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)

Addition of 1 mM-carbachol to [3H]inositol-labelled rat parotid slices stimulated rapid formation of [3H]inositol 1,3,4,5-tetrakisphosphate, the accumulation of which reached a peak 20 s after stimulation, and then declined rapidly towards a new steady state. The initial rate of formation of inositol 1,3,4,5-tetrakisphosphate was slower than that for inositol 1,4,5-trisphosphate. The radioactivity in [3H]inositol 1,3,4,5-tetrakisphosphate fell quickly in carbachol-stimulated and then atropine-blocked parotid slices, suggesting that it is rapidly metabolized during stimulation. Parotid homogenates rapidly dephosphorylated inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate and, less rapidly, inositol 1,3,4-trisphosphate. Inositol 1,3,4,5-tetrakisphosphate was specifically hydrolysed to a compound with the chromatographic properties of inositol 1,3,4-trisphosphate. The only 3H-labelled phospholipids that we could detect in parotid slices labelled with [3H]inositol for 90 min were phosphatidylinositol, phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate. Parotid homogenates synthesized inositol tetrakisphosphate from inositol 1,4,5-trisphosphate. This activity was dependent on the presence of ATP. We suggest that, during carbachol stimulation of parotid slices, the key event in inositol lipid metabolism is the activation of phosphatidylinositol 4,5-bisphosphate-specific phospholipase C. The inositol 1,4,5-trisphosphate thus liberated is metabolized in two distinct ways; by direct hydrolysis of the 5-phosphate to form inositol 1,4-bisphosphate and by phosphorylation to form inositol 1,3,4,5-tetrakisphosphate and hence, by hydrolysis of this tetrakisphosphate, to form inositol 1,3,4-trisphosphate.
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PMID:Rapid formation of inositol 1,3,4,5-tetrakisphosphate and inositol 1,3,4-trisphosphate in rat parotid glands may both result indirectly from receptor-stimulated release of inositol 1,4,5-trisphosphate from phosphatidylinositol 4,5-bisphosphate. 302 54

We prepared [3H]inositol-,3-[32P]phosphate-and 4-[32P]phosphate-labeled inositol phosphate substrates to investigate the metabolism of inositol 1,3,4-trisphosphate and inositol 1,4-bisphosphate. In crude extracts of calf brain, inositol 1,3,4-trisphosphate is first converted to inositol 3,4-bisphosphate, then the inositol 3,4-bisphosphate intermediate is further converted to inositol 3-phosphate. Similarly, inositol 1,4-bisphosphate is converted to inositol 4-phosphate, and no inositol 1-phosphate is formed. We partially purified an enzyme that we tentatively name inositol polyphosphate 1-phosphatase. This cytosolic enzyme converts inositol 1,3,4-trisphosphate to inositol 3,4-bisphosphate and also converts inositol 1,4-bisphosphate to inositol 4-phosphate. The enzyme does not utilize inositol 1,3,4,5-tetrakisphosphate, inositol 1,4,5-trisphosphate, or inositol 1-phosphate as substrates. Thus we propose a new scheme for inositol phosphate metabolism. According to this pathway inositol 1,4,5-trisphosphate and inositol 1,4-bisphosphate are degraded to inositol 4-phosphate. Inositol 1-phosphate, which is the major inositol monophosphate formed in stimulated brain, is derived either from phospholipase C cleavage of phosphatidylinositol or from the degradation of inositol cyclic phosphates.
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PMID:Pathway for inositol 1,3,4-trisphosphate and 1,4-bisphosphate metabolism. 303 69

Despite their physicochemical and mechanistic differences platelet activating factor (or acetylglycerylether phosphorylcholine; AGEPC) and thrombin, both platelet stimulatory agents, induce phosphoinositide turnover in platelets. We therefore investigated the stimulation of the phosphoinositide phosphodiesterase by these agents and questioned whether they evoked hydrolysis of the same or different pools of phosphoinositides. [3H]Inositol-labelled rabbit platelets were challenged with thrombin and/or AGEPC under a variety of protocols, and the phospholipase C mediated production of radioactive inositol monophosphate (IP); inositol bisphosphate (IP2) and inositol trisphosphate (IP3) was used as the parameter. AGEPC (1 X 10(-9) M) caused a transient maximum (5 to 6-fold) increase in [3H]IP3 at 5 s followed by a decrease. Thrombin (2 U/ml) elicited an increase in [3H]IP3 at a much slower rate than AGEPC; 2 fold at 5 s, 5 fold at 30 s and a maximum 6 to 8-fold at 2-5 min. Compared to AGEPC, thrombin stimulated generation of [3H]IP2 and [3H]IP were severalfold higher. When thrombin and AGEPC were added together to platelets there was no evidence for an additive increase in inositol polyphosphate levels except at earlier time points where increases were submaximal. When AGEPC was added at various time intervals after thrombin pretreatment, no additional increases in [3H]IP3 were observed over that maximally seen with thrombin or AGEPC alone. In another set of experiments, submaximal increases (about 1/4 and 1/2 of maximum) in [3H]IP3 were achieved by using selected concentrations of thrombin (0.1 U and 0.3 U, respectively) and then AGEPC (1 X 10(-9) M) was added for 5 s. Once again the increase in [3H]IP3 was close to the maximal level seen with thrombin or AGEPC individually. It is concluded that thrombin and AGEPC differentially activated phosphoinositide phosphodiesterase (phospholipase C) in rabbit platelets and that the stimulation of the phospholipase C by these two stimuli causes IP3 production via hydrolysis of a common pool of phosphatidylinositol 4,5-bisphosphate.
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PMID:Activation of phospholipase C in platelets by platelet activating factor and thrombin causes hydrolysis of a common pool of phosphatidylinositol 4,5-bisphosphate. 303 49

