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)

Lithium interferes with the responses of neural and secretory cells to calcium-mobilizing agonists by blocking the generation of phospholipase C-dependent second messengers. However, the mechanism by which lithium stimulates the proliferation of other cells in response to agonists that do not activate phospholipase C remains obscure. We investigated the pathways that mediate the mitogenic action of lithium on WI-38 cells in a defined, serum-free medium. Lithium, like dexamethasone (Dex), potentiated DNA synthesis in response to the combination of insulin+epidermal growth factor (EGF) (+50%), but not in response to either growth factor alone or with Dex. As in the case of Dex, lithium could be added as late as 8 h following stimulation of quiescent cells by insulin+EGF without loss of potentiating activity. While DNA synthesis in control cultures was essentially complete by 24 h, lithium and Dex stimulated "late" DNA synthesis (24-30 h) 10-fold and 5-fold, respectively. The potentiating activity of Dex, but not that of lithium, was blocked by the specific glucocorticoid receptor antagonist, RU486. Both lithium and Dex stimulated log-phase growth, but only Dex increased saturation density. These data indicate that both lithium and Dex recruit into the cell cycle a subpopulation of cells with a longer mean prereplicative phase (G1). The effect of lithium on DNA synthesis in WI-38 cells may be mediated by the glucocorticoid response pathway at some point distal to activation of the glucocorticoid receptor, or by an independent mechanism that can be switched on late in G1.
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PMID:Lithium mimics dexamethasone in stimulating DNA synthesis by WI-38 cells. 163 35

It has been suggested that K+, Li+ and Fl- affect the function of G proteins coupled to signal transducing enzymes. Lithium, at concentrations which were found to reduce forskolin-stimulated adenylate cyclase activity, was without effect on either membrane [3H]phosphatidylinositol-4,5-bisphosphate ([3H]PIP2) hydrolysis measured in the absence or presence of 5'-guanylyl-imidodiphosphate (Gpp(NH)p), or (at greater than or equal to 2.3 mM Li+) upon the stimulation of rat cerebral cortical inositol phospholipid breakdown by either carbachol, noradrenaline or NaF measured at either 6 or 18 mM K+. The increase in assay [K+] greatly enhanced the inositol phospholipid response to carbachol but not to NaF. The inhibitory effect of carbachol upon forskolin-stimulated adenylate cyclase was not affected by raising the [K+] from 6 to 18 mM. At 6 mM K+ (both in the absence and presence of 15 microM AlCl3), the effects of carbachol and NaF upon inositol phospholipid breakdown were essentially additive, whereas at 18 mM K+, the breakdown response to carbachol (antagonised by pirenzepine with a pA2 value of 7.6) was similar in the absence and presence of NaF. It is concluded that in the rat cerebral cortex: (a) Li+ does not affect the function of either the phosphoinositide-specific phospholipase C enzyme itself or the Gp coupled to this enzyme; (b) the difference between the additivity between NaF and carbachol seen at different assay [K+] may reflect the K(+)-dependent changes in the tetrodotoxin-resistant and tetrodotoxin-sensitive pathways of carbachol stimulation of inositol phospholipid breakdown reported by Gurwitz and Sokolovsky (1987, Biochemistry 26, 633); and (c) the effect of K+ on muscarinic receptor-coupled inositol phospholipid breakdown is not found for muscarinic receptors inhibitorily coupled to adenylate cyclase. Evidence is also presented to suggest that NaF affects the dephosphorylation of the formed [3H]inositol polyphosphates.
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PMID:Effect of monovalent ions upon G proteins coupling muscarinic receptors to phosphoinositide hydrolysis in the rat cerebral cortex. 215 22

