Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Olfactory transduction is thought to be mediated by a membrane-bound receptor protein initiating a multistep reaction cascade which ultimately leads to a depolarizing generator current. There is considerable evidence for the involvement of adenylate cyclase in vertebrate olfactory transduction, and some data indicate that phospholipase C may have a central role in insect olfaction. However, one must show that odorants not only stimulate enzyme activity but also induce changes in concentrations of relevant second messengers. One important criterion for a candidate second messenger of chemo-electrical transduction is that its formation must precede the onset of the odorant-induced membrane permeability changes which proceed on a subsecond time-scale. Here we report an odorant-induced, transient accumulation of cyclic AMP in isolated olfactory cilia from rats, and the generation of inositol trisphosphate in antennal preparations from insects, both of which show subsecond time courses that are sufficiently rapid to mediate the odorant-regulated permeability of olfactory receptor cells.
 ...
PMID:Rapid kinetics of second messenger formation in olfactory transduction. 215 31

The granular ATP released from chromaffin cells during the secretory response can be hydrolyzed by ectonucleotidases that are present in the plasma membrane of these cells. The ecto-ATPase activity showed a Km for ATP of 250 +/- 18 microM and a VMAX value of 167 +/- 25 nmol/10(6) cells x min (1.67 mumol/mg protein x min) for cultured chromaffin cells, while the ecto-ADPase activity showed a Km value for ADP of 375 +/- 40 microM and a VMAX of 125 +/- 20 nmol/10(6) cells x min (1.25 mumol/mg protein x min). The ecto 5'-nucleotidase activity of cultured chromaffin cells was more specific for the purine nucleotides, AMP and IMP, than for the pirimidine nucleotides, CMP and TMP. The Km for AMP was 55 +/- 5 microM and the VMAX value was 4.3 +/- 0.8 nmol/10(6) cells x min (43 nmol/mg protein x min). The nonhydrolyzable analogs of ADP and ATP, alpha, beta-methylene-adenosine 5'-diphosphate and adenylyl-(beta, gamma-methylene)-diphosphonate were good inhibitors of ecto 5'-nucleotidase activity, the KI values being 73.3 +/- 3.5 nM and 193 +/- 29 nM, respectively. The phosphatidylinositol-specific phospholipase C released the ecto-5'-nucleotidase from the chromaffin cells in culture, thus suggesting an anchorage through phosphatidylinositol to plasma membranes. The presence of ectonucleotidases in chromaffin cells may permit the recycling of the extracellular ATP exocytotically released from these neural cells.
 ...
PMID:Presence of ectonucleotidases in cultured chromaffin cells: hydrolysis of extracellular adenine nucleotides. 215 57

Ca2+, an obligatory mediator of the secretory process, acts in concert with other second messengers that further amplify or inhibit the secretory response. In this overview, we will consider the relative roles of diacylglycerol (DAG), arachidonic acid, and cyclic AMP (cAMP) in modulating Ca2(+)-dependent secretion in nonexcitable cells. DAG, a product of phospholipase C (PLC)-catalyzed breakdown of phosphoinositides, stimulates protein kinase C. Ca2+ ionophores and phorbol esters (or DAG analogues) elicit a synergistic secretory response in the exocrine pancreas and parotid gland. These findings suggest that the complete activation of secretion requires stimulation of both Ca2(+)-dependent and protein kinase C-dependent pathways. Hydrolysis of phospholipids can also lead to the liberation of arachidonic acid in secretory cells. Endogenously generated arachidonic acid inhibits polyphosphoinositide synthesis in exocrine pancreas, leading to inhibition of agonist-induced IP3 formation, Ca2(+)-mobilization and amylase secretion. By contrast, arachidonic acid and its metabolites stimulate PLC in the rabbit peritoneal neutrophil, causing Ca2(+)-mobilization and lysosomal enzyme secretion. Arachidonic acid can thus serve as a positive or negative feedback regulator of secretion induced by Ca2(+)-mobilizing agonists. Finally, in the parotid gland, stimulation of amylase secretion by norepinephrine, the physiological mediator, which stimulates both the alpha and beta adrenoceptors, requires the interaction of both Ca2+ and cAMP pathways to produce a full secretory response. These studies, taken together, indicate that phosphoinositide and cAMP-dependent pathways play coordinate roles in signal transduction, leading to the Ca2(+)-mediated secretion.
 ...
PMID:Mediators of Ca2(+)-dependent secretion. 216 54

