Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The channel forming alpha-toxin of Staphylococcus aureus (about 50 micrograms/ml) markedly reduces the Ca2+ requirement for dopamine release by the rat pheochromocytoma cell line (PC 12). Maximal secretion by intact cells requires approximately 1 mM Ca2+, whereas release by alpha-toxin-permeabilized cells can already be triggered with microM concentrations of Ca2+. The latter process reaches a plateau at about 1 microM free Ca2+ and increases again with 10-20 microM free Ca2+. The sensitivity to low concentrations of Ca2+ indicates that the toxin, as a selective cell membrane permeabilizing agent, can be used as a powerful instrument to study stimulus-secretion coupling.
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PMID:Alpha-toxin permeabilized rat pheochromocytoma cells: a new approach to investigate stimulus-secretion coupling. 404 68

Fibroblast growth factors (FGF) stimulate growth arrest and differentiation in rat pheochromocytoma PC12 cells. We examined the role of phosphatidylinositol (PI) hydrolysis in FGF-induced differentiation of PC12 cells by exploring the biological and biochemical activity of a mutant FGF receptor 1 (flg) defective in stimulation of PI hydrolysis. We show that point mutation at Tyr-766 (Y766F) of the FGF receptor prevents tyrosine phosphorylation of phospholipase C gamma and eliminates acidic FGF (aFGF)-induced stimulation of PI hydrolysis in PC12 cells. Treatment of PC12 cells expressing either wild-type or the Y766F mutant with aFGF led to tyrosine phosphorylation of Shc, the association of Shc with GRB2, a shift in the electrophoretic mobility of the Ras guanine nucleotide-releasing factor, Sos (son of sevenless), and enhancement in mitogen-activated protein kinase phosphorylation. Moreover, stimulation with aFGF led to a typical neurite outgrowth of PC12 cells expressing either wild-type or the Y766F FGF receptor mutant. These experiments indicate that PI hydrolysis is not essential for FGF-induced neuronal differentiation of PC12 cells. Moreover, the aFGF-induced Ras signaling pathway, which is essential for PC12 cell differentiation, is not affected by elimination of PI hydrolysis.
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PMID:Point mutation in the fibroblast growth factor receptor eliminates phosphatidylinositol hydrolysis without affecting neuronal differentiation of PC12 cells. 751 69

The ability of beta-amyloid peptides to activate the classical complement cascade and the presence of various complement proteins including the membrane attack complex (C5b-9) on dystrophic neurites in Alzheimer's disease brains, raises the possibility that the complement system may contribute to this neurodegenerative disorder. To address this issue, we have studied the effect of complement activation on nerve growth factor (NGF)-differentiated rat pheochromocytoma PC12 cells, and on retinoic acid (RA)-differentiated human neuroblastoma SH-SY5Y cells. Although incubation of both cell types with human serum resulted in activation of complement, as indicated by iC3b formation, only PC12 but not SH-SY5Y cells were killed by human serum treatment. In contrast, heat-inactivated serum (56 degrees C, 45 min) was not neurotoxic. On SH-SY5Y cells, both PCR amplification and immunocytochemistry demonstrated the presence of CD59, a glycosylphosphatidylinositol-anchored protein that restricts homologous complement activation by inhibiting the formation of the membrane attack complex. The presence of CD59 probably accounts for the inability of human complement to lyse the human cell lines. Indeed, removal of glycosylphosphatidylinositol (GPI)-anchored proteins with phosphatidylinositol-specific phospholipase C (PI-PLC) rendered SH-SY5Y cells vulnerable to complement attack and eventually led to serum-medicated cell death. Reconstituted C5b-9 was also toxic to both PC12 and PI-PLC-pretreated SH-SY5Y cells. These observations suggest that complement activation can cause neuronal cell death and that this process is regulated by homologous restriction.
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PMID:Complement-mediated neurotoxicity is regulated by homologous restriction. 774 16

We used the patch clamp technique to study the effect of acetyl-L-carnitine arginyl amide (ALCAA) and of nerve growth factor (NGF) on availability of L-type Ca2+ channels in rat pheochromocytoma (PC12) cells maintained in defined medium. Channel availability was measured as number of channels in the patch x the probability of opening (n.Po). In patches from control cells, cells exposed to NGF (10 ng/ml) for six days, and cells exposed to ALCAA (1 mM) for six days, n.Po, measured during 200-240 ms pulses to -10 mV (holding potential, -60 mV), was 0.102 +/- 0.089 (5 cells), 0.173 +/- 0.083 (5 cells), and 0.443 +/- 0.261 (7 cells), respectively. The 4.3-fold increase for the ALCAA-treated cells was significantly different from control (P < 0.05), whereas that for the NGF-treated cells was not. For the same conditions, the maximum number of superimposed openings at -10 mV was 1.3 +/- 0.5 (6 cells), 1.6 +/- 0.5 (8 cells), and 3.3 +/- 1.8 (8 cells), with the value for the ALCAA-treated cells being significantly different from control (P < 0.001). Additional analysis showed that the distribution of channel open times, the time constants, and the voltage dependence of activation were not changed by prolonged exposure to ALCAA. Short-term exposure to both ALCAA as well as to the parent compound, acetyl-L-carnitine (ALCAR), did not cause an increase but rather a decrease in n.Po, and this short-term effect of both compounds was blocked by neomycin, an inhibitor of phospholipase C.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acetyl-L-carnitine arginyl amide (ST857) increases calcium channel density in rat pheochromocytoma (PC12) cells. 774 31