We have investigated the effects of in vivo lithium treatment on cerebral inositol phospholipid metabolism. Twice-daily treatment of rats with LiCl (3 mEq/kg) for 3 or 16 days resulted in a 25-40% reduction in agonist-stimulated inositol phosphate production, compared with NaCl-treated controls, in cortical slices prelabelled with [3H]inositol. A small effect was also seen with 5-hydroxytryptamine (5-HT) 24 h after a single dose of LiCl (10 mEq/kg). Dose-response curves to carbachol and 5-HT showed that lithium treatment reduced the maximal agonist response without altering the EC50 value. This inhibition was not affected by the concentration of LiCl in the assay buffer. Stimulation of inositol phosphate formation by 10 mM NaF in membranes prepared from cortex of 3-day lithium-treated rats was also inhibited, by 35% compared with NaCl-treated controls. Lithium treatment did not alter the kinetic profile of inositol polyphosphate formation in cortical slices stimulated with carbachol. Muscarinic cholinergic and 5-HT2 bindings were unaltered by lithium, as was cortical phospholipase C activity and isoproterenol-stimulated cyclic AMP formation. [3H]Inositol labelling of phosphatidylinositol 4,5-bisphosphate was significantly enhanced by 3-day lithium treatment. The results, therefore, indicate that subacute or chronic in vivo lithium treatment reduces agonist-stimulated inositol phospholipid metabolism in cerebral cortex; this persistent inhibition appears to be at the level of G-protein-phospholipase C coupling.
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PMID:Subacute and chronic in vivo lithium treatment inhibits agonist- and sodium fluoride-stimulated inositol phosphate production in rat cortex. 253 74

Rats were treated with dietary lithium for 30 days, followed by assessment of the activity of the receptor-coupled inositol phospholipid second messenger-producing system in three brain regions. The major effect of long-term lithium treatment was a significant reduction of the response to norepinephrine in all three brain regions that were examined: the cerebral cortex, the hippocampus, and the striatum. After long-term lithium treatment, the response to serotonin was reduced in the hippocampus and striatum, but not the cortex, and the carbachol-induced response was only reduced in the striatum. Lithium treatment did not alter the incorporation of [3H]inositol into phospholipids, the in vitro lithium concentration-dependent accumulation of [3H]inositol monophosphate, or the stimulation by NaF of inositol phospholipid hydrolysis. These results indicate that the decreased responses to agonists after long-term lithium treatment are not likely to be due to depletion of inositol phospholipids or to altered activity of myo-inositol-1-phosphatase, phospholipase C, or the guanine nucleotide-binding protein. It is suggested that long-term lithium treatment may alter receptor number or receptor coupling, perhaps by phosphorylation, thereby selectively lowering the agonist-induced generation of second messengers by the inositol phospholipid system.
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PMID:Long-term lithium treatment selectively reduces receptor-coupled inositol phospholipid hydrolysis in rat brain. 253 62

The mechanism of action of lithium regarding its therapeutic effects has not yet been established, despite many years of clinical use and scientific investigations. We recently reported that lithium stimulates the phospholipase C of NGF differentiated PC12 cells membranes. In view of the coupling between growth factor receptors, G proteins and phospholipase C, we investigated the effects of lithium on the binding of GTP to the membranes of PC12 cells cultured with NGF. Lithium (1.1 mM) increased 4-5-fold the Bmax of the binding of [3H]GTP to the PC12 membranes. NaF did not induce a similar stimulation.
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PMID:Lithium stimulates the binding of GTP to the membranes of PC12 cells cultured with nerve growth factor. 283 84