We have employed a neutral-pH extraction technique to look for inositol 1,2-cyclic phosphate derivatives in [3H]inositol-labelled parotid gland slices stimulated with carbachol. The incubations were terminated by adding cold chloroform/methanol (1:2, v/v), the samples were dried under vacuum and inositol phosphates were extracted from the dried residues by phenol/chloroform/water partitioning. Water-soluble inositol metabolites were separated by h.p.l.c. at pH 3.7. 32P-labelled inositol phosphate standards (inositol 1-phosphate, inositol 1,2-cyclic phosphate, inositol 1,4,5-trisphosphate and inositol 1,2-cyclic 4,5-trisphosphate) were quantitively recovered through both extraction and chromatography steps. Treatment of inositol cyclic phosphate standards with 5% (w/v) HClO4 for 10 min prior to chromatography resulted in formation of the expected non-cyclic compounds. [3H]Inositol 1-phosphate and [3H]inositol 1,4,5-trisphosphate were both present in parotid gland slices and both increased during stimulation with 1 mM-carbachol. There was no evidence for significant quantities of [3H]inositol 1,2-cyclic phosphate or [3H]inositol 1,2-cyclic 4,5-trisphosphate in control or carbachol-stimulated glands. Parotid gland homogenates rapidly converted inositol 1,4,5-trisphosphate to inositol bisphosphate and inositol tetrakisphosphate, but metabolism of the inositol cyclic trisphosphate was much slower. The results suggest that inositol 1,4,5-trisphosphate, but not inositol 1,2-cyclic 4,5-trisphosphate, is the water-soluble product of muscarinic receptor-stimulated phospholipase C in rat parotid glands.
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PMID:Inositol 1,2-cyclic 4,5-trisphosphate is not a product of muscarinic receptor-stimulated phosphatidylinositol 4,5-bisphosphate hydrolysis in rat parotid glands. 303 79

Hydrolysis of membrane inositol phospholipids during agonist-induced contraction in bronchial smooth muscle leads to formation of inositol phosphates. Inositol phosphates are associated with intracellular Ca++ mobilization, which in smooth muscle leads to contraction. We have investigated the effects of inhibitors of the contraction, theophylline, isoproterenol (isoprenaline), and verapamil, on contraction due to carbachol and histamine in bovine airway smooth muscle, and on the formation of inositol phosphates in the same preparation. Since phospholipase C and A2 are involved in the formation of inositol phosphates, we have also studied the effect of inhibitors of phospholipases, dexamethasone and mepacrine, on the accumulation of inositol phosphates. Theophylline, isoproterenol and verapamil elicited a concentration-dependent relaxation of pre-contracted smooth muscle, with the following order of potency: Isoproterenol greater than verapamil greater than theophylline. The relaxant effect was more effective on histamine than on carbachol-induced contraction and depended on the initial airway tone. However, neither theophylline, isoproterenol or verapamil, nor dexamethasone or mepacrine changed the basal level of inositol phosphates or affected the rise due to agonists. We conclude that the smooth muscle effects of theophylline, isoproterenol, verapamil, dexamethasone and mepacrine are not mediated by interference with membrane phosphoinositide breakdown.
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PMID:Breakdown of phosphoinositides in airway smooth muscle: lack of influence of anti-asthmatic drugs. 304 Nov 48

Inositol phospholipid degradation and release of phospholipid-bound arachidonic acid was induced in intact peritoneal macrophages by exposure to phorbol myristate acetate (PMA) or zymosan particles. PMA, known to activate protein kinase C, selectively enhanced the deacylation of phosphatidylinositol (i.e., degradation by phospholipase A), while zymosan particles enhanced degradation via both phospholipase A and inositol lipid phosphodiesterase (phospholipase C). The release of arachidonic acid was found to correlate with the degradation of phosphatidylinositol by the phospholipase A pathway and could be dissociated from the phospholipase C-catalyzed cleavage of inositol phospholipids in several experimental situations: (i) when PMA was the stimulus, (ii) by the difference in Ca2+ dependence between the two enzymatic processes when zymosan was the stimulus and (iii) by the parallel inhibition by chlorpromazine of the phospholipase A pathway and arachidonic acid release, but not inositol phospholipid phosphodiesterase. In addition, phloretin, a reported inhibitor of protein kinase C, was found to inhibit arachidonic acid release and the deacylation of phosphatidylinositol. The results are consistent with a model in which arachidonic acid release is mediated by phospholipase(s) A and in which PMA or the phosphodiesterase-catalyzed degradation of phosphoinositides causes activation of the phospholipase A pathway via protein kinase C.
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PMID:Evidence for a catalytic role of phospholipase A in phorbol diester- and zymosan-induced mobilization of arachidonic acid in mouse peritoneal macrophages. 308 22