1. The amphiphilic peptide mastoparan is known to affect phosphoinositide breakdown, calcium influx, and exocytosis of hormones and neurotransmitters and to stimulate the GTPase activity of guanine nucleotide-binding regulatory proteins. Another amphiphilic peptide, adenoregulin was recently identified based on stimulation of agonist binding to A1-adenosine receptors. 2. A comparison of the effects of mastoparan and adenoregulin reveals that these peptides share many properties. Both stimulate binding of agonists to receptors and binding of GTP gamma S to G proteins in brain membranes. The enhanced guanyl nucleotide exchange may be responsible for the complete conversion of receptors to a high-affinity state, complexed with guanyl nucleotide-free G proteins. 3. Both peptides increase phosphoinositide breakdown in NIH 3T3 fibroblasts. Pertussis toxin partially inhibits the phosphoinositide breakdown elicited by mastoparan but has no effect on the response to adenoregulin. N-Ethylmaleimide inhibits the response to both peptides. 4. In permeabilized 3T3 cells, both adenoregulin and mastoparan inhibit GTP gamma S-stimulated phosphoinositide breakdown. Mastoparan slightly increases basal cyclic AMP levels in cultured cells, followed at higher concentrations by an inhibition, while adenoregulin has minimal effects. 5. Both peptides increase calcium influx in cultured cells and release of norepinephrine in pheochromocytoma PC12 cells. The calcium influx elicited by the peptides in 3T3 cells is not markedly altered by N-ethylmaleimide. 6. Multiple sites of action appear likely to underlie the effects of mastoparan/adenoregulin on receptors, G proteins, phospholipase C, and calcium.
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PMID:Effects of the amphiphilic peptides mastoparan and adenoregulin on receptor binding, G proteins, phosphoinositide breakdown, cyclic AMP generation, and calcium influx. 784 73

1. In pheochromocytoma PC12 cells ATP and, to a lesser extent, 2-methylthioATP stimulate phosphoinositide breakdown, release of intracellular calcium, and influx of external calcium, leading to stimulation of norepinephrine release. In contrast, although UTP also stimulates phosphoinositide breakdown, release of intracellular calcium, and influx of external calcium, there is no stimulation of norepinephrine release. 2. 2-MethylthioATP, presumably acting at P2y receptors, and UTP, presumably acting at P2u receptors, in combination elicit a phosphoinositide breakdown greater than that elicited by either alone. Intracellular levels of calcium measured with Fura-2 increase to greater levels with ATP than with UTP and are sustained, while the UTP intracellular levels of calcium rapidly return to basal values. Both ATP and UTP cause a similar influx of 45 Ca2+ presumably by stimulation of a P2 receptor directly linked to a cation channel. 3. It is proposed that PC12 cells contain two distinct G protein-coupled P2 receptors that activate phospholipase C and a P2 receptor linked to a cation channel. The P2y receptor sensitive to ATP (and to 2-methylthioATP) causes the depletion of a pool of intracellular calcium, sufficient to activate so-called "receptor-operated calcium entry". The sustained elevation of intracellular calcium after ATP treatment is proposed to result in stimulation of norepinephrine release and activation of calcium-dependent potassium channels and sodium-calcium exchange pathways. 4. The P2u receptor sensitive to UTP (and to ATP) causes only a transient elevation in levels of intracellular calcium, perhaps from a different pool, insufficient to activate so-called receptor-operated calcium entry. Further sequelae do not ensue, and the functional role of the UTP-sensitive P2u receptor is unknown.
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PMID:Effects of ATP and UTP in pheochromocytoma PC12 cells: evidence for the presence of three P2 receptors, only one of which subserves stimulation of norepinephrine release. 795 59

Previous investigations have demonstrated the existence of an autonomous intranuclear inositide cycle endowed with conventional lipid kinases and phospholipase C (PLC) which is the isoform beta in Swiss 3T3 cells, PC12 pheochromocytoma cells, human osteosarcoma SaOS-2 cells, and rat liver. The presence of PLC has been investigated in nuclei of Friend erythroleukemia cells. Both beta and gamma isoforms are present in these nuclei. When Friend cells undergo terminal erythroid differentiation in the presence of dimethyl sulfoxide the PLC beta isoform is down-regulated as shown by immunochemical and immunocytochemical analysis, by determination of enzymatic activity directly and in the presence of neutralizing monoclonal antibodies and also by Northern blot for PLC beta message. By contrast, the amount of PLC gamma and its activity are unaffected by erythroid differentiation. Thus, the presence of a nuclear PLC beta, the activity and expression of which are modulated during differentiation of erythroleukemia cells, implicates a role for nuclear phosphoinositide signaling in the processes of cell determination and indicates the nuclear PLC beta as a key enzyme of the cycle in relation to the erythroid differentiative commitment of murine erythroleukemia cells.
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PMID:Phosphoinositide signaling in nuclei of Friend cells: phospholipase C beta down-regulation is related to cell differentiation. 816 74