Cyclic nucleotide phosphodiesterase activity in rat heart microsomes is attributable to several isoenzymatic forms: a cyclic AMP-specific, a cyclic GMP-specific, and a cyclic GMP-stimulated enzyme. Incubation of microsomes with an exogenous phospholipase C (C. welchii) induced a marked stimulation (+126%) of cyclic AMP phosphodiesterase and a moderate stimulation (+49%) of cyclic GMP-phosphodiesterase in the membrane-bound fraction. Besides, a notable fraction of activity was solubilized by the treatment. A parallel decrease in the activating effect of cyclic GMP on the hydrolysis of cyclic AMP was observed in the membranes (down to 18% of the control effect). It resulted from a marked stimulation of the basal activity, while the activated level was unaffected. The treatment by an exogenous phospholipase D induced more moderate modifications. The addition to microsomes of oleyl,acetyl-glycerol, but not of long chain-diacylglycerols, partly reproduced the phospholipase C effect. Phosphatidate also induced variations in phosphodiesterase activity, and could thus participate in the phospholipase effects. These results suggest that endogenous phospholipases, the activity of which is modulated by hormonal stimuli, might influence phosphodiesterase activity in cardiac membranes by producing phospholipid metabolites, with potential consequences on heart contractility.
 ...
PMID:Phospholipid metabolism modulates cyclic nucleotide phosphodiesterase activity in rat heart microsomes. 216 7

The exotoxins of Bordetella pertussis and Vibrio cholera have been used to investigate signal transduction in the human T-cell lymphoma Jurkat. Stimulation of the cells, leading to an increase in cytoplasmic free calcium, could be achieved by the anti-T-cell receptor complex antibody OKT3 and by pertussis holotoxin (PTHT), or its B-subunit (PTB), but not by cholera holotoxin (CTHT) or its B-subunit (CTB). Both holotoxins ADP-ribosylated specifically G-proteins in the plasma membrane of intact cells, while their B-subunits had no ADP-ribosyltransferase activity. Incubation of the cells with CTHT led to a state of unresponsiveness to all stimulants. CTB was without any effect, indicating that the ADP-ribosyltransferase activity of cholera toxin (located in the A-subunit of the holotoxin) was necessary for the inhibition of cellular signalling. The inhibitory effect of cholera toxin on the pertussis toxin action was not due to a blockade of pertussis toxin interaction with the cell surface, because pertussis toxin was still able to ADP-ribosylate membrane proteins in cholera toxin treated intact cells. In addition, the cholera toxin mediated inhibition was not due to elevated levels of cyclic-AMP, as forskolin (a direct activator of the adenylate cyclase) and no inhibitory effect. The stimulating effect of PTHT was independent of its ADP-ribosyltransferase activity, because it could also be obtained by the B-subunit alone. In addition, the increase of cytoplasmic free calcium after stimulation by PTHT clearly preceded the ADP-ribosylation. Pre-treatment with PTHT, PTB or OKT3, led to a long lasting increase in the level of intracellular Ca2+ in Jurkat cells, which could not, therefore, be stimulated further. Inhibition by cholera holotoxin of the stimulation by OKT3 and pertussis toxin (PTHT and PTB) imply that the mitogenic effect of pertussis toxin is perhaps mediated via the T-cell antigen receptor signalling cascade. The presented data do not support the idea that a pertussis toxin-sensitive G-protein is involved in coupling the T-cell antigen receptor to the phospholipase C.
 ...
PMID:Pertussis toxin B-subunit-induced Ca2(+)-fluxes in Jurkat human lymphoma cells: the action of long-term pre-treatment with cholera and pertussis holotoxins. 216 84

