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)

A portion of the specific binding of tritiated SKF-10047 to the guinea-pig brain suspension of the particulate fraction is not inhibited by the strong narcotic analgesic l-etorphine. The binding properties of these etorphine-inaccessible (EI) sites were examined. The specific binding of [3H]SKF-10047 to the EI sites is saturable. Scatchard analysis of the saturation curve revealed a single class of binding sites with apparent Kd of 252 nM and an estimated Bmax of 663 fmol/mg of protein. The EI binding was reduced by heat treatment, trypsin digestion and phospholipase C digestion. The presence of sodium ions slightly increased specific EI binding. Lithium ion increased the EI binding by about 38% at the optimal concentration of 1 mM. Divalent cations such as Mg++, Ca++ and Mn++ reduced EI binding. Morphine-like drugs such as morphine, levorphanol and naltrexone were poor inhibitors for the EI binding, whereas opioid derivatives such as pentazocine, dextrallorphan, cyclazocine, SKF-10047 and dextrorphan were potent inhibitors. Nonopioid drugs such as haloperidol, imipramine, pimozide and propranolol were also potent inhibitors of the EI binding. Distribution of the EI sites in brain was different from that of the mu receptor: highest concentration of EI sites was found in brainstem, midbrain and cerebellum, whereas lower concentrations were found in striatum and cortex. It is suggested that EI sites are not mu receptors but may represent sigma receptors in the central nervous system, mediating psychotomimetic effects of several opioids and other drugs.
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PMID:Evidence for sigma opioid receptor: binding of [3H]SKF-10047 to etorphine-inaccessible sites in guinea-pig brain. 629 Jun 34

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

This investigation examined if lithium, the primary therapeutic treatment for bipolar affective disorder, modulated the levels of selected signal transduction proteins in PC12 cells. Nerve growth factor (NGF) induced differentiation of PC12 cells, and after 12 days of NGF treatment there were large increases in the levels of the heterotrimeric G protein subunits alpha o1, alpha i1, beta, and alpha s, small increases in those of alpha i2 and alpha q, and a slight decrease in that of alpha o2. Lithium (1 mM, equivalent to the therapeutic concentration) selectively reduced NGF-induced increases in levels of G protein subunits, generally having the greatest inhibition on those that were increased the most by NGF. Lithium at 5 mM had greater inhibitory effects than 1 mM lithium on NGF-induced increases in levels of G proteins, but neither concentration of lithium affected the induction of the cytoskeletal protein beta-tubulin. Examination of other proteins involved in signal transduction revealed that 12 days of NGF treatment increased the level of protein kinase C-alpha, but not those of the beta, epsilon, or zeta subtypes, and did not alter the levels of beta, gamma, or delta phospholipase C. Pretreatment with lithium inhibited the increase in content of protein kinase C-alpha induced by NGF but had little effect on the proteins not responsive to NGF except for decreasing the levels of protein kinase C-epsilon. The inhibitory effect of lithium was found not to be due to inhibition of NGF-induced tyrosine phosphorylation, which was unaffected by 5 mM lithium, or to inositol depletion. In summary, use of the dynamic system of NGF-induced PC12 cell differentiation provided a sensitive model in which to identify signal transduction proteins that were influenced by lithium treatment. The large changes caused by a therapeutically equivalent concentration of lithium lend support to the proposal that the selective inhibitory effects of lithium on subtypes of G proteins and protein kinase C may be important therapeutic targets.
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PMID:Selective inhibition of the expression of signal transduction proteins by lithium in nerve growth factor-differentiated PC12 cells. 759 44

