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)

In order to approach the molecular mechanism of Li+'s mood-stabilizing action, the effect of Li+ (LiCl) on inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] mass was investigated in human neuroblastoma SH-SY5Y cells, which express muscarinic M3 receptors, coupled to PtdIns hydrolysis. Stimulation of these cells, with the cholinergic agonist acetylcholine, resulted in a rapid and transient increase in Ins(1,4,5)P3 with a maximum at 10 s. This was followed by a rapid decline in Ins(1,4,5)P3 within 30 s to a plateau level above baseline, which gradually declined to reach a new steady state, which was significantly higher than resting Ins(1,4,5)P3 at 30 min. Li+ had no effect on Ins(1,4,5)P3 in resting cells, as well as on the acetylcholine-dependent peak of Ins(1,4,5)P3. However, Li+ caused a transient reduction (at 45 s), followed by a long lasting increase in the Ins(1,4,5)P3 (30 min), as compared with controls. The Li+ effects were dose-dependent and were observed at concentrations used in the treatment of bipolar disorders. Supplementation with inositol had no effect on the level of Ins(1,4,5)P3, at least over the time periods studied. Stimulation of muscarinic receptors with consequent activation of phospholipase C were necessary for the manifestation of Li+ effects in SH-SY5Y cells, Li+ did not interfere with degradation of Ins(1,4,5)P3 after receptor-blockade with atropine, suggesting that Li+ has no direct effect on the Ins(1,4,5)P3-metabolizing enzymes. A direct effect of Li+ on the phospholipase C also is unlikely. Blockade of Ca2+ entry into the cells by Ni2+, or incubation with EGTA, which reduces agonist-stimulated accumulation of Ins(1,4,5)P3, had no effect on the Li(+)-dependent increase in Ins(1,4,5)P3.
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PMID:Time-dependent effects of lithium on the agonist-stimulated accumulation of second messenger inositol 1,4,5-trisphosphate in SH-SY5Y human neuroblastoma cells. 757 58

Lithium-stimulated MCF-7 cell proliferation was compared to proliferation stimulated by other mitogens for this cell line-estradiol (E2) and epidermal growth factor (EGF)-and lithium was found to be effective within a narrow concentration range. Mitogenic effects of lithium on proliferation stimulated by E2 and EGF were additive below maximum, but were not synergistic. The phosphoinositide pathway is a cell signaling system involved in cell proliferation, within which phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] leads to the production of the second messengers inositol-1,4,5-trisphosphate [Ins(1,4,5)P3] and diacylglycerol (DAG), as well as to calcium mobilization. At mitogen concentrations which maximally stimulated cell growth, estradiol stimulated both growth and PLC activity, while EGF and lithium stimulated cell growth but had little effect on the activity of the enzyme. Dose-responses with EGF revealed that a low concentration (0.1 ng/ml, 0.017 nM) of EGF appeared to stimulate both PLC activity and cell growth, but that higher concentrations of EGF which stimulated greater proliferation inhibited PLC activity. Steady-state levels of inositol phosphates including inositol trisphosphate were increased by all three mitogens. In growth assays, the phorbol ester phorbol 12-myristate-13-acetate (PMA), which mimics the actions of DAG, stimulated some cell growth, but dioctanoylglycerol, an additional DAG analog, and the calcium ionophore A23187, alone or with the DAG analogs, had no effect. These results suggest that PLC-mediated PtdIns(4,5)P2 hydrolysis is not primarily associated with signaling proliferation by lithium or EGF in MCF-7 breast cancer cells.
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PMID:Relationship of growth stimulated by lithium, estradiol, and EGF to phospholipase C activity in MCF-7 human breast cancer cells. 757 91

We tested lysophosphatidic acid (LPA) known to induce inositol phosphate generation and calcium signals as well as rearrangements of the cytoskeleton and mitogenic responses in fibroblasts, for its ability to activate phospholipase C in an exocrine cell system, the salt-secreting cells from the avian nasal salt gland. LPA (> 10 nmol/l) caused the generation of inositol phosphates from membrane-bound phosphatidylinositides. The resulting calcium signals resembled those generated upon activation of muscarinic receptors, the physiological stimulus triggering salt secretion in these cells. However, close examination of the LPA-mediated calcium signals revealed that the initial calcium spike induced by high concentrations of LPA (> 10 mumol/l) may contain a component that is not dependent upon generation of inositol (1,4,5)-trisphosphate (Ins(1,4,5)P3) and may result from calcium influx from the extracellular medium induced by LPA in a direct manner. Low concentrations of LPA (< 10 mumol/l), however, induce inositol phosphate generation, Ins(1,4,5)P3-mediated release of calcium from intracellular pools and calcium entry. These effects seem to be mediated by a specific plasma membrane receptor and a G protein transducing the signal to phospholipase C in a pertussis-toxin-insensitive manner. Signaling pathways of the muscarinic receptor and the putative LPA-receptor seem to merge at the G-protein level as indicated by the fact that carbachol and LPA trigger hydrolysis of the same pool of phosphatidylinositol (4,5)-bisphosphate (PIP2) and mobilize calcium from the same intracellular stores.
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PMID:Lysophosphatidic acid induces inositol phosphate and calcium signals in exocrine cells from the avian nasal salt gland. 759 41