All of the known pathways for metabolizing the phospholipase C (EC 3.1.4.10) products of phosphoinositide metabolism eventually lead to myo-inositol monophosphates and products that are hydrolyzed by myo-inositol 1-phosphatase (EC 3.1.3.25). That enzyme is inhibited by lithium (Ki about 1 mM). In animals treated with LiCl, elevations of myo-inositol 1-phosphate (1-IP) occur in brain that appear to result from endogenous neural activity for they are diminished by the anesthetics halothane and pentobarbital. Lithium is thus a useful tool for assessing endogenous in vivo cerebral phosphoinositide metabolism. The 1-IP elevation is also useful for revealing in vivo central nervous system (CNS) receptor activity that is stimulated by endogenous or exogenous processes such as the effects of centrally acting drugs and of seizures. Stimulation of the CNS in the presence of lithium causes myo-inositol to be sequestered in 1-IP in proportion to the amount of stimulation. Thus if the inositol level falls sufficiently resynthesis of the phosphoinositides may be compromised and receptor response to stimuli may be reduced. Evidence for such an occurrence would support the theory that this is one mechanism by which lithium acts in the therapy of manic illness. We extended our efforts to identify such a lowering of phosphoinositide levels to mice where cerebral metabolism can be halted more rapidly than in rats. However, the only change detected was a small elevation in phosphatidylinositol 4-phosphate. We were successful, however, in causing all of the phosphoinositides to be reduced in rat cerebral cortex by pilocarpine stimulation after lithium treatment, a procedure that causes seizures. The same procedure causes the largest reduction in cortical myo-inositol levels that we have observed, and thus may represent the point where the inositol decrement is sufficient to interfere with resynthesis of the lipids.
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PMID:Effects of lithium on phosphoinositide metabolism in vivo. 301 84

Interactions among lithium, calcium, and phorbol esters in the regulation of adrenocorticotropin hormone (ACTH) release were examined in a tumor cell line (AtT-20) of the anterior pituitary. Lithium, which blocks the phosphatase that converts inositol phosphates (IPs) to inositol, increases the levels of IPs in these cells and stimulates ACTH release. This ion potentiates the ability of calcium, an activator of phospholipase C, to raise levels of IPs in these cells and to stimulate ACTH secretion. Pretreatment of AtT-20 cells with calcium specifically abolishes the ACTH release response to lithium or calcium, a result suggesting that these secretagogues may act through a common mechanism to induce hormone secretion. Prior exposure of AtT-20 cells to either lithium or calcium also attenuates the ACTH release induced by phorbol ester, an activator of protein kinase C. To examine the link among lithium, calcium, phosphatidylinositol (PI) turnover, and phorbol ester-evoked ACTH secretion, AtT-20 cells were treated with 1-oleoyl-2-acetoyl-sn-3-glycerol (OAG), an analogue of the diacylgylcerols that are formed by phospholipase C during PI metabolism and that also activate protein kinase C. OAG itself does not alter ACTH release or the levels of IPs in AtT-20 cells. Pretreatment of AtT-20 cells with OAG, however, selectively blocks the ACTH release response to lithium, calcium, or phorbol ester. Furthermore, such pretreatment reduced the ability of lithium to increase levels of IPs. The results suggest that one mechanism of action of lithium is to potentiate selectively an action of calcium, possibly the stimulation of phospholipase C activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interactions among lithium, calcium, diacylglycerides, and phorbol esters in the regulation of adrenocorticotropin hormone release from AtT-20 cells. 303 56

