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1.
Docosahexaenoic acid (DHA) and arachidonic acid (AA) are found in high concentrations in brain cell membranes and are important for brain function and structure. Studies suggest that AA and DHA are hydrolyzed selectively from the sn-2 position of synaptic membrane phospholipids by Ca2+-dependent cytosolic phospholipase A2 (cPLA2) and Ca2+-independent phospholipase A2 (iPLA2), respectively, resulting in increased levels of the unesterified fatty acids and lysophospholipids. Cell studies also suggest that AA and DHA release depend on increased concentrations of Ca2+, even though iPLA2 has been thought to be Ca2+-independent. The source of Ca2+ for activation of cPLA2 is largely extracellular, whereas Ca2+ released from the endoplasmic reticulum can activate iPLA2 by a number of mechanisms. This review focuses on the role of Ca2+ in modulating cPLA2 and iPLA2 activities in different conditions. Furthermore, a model is suggested in which neurotransmitters regulate the activity of these enzymes and thus the balanced and localized release of AA and DHA from phospholipid in the brain, depending on the primary source of the Ca2+ signal.  相似文献   

2.
In vitro studies show that docosahexaenoic acid (DHA) can be released from membrane phospholipid by Ca2+-independent phospholipase A2 (iPLA2), Ca2+-independent plasmalogen PLA2 or secretory PLA2 (sPLA2), but not by Ca2+-dependent cytosolic PLA2 (cPLA2), which selectively releases arachidonic acid (AA). Since glutamatergic NMDA (N-methyl-D-aspartate) receptor activation allows extracellular Ca2+ into cells, we hypothesized that brain DHA signaling would not be altered in rats given NMDA, to the extent that in vivo signaling was mediated by Ca2+-independent mechanisms. Isotonic saline, a subconvulsive dose of NMDA (25 mg/kg), MK-801, or MK-801 followed by NMDA was administered i.p. to unanesthetized rats. Radiolabeled DHA or AA was infused intravenously and their brain incorporation coefficients k*, measures of signaling, were imaged with quantitative autoradiography. NMDA or MK-801 compared with saline did not alter k* for DHA in any of 81 brain regions examined, whereas NMDA produced widespread and significant increments in k* for AA. In conclusion, in vivo brain DHA but not AA signaling via NMDA receptors is independent of extracellular Ca2+ and of cPLA2. DHA signaling may be mediated by iPLA2, plasmalogen PLA2, or other enzymes insensitive to low concentrations of Ca2+. Greater AA than DHA release during glutamate-induced excitotoxicity could cause brain cell damage.  相似文献   

3.
Abstract: Nerve growth cones isolated from fetal rat brain exhibit in their cytosol a robust level of phospholipase A2 activity hydrolyzing phosphatidylinositol (PI) and phosphatidylethanolamine (PE) but not phosphatidylcholine (PC). Western blot analysis with an antibody to the well-characterized cytosolic phospholipase A2 (mol wt 85,000) reveals only trace amounts of this PC- and PE-selective enzyme in growth cones. By gel filtration on Superose 12, growth cone phospholipase A2 activity elutes essentially as two peaks of high molecular mass, at ~65 kDa and at well over 100 kDa. Anion exchange chromatography completely separates a PI-selective from a PE-selective activity, indicating the presence of two different, apparently monoselective phospholipase A2 species. The PI-selective enzyme, the predominant phospholipase A2 activity in whole growth cones, is enriched greatly in these structures relative to their parent fractions from fetal brain. This phospholipase A2 is resistant to reducing agents and is found in the cytosol as well as membrane-associated in the presence of Ca2+. However, its catalytic activity is Ca2+-independent regardless of whether the enzyme is associated with pure substrate or mixed-lipid growth cone vesicles. The PE-selective phospholipase A2 in growth cones was studied in less detail but shares with the PI-selective enzyme several properties, including intracellular localization, the existence of cytosolic and membrane-associated forms, and Ca2+ independence. Our data indicate growth cones contain two high-molecular-weight forms of phospholipase A2 that share many properties with known, Ca2+-independent cytosolic phospholipase A2 species but that appear to be monoselective for PI and PE, respectively. In particular, the PI-selective enzyme may represent a new member of the growing family of cytoplasmic phospholipase A2. The enrichment of the PI-selective phospholipase A2 in growth cones suggests it plays a major role in the regulation of growth cone function.  相似文献   