A novel autoradiographic method to identify individual neurons responding to neurotransmitter stimulation with increased phosphoinositide turnover is described. When phosphoinositide-coupled receptors are activated, phosphatidylinositol 4,5-bisphosphate is hydrolysed by phospholipase C generating the two second messengers, inositol 1,4,5-trisphosphate and diacylglycerol. During prolonged receptor stimulation, both second messengers are actively recycled to maintain the effective intracellular levels of agonist-sensitive phosphoinositides. Lithium ions inhibit this recycling pathway by blocking the recovery of free inositol from inositol 1,4,5-trisphosphate thus leading to the accumulation of phosphatidyl cytidine monophosphate, a membrane bound molecule which is the activated precursor of the synthesis of phosphoinositides. Therefore, addition of excess myo-inositol reverts the effects of lithium inhibition. Thus, taking advantage of this fact and using [3H]cytidine as precursor, phosphatidyl [3H]cytidine monophosphate accumulation was induced in rat neocortical and hippocampal slices after muscarinic or metabotropic glutamate receptor stimulation. The labelled slices were then fixed, dehydrated and embedded in Durcupan resin. Semithin sections (1 micron thick) were cut and exposed to autoradiographic emulsion for several weeks. Biochemical analysis of the incorporation of [3H]cytidine into the chloroform extracted (containing lipids) and the alkali-solubilized (containing nucleic acids and proteins) fractions were carried out in parallel with morphological studies. The stimulation of both receptor types induced labelling of neurons in neocortex and hippocampus. In labelled cells silver grains were characteristically observed over the cytoplasm surrounding the nucleus and main dendritic processes. The anatomical location and distribution of labelled cells as well as the levels of response obtained in both brain regions studied, was found to be receptor specific. Inclusion of 30 mM myo-inositol in the incubation media reversed completely both the accumulation of phosphatidyl [3H]cytidine monophosphate and the labelling of cells, thus demonstrating that the label detected autoradiographically corresponds to phosphatidyl [3H]cytidine monophosphate. It is concluded that the method is sensitive and specific, allowing identification of individual neurons in both neocortical and hippocampal slices and after stimulation of both muscarinic and metabotropic glutamate receptor subtypes. The method may open a new means to study the phosphoinositide second messenger signalling pathway and the cells in which it takes place.
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PMID:Visualization of agonist-stimulated inositol phospholipid turnover in individual neurons of the rat cerebral cortex and hippocampus. 793 13

Lithium is thought to have an insulin-like effect on glucose transport and metabolism in skeletal muscle and adipocytes. However, we found that lithium had only a minimal effect on basal glucose transport activity in rat epitrochlearis muscles. Instead, lithium markedly increased the sensitivity of glucose transport to insulin, so that the increase in glucose transport activity induced by 300 pM insulin was approximately 2.5-fold greater in the presence of lithium than in its absence. Lithium also caused a modest increase in insulin responsiveness. This enhancement of the susceptibility of the glucose transport process to stimulation was not limited to insulin, because lithium induced increases in the susceptibility of glucose transport to stimulation by contractile activity, hypoxia, a phorbol ester, and phospholipase C. Lithium also blunted the activation of glycogen phosphorylase by epinephrine. These effects were not mediated by inhibition of adenylate cyclase, because neither basal- nor epinephrine-stimulated muscle cAMP concentration was affected by lithium treatment. The effects of lithium on glucose transport and metabolism in skeletal muscle are strikingly similar to the persistent effects of exercise. These results support the possibility that lithium might be useful in the treatment of insulin resistance in patients with non-insulin-dependent diabetes mellitus.
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PMID:Lithium increases susceptibility of muscle glucose transport to stimulation by various agents. 801 55