The production and metabolism of inositol 1,4,5-trisphosphate (Ins-1,4,5-P3) and other inositol polyphosphates was studied in cultured bovine adrenal glomerulosa cells prelabeled for 24 h with [3H]inositol. During stimulation with angiotensin II, Ins-1,4,5-P3 increased to a peak of 15-fold above basal within 10 s, followed by a second phase of continuous increase over the next 30 min. Ins-1,4,5-P3 formed during agonist stimulation was rapidly metabolized by two distinct pathways. The more direct metabolic route was via degradation by sequential dephosphorylations to form inositol 1,4-bisphosphate and inositol 4-phosphate, and ultimately inositol. Lithium ions inhibited both the formation and dephosphorylation of inositol 4-monophosphate, which is a specific product of inositol polyphosphate metabolism. In addition, a cyclical metabolic sequence was initiated by the 3-phosphorylation of Ins-1,4,5-P3 to form inositol 1,3,4,5-tetrakisphosphate. The Ins-1,4,5-P3 3-kinase responsible for this reaction had a Km of 0.4 microM for Ins-1,4,5-P3 and a Vmax of 208 pmol/min/mg and was stimulated by increased Ca2+ concentrations in the micromolar range. Inositol 1,3,4,5-tetrakisphosphate was then dephosphorylated to inositol 1,3,4-trisphosphate, which in turn was either further degraded to inositol 3,4-bisphosphate or rephosphorylated to inositol 1,3,4,6-tetrakisphosphate. Lithium ions also inhibited the production of inositol 3,4-bisphosphate, explaining the large accumulation of inositol 1,3,4-trisphosphate in cells stimulated in the presence of lithium. Prolonged exposure to angiotensin II in the presence of Li+ caused a progressive decline in inositol polyphosphate formation without depletion of the lipid precursor, phosphatidyl-inositol 4,5-bisphosphate, suggesting that an accumulating product of polyphosphoinositide hydrolysis (possibly diacylglycerol) has an inhibitory effect on the phospholipase C-catalyzed breakdown process. These results indicate that, in addition to its breakdown by sequential dephosphorylations through Ins-1,4-P2 and Ins-4-P, Ins-1,4,5-P3 undergoes a complex series of phosphorylations and dephosphorylations to form at least two inositol tetrakisphosphates and their metabolites. These newly defined pathways may provide additional regulatory steps in the mechanism of cell activation by angiotensin II and other Ca2+-mobilizing hormones.
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PMID:Multiple pathways of inositol polyphosphate metabolism in angiotensin-stimulated adrenal glomerulosa cells. 325 63

The accumulation of labelled inositol mono-, bis-, and trisphosphate in rat cerebral cortex slices was examined following preincubation with [3H]inositol. The muscarinic receptor agonist carbachol produced a rapid and sustained increased accumulation of each labelled inositol phosphate both in the presence and absence of 5 mM lithium. Lithium potentiated carbachol-stimulated accumulation of inositol monophosphate (EC50 0.5 mM) and inositol bisphosphate (EC50 4 mM) in a concentration-dependent manner. However, exposure to lithium in the presence of the muscarinic agonist produced a concentration- and time-dependent inhibition of inositol trisphosphate accumulation that was not related to receptor desensitisation. Although the present data do suggest that polyphosphoinositides are substrates for agonist-stimulated phospholipase C in brain, these results may not be entirely consistent with the production of inositol mono- and bisphosphate through inositol trisphosphate dephosphorylation. Furthermore, these data suggest site(s) additional to inositol monophosphatase that are affected by lithium.
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PMID:Differential effects of lithium on muscarinic receptor stimulation of inositol phosphates in rat cerebral cortex slices. 404 61

Muscarinic agonists cause a stable activation of tyrosine 3-monooxygenase in the superior cervical ganglion and increase the incorporation of 32Pi into phospholipids in the ganglion. We have studied the relationship between muscarine-stimulated phospholipid turnover and the muscarine-induced activation of tyrosine 3-monooxygenase. Both effects of muscarine are apparent within 2 min of incubation, and both are essentially independent of extracellular Ca++. All concentrations of muscarine that increase dopa synthesis also stimulate phospholipid turnover. Bethanechol is less efficacious than muscarine in producing both of these effects. Lithium, which disrupts phospholipid metabolism, inhibits the muscarine-stimulated accumulation of dopa. Other agents which affect phospholipid metabolism, including phospholipase C and deoxycholate, also increase the synthesis of dopa in the ganglion. These data support the hypothesis that changes in phospholipid metabolism mediate the activation of tyrosine 3-monooxygenase by muscarinic agonists.
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PMID:Muscarine increases tyrosine 3-monooxygenase activity and phospholipid metabolism in the superior cervical ganglion of the rat. 614 20


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