4.
An enhancement of glutamate release from hippocampal neurons has been implicated in long-term potentiation, which is thought to be a cellular correlate of learning and memory. This phenomenom appears to be involved the activation of protein kinase C and lipid second messengers have been implicated in this process. The purpose of this study was to examine how lipid-derived second messengers, which are known to potentiate glutamate release, influence the accumulation of intraterminal free Ca2+, since exocytosis requires Ca2+ and a potentiation of Ca2+ accumulation may provide a molecular mechanism for enhancing glutamate release. The activation of protein kinase C with phorbol esters potentiates the depolarization-evoked release of glutamate from mossy fiber and other hippocampal nerve terminals. Here we show that the activation of protein kinase C also enhances evoked presynaptic Ca2+ accumulation and this effect is attenuated by the protein kinase C inhibitor staurosporine. In addition, the protein kinase C-dependent increase in evoked Ca2+ accumulation was reduced by inhibitors of phospholipase A2 and voltage-sensitive Ca2+ channels, as well as by a lipoxygenase product of arachidonic acid metabolism. That some of the effects of protein kinase C activation were mediated through phospholipase A2 was also indicated by the ability of staurosporine to reduce the Ca2+ accumulation induced by arachidonic acid or the phospholipase A2 activator melittin. Similarly, the synergistic facilitation of evoked Ca2+ accumulation induced by a combination of arachidonic acid and diacylglycerol analogs was attenuated by staurosporine. We suggest, therefore, that the protein kinase C-dependent potentiation of evoked glutamate release is reflected by increases in presynaptic Ca2+ and that the lipid second messengers play a central role in this enhancement of chemical transmission processes.  相似文献   

5.
Depolarization-evoked increases in intraterminal free Ca2+ are required for the induction of neurotransmitter release from nerve terminals. Although the mechanisms that regulate the voltage-induced accumulation of presynaptic Ca2+ remain obscure, there is evidence that the phospholipase-dependent accumulation of arachidonic acid, or its metabolites, may be involved. Therefore, fura-2 loaded hippocampal mossy fiber nerve endings were used to investigate the relationships between membrane depolarization, lipid metabolism and presynaptic Ca2+ availability. It was observed that depolarization of the nerve terminals with KCl induced an increase in intraterminal free calcium that was inhibited more than 90% by a combination of voltage-sensitive Ca2+ channel blockers. In addition, the K+-dependent effects on Ca2+ concentrations were attenuated in the presence of phospholipase A2 inhibitors, but were mimicked by the phospholipase A2 activator melittin and exogenous arachidonic acid. Both the melittin- and arachidonic acid-induced increases in presynaptic Ca2+ were reduced by voltage-sensitive Ca2+ channel blockers. The stimulatory effects of arachidonic acid appeared to be independent of its further metabolism to prostaglandins. In fact, inhibition of either cyclooxygenase or lipoxygenase pathways resulted in a potentiation of the depolarization-evoked increase in intraterminal free Ca2+. From these results, we propose that some portion of the depolarization-evoked increase in intraterminal free calcium depends on the activation of phospholipase A2 and the subsequent accumulation of unesterified arachidonic acid.  相似文献   

6.
Phospholipase A2 activity was measured in cerebral microvessels isolated from 5 to 6 month (young adult) and 21 to 24 month (aged adult) old mice. Radiolabeled 1-stearoyl-2-[1-14C]arachidonyl choline phosphoglyceride was used as the enzyme substrate, and enzyme activity determined at pH 8 and pH 9. Activity in older animals was significantly less than in younger animals at both pH's. With choline phosphoglyceride as a substrate, phospholipase A2 activity was predominantly Ca2+-dependent, although a small, but measurable Ca2+-independent component was present. Negligible production of diacylglycerol indicated little or no phospholipase C activity. These findings indicate that activity of a phospholipase A2, which utilizes choline phosphoglyceride as a substrate, is affected by the aging process. Moreover, a change in PLA2 activity would result in altered metabolism of specific phosphoglycerides and turnover of fatty acids at the sn-2 position in cerebral microvessels.  相似文献   