Bombesin is a potent mitogen for Swiss 3T3 cells and can stimulate DNA synthesis in the absence of any other growth factor. This effect is mediated by multiple synergistic signaling pathways, including an accumulation of intracellular cyclic AMP (cAMP) and an increase in c-fos mRNA expression. The cyclooxygenase inhibitor indomethacin abolished prostaglandin E2 release and substantially depressed cAMP levels induced by bombesin (EC50 congruent to 10 nM). In contrast, indomethacin at 1 microM did not affect 80K phosphorylation or Ca2+ mobilization by bombesin, indicating that cAMP synthesis can occur through a phospholipase C-independent pathway. Indomethacin caused a 30 to 35% decrease in c-fos induction and DNA synthesis in cells treated with bombesin (EC50 congruent to 40 nM). Significantly, the inhibitory effect of indomethacin was reversed in the presence of forskolin, a direct activator of adenylate cyclase. We conclude that cAMP plays a regulatory role in c-fos induction and mitogenesis in Swiss 3T3 cells treated with bombesin.
 ...
PMID:Bombesin stimulation of c-fos expression and mitogenesis in Swiss 3T3 cells: the role of prostaglandin E2-mediated cyclic AMP accumulation. 217 Jan 55

Extracellular ATP, N6-(L-2-phenylisopropyl)adenosine (PIA) and other purinergic agonists inhibited atrial natriuretic peptide (ANP)-induced cGMP accumulation in FRTL-5 thyroid cells. These agonists were functionally classified into three groups. Group 1 agonists represented by ATP inhibited the ANP action in association with phospholipase C activation in a partially islet-activating protein (IAP, pertussis toxin)-sensitive manner. Group 2 including GTP and 8-bromoadenosine 5'-triphosphate acted similarly to Group 1 except for total insensitivity of the former to IAP. The IAP-insensitive portion of Group 1 actions and the actions of Group 2 as well as of A23187, a Ca2+ ionophore which mimicked the Group 2 agonist actions, were almost completely inhibited by phosphodiesterase inhibitors such as M & B 22948 (2-O-propoxyphenyl-8-azapurin-6-one) and 3-isobutyl-1-methylxanthine. Group 3 including PIA and AMP did not affect phospholipase C, but inhibited the ANP performance in an IAP-sensitive fashion. This action of Group 3 and the IAP-sensitive portion of Group 1 actions were insensitive to the phosphodiesterase inhibitors. We conclude that ATP and other Group 1 agonists attenuated the ANP-induced cGMP accumulation by at least two mechanisms: 1) stimulation of cGMP hydrolysis via a phospholipase C-Ca2(+)-phosphodiesterase system and 2) inhibition of cGMP generation, probably by an IAP-sensitive G-protein-mediated inactivation of the ANP-receptor-coupled guanylate cyclase. Group 2 agonists stimulate only the first mechanisms, whereas Group 3 agonists prefer the second one.
 ...
PMID:Inhibition of atrial natriuretic peptide-induced cGMP accumulation by purinergic agonists in FRTL-5 thyroid cells. Involvement of both pertussis toxin-sensitive and insensitive mechanisms. 217 85

Cholera toxin (CT) inhibited the in vitro growth of three of four human small-cell lung carcinoma (SCLC) cell lines with a 50% inhibitory concentration of 27-242 ng/ml. Loss of surface membrane ruffling and the capacity of [Tyr4]-bombesin, vasopressin, and fetal calf serum to stimulate increases in intracellular free calcium clearly preceded effects on cellular metabolic activity and cell growth. 125I-[Tyr4]-bombesin binding was unaffected by CT treatment but [Tyr4]-bombesin stimulated phospholipase C activity was decreased in membranes from CT-treated SCLC cells. CT stimulated a rapid but transient increase in intracellular cyclic AMP ([cAMP]i) in SCLC. The effects of CT on susceptible SCLC were not reproduced by elevations of [cAMP]i induced by forskolin or cyclic AMP analogues. GM1 ganglioside, the cellular binding site for CT, was highly expressed in the CT-sensitive but not the CT-resistant SCLC cell lines. In contrast, expression of guanine nucleotide binding protein substrates for ADP-ribosylation by CT was similar. These data demonstrate the existence of a CT-sensitive growth inhibitory pathway in SCLC-bearing GM1 ganglioside. Addition of CT results in decreased responsiveness to several mitogenic stimuli. These results suggest novel therapeutic approaches to human SCLC.
 ...
PMID:Cholera toxin inhibits signal transduction by several mitogens and the in vitro growth of human small-cell lung cancer. 217 11