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

We have previously demonstrated that the chlorphentermine (CP)1-induced impairment in lymphocyte blastogenesis involves drug-induced inhibition of an event which occurs very early during lymphocyte activation. An early event, which is associated with mitogen-induced lymphocyte activation, involves the hydrolysis of phosphatidylinositol by phospholipase C to yield inositol phosphates and diacylglycerol as products. Inositol phosphates and diacylglycerol then function as mediators of a trans-membrane signal for the continuation of the cellular response. It was the purpose of the present study to determine the effects of CP on this phosphatidylinositol pathway. We demonstrated that formation of inositol phosphates in lymphocytes increases progressively above control over a 2 hour period following concanavalin A (Con A)-stimulation. In contrast, lymphocytes pre-incubated with 10(-5)M CP for 60 min, then stimulated with Con A for 2 hours in the presence of 10(-5)M CP, exhibit a significantly depressed inositol phosphate formation. In addition, CP also inhibited the activity of phospholipase C (IC50 = 0.58 mM), the enzyme responsible for the formation of inositol phosphates during lymphocyte activation. Further, lymphocytes activated in a manner that bypasses the phosphatidylinositol pathway are not inhibited by 10(-7)M or 10(-9)M CP as are cells activated with Con A. These results suggest that the suppression of the phosphatidylinositol pathway may be involved in the inhibition by CP of lymphocyte blastogenesis induced by Con A.
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PMID:Chlorphentermine suppresses the phosphatidylinositol pathway in concanavalin A-activated mouse splenic lymphocytes. 336 Oct 70

Maitotoxin (3 ng/mol) induced a massive uptake of 45Ca2+ into BC3H1 cells. This effect exhibits a lag phase of 3 min. Inositol diphosphate formation occurred concomittantly with the 45Ca2+ uptake but inositol monophosphate formation was found only after a 5-min delay following toxin addition. Maitotoxin-induced 45Ca2+ influxes could not be blocked by either 1 microM verapamil, 1 microM nifedipine or 1 mM La3+ but was blocked by Zn2+ (IC50 = 41 microM). In addition to inositol phosphate formation and 45Ca2+ uptake, maitotoxin stimulated a large uptake of Na+ and a great loss of K+ in BC3H1 cells. In the absence of Ca2+ (1 mM EGTA) none of the four maitotoxin effects could be detected. After restoration of Ca2+, the maitotoxin effects reappeared even when the toxin itself was no longer present. The divalent cation, Co2+ (1 mM), inhibited ion movements induced by maitotoxin and also digitonin (8.1 microM). The toxin action showed a very pronounced pH dependence. At low pH, maitotoxin was inactive. The dose-response curves for H+ ion inhibition of maitotoxin-induced Ca2+ uptake showed a shift to the right when determined in the absence of HCO3- and HCO3-/Cl- ions. It was concluded that the primary action of maitotoxin in BC3H1 cells was a pore-forming or channel-forming activity of a non-classical type. Some properties of maitotoxin resemble those of alpha-latrotoxin, others those of pore-forming agents such as melittin or alpha-toxin of Staphylococcus aureus.
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PMID:New insights into maitotoxin action. 339 Nov 76

Inositol (1,4,5)triphosphate (InsP3) and tetrakisphosphate (InsP4) have been observed in a variety of cell types and have been proposed to play roles in the receptor-mediated rise in intracellular Ca2+ (refs 2, 3). Recently, they have been shown to act synergistically in the activation of a Ca2+-dependent K+ channel in lacrimal acinar cells. InsP3 is the product of phospholipase C (PLC) action on phosphatidylinositol 4,5-bisphosphate (PtdInsP2) whereas InsP4 is believed to arise from phosphorylation of InsP3 by a cytosolic kinase. Although sought as a source for InsP4, PtdInsP3 has not been identified in any specific cell type. There were early reports of InsP4-containing phospholipids in crude extract from bovine brain, but this finding was later withdrawn. Recently, however, a membrane-bound enzyme (Type 1 PI kinase) which adds phosphate onto the 3 position of inositol phospholipids has been identified and the phosphatidylinositol-3-phosphate (PtdIns(3)P) product characterized. This suggests that several forms of phosphoinositides may exist and could be precursors for some of the variety of soluble inositol phosphate products which have been reported in recent years. Here we report the appearance of another novel phosphoinositide containing four phosphates, phosphatidylinositol trisphosphate (PtdInsP3) which we find only in activated but not in unstimulated neutrophils from human donors.
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PMID:An inositol tetrakisphosphate-containing phospholipid in activated neutrophils. 339 26


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