but probably does not involve phospholipase C and protein kinase C, and is not highly dependent on the availability of Ca2+. Phospholipase C and kinase C may, however, be components of the pathway leading from C5a binding to superoxide production.
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PMID:Recruitment of actin to the cytoskeletons of human monocyte-like cells activated by complement fragment C5a. Is protein kinase C involved? 342 21


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