Histamine stimulation of bovine adrenal medullary cells rapidly activated phospholipase C. [3H]Inositol 1,4,5-trisphosphate [[3H]Ins(1,4,5)P3] levels were transiently increased (200% of basal values between 1 and 5 s) before declining to a new steady-state level of approximately 140% of basal values. [3H]Inositol 1,4-bisphosphate [[3H]Ins(1,4)P2] content increased to a maximal and maintained level of 250% of basal values after 1 s, whereas levels of [3H]inositol 1,3,4-trisphosphate [[3H]Ins(1,3,4)P3], [3H]inositol 1,3-bisphosphate, and [3H]inositol 4-monophosphate ([3H]Ins4P) increased more slowly. The rapid responses were not reduced by the removal of extracellular Ca2+, but they were no longer sustained over time. The turnover rates of selected inositol phosphate isomers have been estimated in the intact cell. [3H]Ins(1,4,5)P3 was rapidly metabolized (t1/2 of 11 s), whereas the other isomers were metabolized more slowly, with t1/2 values of 113, 133, 104, and 66 s for [3H]Ins(1,3,4)P3, [3H]Ins(1,4)P2, an unresolved mixture of [3H]inositol 1- and 3-monophosphate ([3H]Ins1/3P), and [3H]Ins4P, respectively. The calculated turnover rate of [3H]Ins(1,4,5)P3 was sufficient to account for the turnover of the combination of both [3H]Ins(1,4)P2 and [3H]Ins(1,3,4)P3 but not that of [3H]Ins1/3P or [3H]Ins4P. These observations demonstrate that histamine stimulation of these cells results in a complex Ca(2+)-dependent and -independent response that may involve the hydrolysis of inositol phospholipids in addition to phosphatidylinositol 4,5-bisphosphate.
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PMID:Histamine-stimulated inositol phospholipid metabolism in bovine adrenal medullary cells: a kinetic analysis. 761 18

Stimulation of rat lacrimal acinar cells with ATP and acetylcholine (ACh) induced a rapid accumulation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and its degradation products, resulting in an initial release of Ca2+ from intracellular stores. However, after pretreating the acini with U73122 no increase in the intracellular free Ca2+ concentration ([Ca2+]i) or Ins(1,4,5)P3 production was observed. A short pretreatment with the phorbol ester 4-beta-phorbol-12-beta-myristate-13-alpha-acetate (PMA) significantly attenuated the ATP- and ACh-induced increase in [Ca2+]i and overall inositol phosphate production. In contrast, staurosporine enhanced Ins(1,4,5)P3 and inositol 1,3,4-trisphosphate [Ins(1,3,4)P3] production and [Ca2+]i above control values in ATP- and ACh-stimulated cells. Stimulation of phospholipase C by ionomycin-evoked changes in [Ca2+]i were unaltered by pretreatment with staurosporine and PMA. The data show that a change in protein kinase C activity during cell stimulation affects the inositol phosphate metabolism and thereby the cellular Ca2+ signalling processes in lacrimal acinar cells.
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PMID:Role of protein kinase C in the regulation of inositol phosphate production and Ca2+ mobilization evoked by ATP and acetylcholine in rat lacrimal acini. 761 49