The role of protein kinase C (PKC) in stimulus recognition and insulin secretion was investigated after long-term (24 h) treatment of RINm5F cells with phorbol 12-myristate 13-acetate (PMA). Three methods revealed that PKC was no longer detectable, and PMA-induced insulin secretion was abolished. Such PKC-deficient cells displayed enhanced insulin secretion (2-6-fold) in response to vasopressin and carbachol (activating phospholipase C) as well as to D-glyceraldehyde and alanine (promoting membrane depolarization and voltage-gated Ca2+ influx). Insulin release stimulated by 1-oleoyl-2-acetylglycerol (OAG) was also greater in PKC-deficient cells. OAG caused membrane depolarization and raised the cytosolic Ca2+ concentration ([Ca2+]i), both of which were unaffected by PKC down-regulation. Except for that caused by vasopressin, the secretagogue-induced [Ca2+]i elevations were similar in control and PKC-depleted cells. The [Ca2+]i rise evoked by vasopressin was enhanced during the early phase (observed both in cell suspensions and at the single cell level) and the stimulation of diacylglycerol production was also augmented. These findings suggest more efficient activation of phospholipase C by vasopressin after PKC depletion. Electrically permeabilized cells were used to test whether the release process is facilitated after long-term PMA treatment. PKC deficiency was associated with only slightly increased responsiveness to half-maximally (2 microM) but not to maximally stimulatory Ca2+ concentrations. At 2 microM-Ca2+ vasopressin caused secretion, which was also augmented by PMA pretreatment. The difference between intact and permeabilized cells could indicate the loss in the latter of soluble factors which mediate the enhanced secretory responses. However, changes in cyclic AMP production could not explain the difference. These results demonstrate that PKC not only exerts inhibitory influences on the coupling of receptors to phospholipase C but also interferes with more distal steps implicated in insulin secretion.
 ...
PMID:Potentiation of stimulus-induced insulin secretion in protein kinase C-deficient RINm5F cells. 217 69

The muscarinic acetylcholine receptor-mediated inhibition of adenylate cyclase was studied in slices of guinea-pig cerebral cortex under normal and depolarizing conditions. Carbachol (1 mM) inhibited basal and isoproterenol (50 microM)-stimulated cyclic AMP (cAMP) accumulation by 20% and 25%, respectively, in normal Krebs-Ringer bicarbonate buffer solution (KRB). High-K+ medium (42 mM K+) increased cAMP accumulation to 330% of the basal level and abolished the inhibitory effect of carbachol. It also abolished the effect of morphine, an agonist of opioid receptors. Low-Ca2+ KRB or the presence of the Ca2+ channel blocker nifedipine, counteracted the effect of high K+ and restored the inhibitory effect of carbachol on the cAMP level. Pretreatment of slices with W-7 or trifluoperazine, two calmodulin antagonists, had the same effect as low Ca2+ or nifedipine on high-K(+)-stimulated cAMP accumulation and caused reappearance of the inhibitory effects of carbachol and morphine. On the contrary, H-7, an inhibitor of protein kinase C, and neomycin, an inhibitor of phospholipase C, had no significant effect on high-K(+)-induced phenomena and did not restore the effect of carbachol. These data suggest that the Ca2(+)-calmodulin system activated by membrane depolarization regulates the cAMP level directly and also by affecting the receptor-mediated process in nerve cells.
 ...
PMID:Disappearance in high-K+ medium of receptor-mediated inhibition of adenylate cyclase in guinea-pig cortical slices. 217 2


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>