Extracellular ATP (a purine nucleotide) and UTP (a pyrimidine nucleotide) both activated phospholipase C with a similar potency and efficacy; however, in contrast to ATP which induced a remarkable norepinephrine release, UTP-induced norepinephrine release was small in PC12 cells, a rat pheochromocytoma cell line. ATP, its derivatives (2-methylthioadenosine 5'-triphosphate (MeSATP) and 2'- and 3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate (BzATP)) and UTP increased intracellular Ca2+ in the presence of 2 mM extracellular Ca2+ with the potency order of ATP > MeSATP > BzATP = UTP. Under the low extracellular Ca2+ conditions, the Ca2+ response to purine nucleotides was markedly reduced, but the UTP response was not. The [32P]BzATP labeling of a 53-kDa putative ATP receptor coupled to a channel system (Majid, M.A., Okajima, F., and Kondo, Y. (1992) Biochim. Biophys. Acta 1136, 283-289) was markedly inhibited by ATP, but not by UTP. These results suggest that UTP activates the phospholipase C-Ca2+ system through a receptor different from the 53-kDa ATP receptor.
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PMID:UTP activates phospholipase C-Ca2+ system through a receptor different from the 53-kDa ATP receptor in PC12 cells. 836 17

Persistent stimulation of specific protein kinase pathways has been proposed as a key feature of receptor tyrosine kinases and intracellular oncoproteins that signal neuronal differentiation of rat pheochromocytoma (PC12) cells. Among the protein serine/threonine kinases identified to date, the p42/44 mitogen-activated protein (MAP) kinases have been highlighted for their potential role in signalling PC12 cell differentiation. We report here that retrovirus-mediated expression of GTPase-deficient, constitutively active forms of the heterotrimeric Gq family members, G alpha qQ209L and G alpha 16Q212L, in PC12 cells induces neuronal differentiation as indicated by neurite outgrowth and the increased expression of voltage-dependent sodium channels. Differentiation was not observed after cellular expression of GTPase-deficient forms of alpha i2 or alpha 0, indicating selectivity for the Gq family of G proteins. As predicted, overexpression of alpha qQ209L and alpha 16Q212L constitutively elevated basal phospholipase C activity approximately 10-fold in PC12 cells. Significantly, little or no p42/44 MAP kinase activity was detected in PC12 cells differentiated with alpha 16Q212L or alpha qQ209L, although these proteins were strongly activated following expression of constitutively active cRaf-1. Rather, a persistent threefold activation of the cJun NH2-terminal kinases (JNKs) was observed in PC12 cells expressing alpha qQ209L and alpha 16Q212L. This level of JNK activation was similar to that achieved with nerve growth factor, a strong inducer of PC12 cell differentiation. Supportive of a role for JNK activation in PC12 cell differentiation, retrovirus-mediated overexpression of cJun, a JNK target, in PC12 cells induced neurite outgrowth. The results define a p42/44 MAP kinase-independent mechanism for differentiation of PC12 cells and suggest that persistent activation of the JNK members of the proline-directed protein kinase family by GTPase-deficient G alpha q and G alpha 16 subunits is sufficient to induce differentiation of PC12 cells.
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PMID:GTPase-deficient G alpha 16 and G alpha q induce PC12 cell differentiation and persistent activation of cJun NH2-terminal kinases. 855 93

The I1-subtype of imidazoline binding sites has been characterized concerning binding specificity and tissue localization, and several physiological functions have been ascribed to it. However, the signaling pathways coupled to this putative receptor are not known. Pheochromocytoma PC12 cells express I1-imidazoline binding sites in plasma membrane and lack alpha2-adrenergic receptors, which recognize many I1-imidazoline ligands. In this cellular model, diacylglycerol (DAG), a second messenger, is generated in response to the putative I1-imidazoline agonist moxonidine. Using radioflux with [3H]myristate and direct measurements of DAG mass, we showed a rapid and transient peak of DAG in undifferentiated PC12 cells within the first 1 min of agonist exposure. In PC12 cells treated with nerve growth factor to initiate differentiation, DAG accumulation at 15 sec was facilitated, and the increase in DAG mass persisted throughout 10 min of agonist treatment. Efaroxan, a putative I1-antagonist, attenuated the effect of moxonidine on DAG accumulation in nerve growth factor-treated cells, as did D609, an inhibitor of phosphatidylcholine-selective phospholipase C. Phospholipase D did not seem to be involved in generation of DAG in response to I1-receptor activation, nor was there accumulation of phosphatidic acid. These findings suggest coupling of I1-imidazoline receptors to a phospholipase C to generate DAG as a second messenger, a process regulated by neuronal differentiation and possibly participating in the physiological responses to I1-imidazoline receptor activation.
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PMID:Coupling of I1-imidazoline receptors to diacylglyceride accumulation in PC12 rat pheochromocytoma cells. 860 95


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