Rab3 proteins are localized on secretory vesicles and appear to be involved in regulated exocytosis. We have previously shown that a modified peptide corresponding to the effector domain of the small molecular mass GTP-binding protein Rab3A, Rab3AAL, stimulates inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] production and amylase release in digitonin-permeabilized pancreatic acini. Experiments using monoclonal antibodies reveal that the Rab3-like protein present in pancreatic acini is not the Rab3A isoform. However, since the putative effector domains of the four as yet known Rab3 proteins (A, B, C and D) differ only in the C-terminal four amino acid residues, Rab3A effector domain peptide could mimic the action of the pancreas-specific Rab3 isoform. In the present study we report that peptides corresponding to the different Rab3 isoforms stimulate both Ins(1,4,5)P3 production and amylase secretion with an order of potency Rab3B/D > Rab3AAL > Rab3A = Rab3C. For Rab3A, B/D and C effector domain peptides the concentrations causing half-maximal response (EC50) were 3, 0.2 and 3 nM for Ins(1,4,5)P3 accumulation and 0.3, 0.02 and 0.3 nM for amylase release, respectively. A Rab1A effector domain peptide, Rab1AAL, and a scrambled peptide of Rab3AAL were less potent by several orders of magnitude in eliciting these responses compared with native Rab3 effector domain peptides. None of the peptides influenced Ins(1,4,5)P3 production and amylase release in intact acini. Cross-linking of 125I-Rab3B/D peptide to pancreatic acinar membranes showed a band at 70 to 75 kDa with maximum intensity at 75 kDa. Radiolabelling of the substrates could be displaced by unlabelled Rab3B/D peptide, and to a lesser extend by Rab3A peptide, whereas the scrambled peptide of Rab3AAL had no effect. These data suggest that phospholipase C and exocytosis might be regulated by Rab3B-or Rab3D-like proteins in pancreatic acinar cells. A 75 kDa protein that preferentially cross-linked to 125I-Rab3B/D effector domain peptide is a potential candidate as an effector protein of Rab3 effector domain peptides.
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PMID:Stimulation of inositol 1,4,5-trisphosphate production by peptides corresponding to the effector domain of different Rab3 isoforms and cross-linking of an effector domain peptide target. 762 28

The interference of several new hexadecylphosphocholine analogues with mitogenic signal transduction was investigated in NIH3T3 fibroblasts by studying the effects of these agents on thrombin-induced inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) formation and the subsequent Ca2+ release, on protein kinase C (PKC) in cell-free extracts, on the PKC-mediated activation of the Na+/H+ antiporter and on c-fos induction. The compounds investigated include hexadecylphosphocholine (HePC), octadecyl-[2-(N-methyl-piperidinio)-ethyl]-phosphate (D20133), octadecyl-(N,N-dimethyl-piperidinio-4-yl)-phosphate (D21266); octadecyl-[2-(trimethyl-arsonio)-ethyl]-phosphate (D21805) and hexadecylphospho-L-serine (HePS). The data indicate that (i) all compounds inhibit the thrombin-induced progression of growth-arrested NIH3T3 cells into S phase with similar IC50 values; (ii) the common denominator of all compounds is a reduction of Ins(1,4,5)P3 formation, resulting in an attenuation of Ca2+ release; (iii) the direct interaction with PKC does not significantly contribute to the antitumor activity of these agents; (iv) the new HePC congeners D21266, D21133 and D21805 affect the same targets as HePC, i.e. PKC and phosphatidylinositol 4,5-bisphosphate-specific phospholipase C (PLC). The lower toxicities of these compounds cannot be explained by a less pronounced inhibition of PKC or PLC, respectively.
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PMID:Interference of new alkylphospholipid analogues with mitogenic signal transduction. 763 30

A cytoskeletal fraction of porcine tracheal smooth muscle (PTSM) was found to contain > 90% of total cellular aldolase (fructose 1,6-bisphosphate aldolase, EC 4.1.2.13) activity. PTSM aldolase was purified by DEAE and inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) affinity chromatography and found to react with an antibody directed against human aldolase C, but not anti-aldolase A and B. The molecular mass of native aldolase was about 138 kDa (on Sephacryl S-300); SDS-denatured enzyme was 35 kDa (comigrated with rabbit skeletal muscle aldolase). Total cellular aldolase tetramer (aldolase4) content was 34.5 pmol/100 nmol lipid P(i). Ins(1,4,5)P3) binding activity coeluted with aldolase during Sephacryl 300, DEAE, and Ins(1,4,5)P3 affinity chromatography. Ins(1,4,5)P3 bound to purified aldolase (at 0 degree C) in a dose-dependent manner over the range [Ins(1,4,5)P3] 20 nM to 20 microM, with maximal binding of 1 mol of Ins(1,4,5)P3/mol aldolase4 and a Kd of 12-14 microM. Fru(1,6)P2 and Fru(2,6)P2 displaced bound Ins(1,4,5)P3) with a 50% inhibition at 30 and 170 microM, respectively. Ins(1,3,4)P3 (20 microM) and glyceraldehyde 3-phosphate (2 mM) were also potent inhibitors of Ins(1,4,5)P3 binding, but not inositol 4-phosphate or inositol 1,4-bisphosphate (20 microM each). Aldolase-bound Ins(1,4,5)P3 may play a role in phospholipase C-independent increases in free [Ins(1,4,5)P3].
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PMID:Inositol 1,4,5-trisphosphate binding to porcine tracheal smooth muscle aldolase. 765 22