We have studied the long-term effects of lithium on neuronal morphology and the functional expression of phospholipase C-coupled m3-muscarinic acetylcholine receptors (mAChRs) in cerebellar granule cells. There was a biphasic dose-dependent effect on cell morphology following treatment with lithium for 7 days. At low concentrations (< or = 2 mM), this drug elicited an increase in the number and thickness of connecting nerve fibers, and the size of neuronal aggregates. At high concentrations (5-10 mM), lithium induced a severe deterioration of cell morphology, which ultimately resulted in neuronal death. Carbachol-induced phosphoinositide (PI) turnover was similarly affected by lithium treatment with a significant potentiation at concentrations up to 2 mM and a marked inhibition at doses higher than 5 mM due to lithium-induced neurotoxicity. The biphasic effect on mAChR-mediated PI hydrolysis was associated with corresponding changes in the maximal extent of carbachol-induced inositol phosphate accumulation, and was accompanied by similar changes in [3H]N-methyl-scopolamine binding to mAChRs and the levels of mRNAs for m3-mAChR and c-Fos. The up-regulation of m3-mAChR mRNA induced by low concentrations of lithium was associated with a down-regulation of m2-mAChR mRNA and no change in either total RNA or beta-actin mRNA. Lithium's effects on m2- and m3-mAChR mRNAs were time-dependent, requiring a pretreatment time of > or = 3 days. The biphasic effect was also demonstrated by the binding of [3H]ouabain to Na+, K(+)-ATPase, which was shown to be a convenient method for quantifying viable neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Long-term biphasic effects of lithium treatment on phospholipase C-coupled M3-muscarinic acetylcholine receptors in cultured cerebellar granule cells. 838 5

Lithium has a biphasic effect of the agonist-dependent accumulation of Ins(1,4,5)P3 in human neuroblastoma SH-SY5Y cells. These effects consist of a transient reduction, followed by a long-lasting increase in Ins(1,4,5)P3 as compared to controls. The Li+ effects are dose dependent, and were observed at concentrations used in the treatment of bipolar disorders, and thus may have therapeutic implications. The mechanism of the Li+ effect on Ins(1,4,5)P3 accumulation requires further investigation. The transient reduction of Ins(1,4,5)P3 was observed under conditions where Li+ causes only a moderate increase in the inositol mono- and bi-phosphates. Supplementation with exogenous inositol had no effect on the level of Ins(1,4,5)P3, indicating that the mechanism of the Li(+)-dependent reduction of Ins(1,4,5)P3 is not due to inositol depletion. Li+ did not interfere with degradation of Ins(1,4,5)P3 after receptor-blockage 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 is also unlikely. Entry of Ca2+ into the cells is an important factor, which affects agonist-stimulated accumulation of Ins(1,4,5)P3, as well as absolute values of Li(+)-dependent increase in Ins(1,4,5)P3; however, it is not essential for the manifestation of Li+ effects. Our results also show that manifestation of Li+ effects in human neuroblastoma cells requires the stimulation of muscarinic receptors and activation of PLCs, PKCs, and/or that other staurosporine/H-7/GF 109203X-sensitive protein kinases are involved in the regulation of Ins(1,4,5)P3 during the plateau phase of ACh-stimulation. We also suggest an important role for these enzymes in the Li(+)-dependent elevation of Ins(1,4,5)P3.
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PMID:Phosphoinositide signalling in human neuroblastoma cells: biphasic effect of Li+ on the level of the inositolphosphate second messengers. 886 50

Lithium is the first-line treatment for bipolar disorder. In the past, genetic studies have attempted to identify factors associated with positive treatment response or side effects. Several research groups have shown that familial factors, family history of primary bipolar disorder, and negative family history of schizophrenia in particular, correlate well with prophylactic lithium response. Conversely, studies of lithium responsive patients and their families can assist genetic research of bipolar disorder. Lithium responders appear to suffer from a form of bipolar disorder that is more genetically based and more homogeneous. In a series of family studies, the author and his colleagues have confirmed the differences in family histories of lithium responders and nonresponders and shown that the mode of inheritance in lithium responders is compatible with a major-gene model. Subsequently, they initiated an international collaborative study to map the gene(s) predisposing to the illness or treatment response, or both, using both linkage and association strategies. To date, a sample of 32 families, 138 unrelated patients and 163 control subjects has been studied. In these studies, they found support for the role of phospholipase C in lithium responsive bipolar disorder.
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PMID:Pharmacogenetics of lithium response in bipolar disorder. 1021 56