7.
Three phospholipases A2 purified from cobra venoms and two presynaptically acting neurotoxins that exhibit phospholipase A2 activity were subjected to tryptophan modification with 2-hydroxy-5-nitrobenzyl bromide. Associated with the modification of an increasing number of Trp residues were marked decreases in enzymatic activity and lethality, whereas antigenicity remained unchanged. The degree of exposure of tryptophanyl groups as determined by acrylamide quenching was consistent with the relative reactivity toward 2-hydroxy-5-nitrobenzyl bromide, except for Hemachatushaemachatus phospholipase A2, which showed unusually high reactivity due to its characteristic dimeric conformation. Difference spectra of Trp-modified derivatives differed from those of their native enzymes by the presence of a new positive perturbation between 350 and 500 nm, with a maximum at 415 nm. Scatchard plots revealed only one type of binding site for Ca2+, and the binding abilities of the modified enzymes were not impaired. At pH 8.0, all native enzymes enhanced the emission intensity of 8-anilinonaphthalene sulfonate (ANS) dramatically, and the emission intensity of the ANS-enzyme complex increased or decreased in parallel with increasing concentration of Ca2+ for the respective enzyme. The Trp-modified derivatives did not enhance the emission intensity of ANS at all either in the presence or absence of Ca2+. By means of tryptophan modification, we were able to infer that the tryptophan residues are in the vicinity of the Ca2+ binding site and are directly involved in the binding with ANS. This, together with the suggestion that the hydrophobic pocket that interacts with ANS might be the site of binding of the phospholipase A2 enzyme with the substrate, suggests that the Trp residues in phospholipase A2 enzymes and presynaptic toxins are involved in substrate binding.  相似文献   

8.
LA-N-1 neuroblastoma cell cultures contain Ca2+-independent phospholipases A2 hydrolyzing phosphatidylethanolamine and ethanolamine plasmalogens. These enzymes differ from each other in their molecular mass, substrate specificity, and kinetic properties. Subcellular distribution studies have indicated that the activity of these phospholipases is not only localized in the cytosol but also in non-nuclear membranes and in nuclei. The treatment of LA-N-1 neuroblastoma cell cultures with retinoic acid results in a marked stimulation of Ca2+-independent phospholipases A2 hydrolyzing phosphatidylethanolamine and plasmenylethanolamine. The increase of the activities of both enzymes was first observed in nuclei followed by those present in the cytosol. No effect of retinoic acid on either phospholipase activity could be observed in non-nuclear membranes. The stimulation of these enzymes may be involved in the generation and regulation of arachidonic acid and its metabolites during differentiation.  相似文献   

9.
This study characterized the phospholipase A2 (PLA2) activity in cerebral cortex of fetal rat brain and investigated effects of chemical inhibition of Ca2+-independent PLA2 (iPLA2) on neurite outgrowth and cell development of cortical neurons in vitro. The PLA2 activity in fetal brain was insensitive to a Ca2+-chelator EGTA and was significantly impaired by an iPLA2 inhibitor, bromoenol lactone (BEL). Following treatment with BEL, cortical neurons showed acute loss of neurites and impaired cell body, which were clearly dose- and time-dependent. Nuclear staining revealed nuclear regression (shrinkage), but not fragmentation, in BEL-treated cells. The cytotoxic effect of BEL was additive with arachidonic acid (AA) and AA alone also induced neurite demise. BEL treatment resulted in increased production of prostaglandin E2. Overall data suggest that iPLA2, a primary PLA2 isoform in cerebral cortex, displays a housekeeping role in development and neurite outgrowth in cortical neurons in vitro probably via maintaining phospholipid membrane remodeling rather than generating free fatty acids and lysophospholipids.  相似文献   

10.
Notexin belongs to a class of snake venom neurotoxins and myotoxins that have phospholipase A2 activity. Previous studies have shown that these toxins affect target cells differently from phospholipases that are not neurotoxic or myotoxic. Notexin inhibited the Ca2+ uptake into fragmented sarcoplasmic reticulum from rabbit skeletal muscle, but it did not cause an efflux of previously accumulated Ca2+ or inhibit the Ca2+–ATPase activity. It is suggested that notexin specifically binds to and decreases the conductance for Ca2+ of the Ca2+ pump and/or the conductance of a channel for an ion that facilitates Ca2+ transport. The K+ ionophore valinomycin reversed the notexin-induced inhibition of Ca2+ uptake into sarcoplasmic reticulum, suggesting that the molecular target of notexin could be a K+ channel. Two types of reconstitution experiments make it unlikely that notexin acts by degrading a minor lipid that is resistant to hydrolysis by nontoxic phospholipases A2. Notexininactivated sarcoplasmic reticulum vesicles were reactivated (with respect to Ca2+ uptake) by simple solubilization with detergent and subsequent reconstitution by detergent removal. Second, notexin was still active on sarcoplasmic reticulum vesicles after >94% of the lipids were replaced by soybean phosphoglycerides during the reconstitution procedure.  相似文献   