One of the developmental pathways used by the social amoeba Dictyostelium discoideum produces dormant spores. As with any temporary resistant stage, these spores must be able to germinate rapidly in response to positive environmental stimuli. One such stimulus is the autoactivator, an endogenous, diffusible molecule that is secreted by spores. Previous work has shown that three phases of germination, autoactivation, spore swelling and amoebal emergence, require the activity of the Ca(2+)-dependent, regulatory protein calmodulin, implicating Ca2+ as an essential cation during germination. In this study we used a pharmacological approach coupled with the direct measurement of Ca2+ levels in germinating spore populations by atomic adsorption to examine Ca(2+)-dependent signal transduction during spore activation and germination in D. discoideum. Inhibitors of both phospholipase C and internal Ca2+ release inhibited autoactivation while exogenously added Ins(1,4,5)P3, acted synergistically with the autoactivator. The antagonists specifically affected spore activation as mediated by the autoactivator, since neither had any effect on heat-activated spores. In contrast, La3+, an inhibitor of Ca2+ uptake, had little or no effect on either autoactivation or the swelling of autoactivated spores. However, an inhibition of Ca2+ influx by La3+ inhibited both the swelling of heat-activated spores and amoebal emergence following each period of autoactivation or heat activation. Ca2+ levels change in the spore population during germination. During activation and swelling, Ca2+ efflux occurs from the spores. Both of the activating stimuli used here, the autoactivator and heat, caused this Ca2+ efflux. The efflux is reversed during emergence when there is a net Ca2+ uptake by the spores and cells from the medium. Together these data provide the first evidence that autoactivation is mediated by Ca(2+)-dependent signal transduction, leading to Ca2+ efflux, and that the late event of germination, amoebal emergence, requires Ca2+ uptake to proceed. The data also suggest that the responses of the spore to the each of autoactivator and heat, i.e. Ca2+ movements and germination, are mediated by different mechanisms.
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PMID:The role of Ca2+ during spore germination in Dictyostelium: autoactivation is mediated by the mobilization of Ca2+ while amoebal emergence requires entry of external Ca2+. 765 15

The effects of A1-adenosine-receptor occupation on Ca2+ handling in the insulin-secreting RINm5F cell line were investigated. The selective A1-agonist N6-cyclopentyladenosine (CPA) had no effect itself on the cytosolic free Ca2+ concentration in cells loaded with Fura 2. However, CPA (1) attenuated the rise due to activation of voltage-gated Ca2+ channels with Bay K 8644, and (2) caused a secondary increase (EC50 approx. 300 nM) if added after the primary Ca(2+)-mobilizing agonists vasopressin or carbamoylcholine (carbachol). Prior addition of CPA (10 microM) also potentiated (by approx. 20%) the subsequent Ca2+ peak due to maximal (100 microM) carbachol, but did not alter the EC50 of the carbachol response. Detailed analysis of the secondary rise in Ca2+ revealed further features. First, it was due to mobilization from intracellular stores, since it persisted in the absence of extracellular Ca2+. Second, it was associated with a rapid (5-15 s) increase in phospholipase C (PLC) activity, as measured by h.p.l.c. analysis of Ins(1,4,5)P3. This increase was only apparent after prior stimulation with carbachol. Third, and unlike the response to carbachol, it was mediated by a pertussis-toxin-sensitive G-protein. Fourth, it was not secondary to a decrease in cyclic AMP. Fifth, it was absolutely dependent on continued occupation of the primary receptor, since it was abolished if carbachol was displaced with the antagonist atropine. This implies a dynamic cross-talk between the two receptor coupling systems, rather than covalent modification as a result of the prior activation of PLC. Sixth, it was not associated with any desensitization of the ability of CPA to inhibit forskolin-stimulated adenylate cyclase activity. Glyceraldehyde (10 mM)-induced insulin secretion was also potently inhibited by CPA > 10 nM, but the secretory response to 100 microM carbachol was unaffected up to 10 microM. The results suggest that, in vivo, adenosine would inhibit secretion due to carbohydrate nutrients much more effectively than that due to stimuli which activate PLC.
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PMID:Cross-talk between muscarinic- and adenosine-receptor signalling in the regulation of cytosolic free Ca2+ and insulin secretion. 768 58


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