Lithium remains the most widely used long-term treatment for bipolar affective disorder, but the molecular mechanisms underlying its therapeutic efficacy have not been fully elucidated. Two enzymes involved in the phospholipase C signalling system, namely the myo-inositol monophosphatase (IMPase) and the inositol polyphosphate 1-phosphatase (IPPase), have been postulated as targets for the therapeutic action of lithium in manic-depressive illness. Intriguingly, Drosophila mutants lacking IPPase activity display a defect in synaptic transmission, and this alteration could be phenocopied by lithium exposure. We recently demonstrated the presence of several polymorphisms in the IPPase-encoding inositol polyphosphate 1-phosphatase gene (INPP1) cDNA and suggested that polymorphic variants of the human IPPase might be associated with the striking difference in lithium response among bipolar patients. We report the genomic structure and organization of the INPP1 gene on chromosome 2q32. Based on DNA sequencing of the entire genomic region containing INPP1, we found that the gene consists of six exons and spans more than 25 kb. Expression analysis showed that INPP1 is present as a 1.9 kb mRNA transcript in all organs and tissues examined, including the central nervous system. The level of expression varies, with at least a fourfold higher transcript level in testis compared with other tissues with high expression. A highly polymorphic dinucleotide repeat, (CA)18-25, with an observed heterozygosity of 0.86 was detected immediately downstream of the gene. The present sequence information will be used to further investigate the possible role of the INPP1 gene in lithium-treated bipolar illness.
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PMID:Genomic structure and sequence analysis of a human inositol polyphosphate 1-phosphatase gene (INPP1). 1078 Feb 72

The effect of experimental procedures designed to modify an intracellular phosphoinositide signalling pathway, which may be instrumental in the photophobic response of the protozoan ciliate Blepharisma japonicum, has been investigated. To assess this issue, the latency time of the photophobic response and the cell photoresponsiveness have been assayed employing newly developed computerized videorecording and standard macro-photographic methods. Cell incubation with neomycin, heparin and Li+, drugs known to greatly impede phosphoinositide turnover, causes evident dose-dependent changes in cell photomotile behaviour. The strongest effect on photoresponses is exerted by neomycin, a potent inhibitor of polyphosphoinositide hydrolysis. The presence of micromolar concentrations of neomycin in the cell medium causes both prolongation of response latency and decrease of cell photoresponsiveness. Neomycin at higher concentrations (> 10 microM) abolishes the cell response to light at the highest applied intensity. A slightly lower inhibition of cell responsiveness to light stimulation and prolongation of response latency are observed in cells incubated in the presence of heparin, an inositol trisphosphate receptor antagonist. Lithium ions, widely known to deplete the intracellular phosphoinositide pathway intermediate, inositol trisphosphate, added to the cell medium at millimolar level, also cause a slowly developing inhibitory effect on cell photoresponses. Mastoparan, a specific G-protein activator, efficiently mimics the effect of light stimulation. In dark-adapted ciliates, it elicits ciliary reversal with the response latency typical for ciliary reversal during the photophobic response. Sustained treatment of Blepharisma cells with mastoparan also suppresses the photoresponsiveness, as in the case of cell adaptation to light during prolonged illumination. The mastoparan-induced responses can be eliminated by pretreatment of the cells with neomycin. Moreover, using antibodies raised against bovine transducin, a cross-reacting protein with an apparent molecular mass of about 55 kDa in the Blepharisma cortex fraction is detected on immunoblots. The obtained results indirectly suggest that the changes in internal inositol trisphosphate level, possibly elicited by G-protein-coupled phospholipase C, might play a role in the photophobic response of Blepharisma. However, further experiments are necessary to clarify the possible coupling between the G-protein and the putative phospholipase C.
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PMID:Contribution of phosphoinositide-dependent signalling to photomotility of Blepharisma ciliate. 1094 76


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