11.
Lipids and lipolytic enzyme activities of rat heart mitochondria   总被引:1,自引:0,他引:1  
The lipid composition and lipolytic enzyme activities in rat cardiac mitochondria were examined. Subsarcolemmal mitochondria were prepared by treatment of heart muscle with a Polytron tissue processor, while interfibrillar mitochondria were released by exposure of the remaining low-speed pellet to the protease, nagarse. These procedures are known to yield two functionally different populations of mitochondria. However, their phospholipid contents and compositions were identical, as were the positional distributions of the constituent fatty acids. Of the ethanolamine phospholipids, 20% were plasmalogens, and about 2% of the choline phospholipids consisted of this alkenylacyl species. Both subsarcolemmal and interfibrillar mitochondria contained a Ca2+-activated phospholipase A2, as evidenced by the Ca2+-dependent release of unsaturated fatty acids and lysophosphatidylethanolamine from endogenous lipids. Ruthenium red prevented the activation of this enzyme by Ca2+, indicating that the activity is located in the matrix space or associated with the inner surface of the inner membrane. Both mitochondrial fractions produced free fatty acids and lysophosphatidylethanolamine in the absence of free Ca2+ apparently due to an outer membrane phospholipase A1. The activity of this enzyme decreased with time, particularly in interfibrillar mitochondria, providing that Ca2+ was absent. Nagarse treatment of subsarcolemmal mitochondria resulted in a preparation with the same phospholipase A1 properties as interfibrillar mitochondria. The possibility that differences in phospholipase A1 properties account for some of the functional variations between the two mitochondrial types is discussed.  相似文献   

12.
Grange  Eric  Rabin  Olivier  Bell  Jane  Chang  Michael C. J. 《Neurochemical research》1998,23(10):1251-1257
The Fatty Acid method was used to determine whether incorporation of plasma radiolabeled arachidonic acid into brain phospholipids is controlled by phospholipase A2. Awake rats received an i.v. injection of a phospholipase A2 inhibitor, manoalide (10 mg/kg), and then were infused i.v. with [1-14C]arachidonate or [3H]arachidonate. Animals were killed after infusion by microwave irradiation, and tracer distribution was analyzed in brain phospholipid, neutral lipid and acyl-CoA pools. Calcium-independent phospholipase A2 activity in brain homogenate was reduced by manoalide, whereas phospholipase C activity was unaffected. At 60 min but not at 20 or 40 min after its injection, manoalide had significantly decreased by 50% incorporation of unesterified arachidonate into and turnover within brain phospholipids, taking into account dilution of the brain arachidonoyl-CoA pool by recycled arachidonate. Manoalide also increased by 100% the net rate of unesterified arachidonate incorporation into brain triacylglycerol. This study indicates that manoalide can be used to inhibit brain phospholipase A2 in vivo, and that phospholipase A2 plays a critical role in arachidonate turnover in brain phospholipids and neutral lipids.  相似文献   

13.
Exposure of rabbit pulmonary arterial smooth muscle cells to 10 M of the calcium ionophore A23187 dramatically stimulates cell membrane-associated phospholipase A2 activity and arachidonic acid release. In addition, A23187 also enhances cell membrane-associated serine esterase activity. Serine esterase inhibitors phenylmethylsulfonylfuoride and diisopropyl fluorophosphate prevent the increase in serine esterase and phospholipase A2 activities and arachidonic acid release caused by A23187. A23187 still stimulated serine esterase and phospholipase A2 activities and arachidonic acid release in cells pretreated with nominal Ca2+ free buffer. Treatment of the cell membrane with A23187 does not cause any appreciable change in serine esterase and phospholipase A2 activities. Pretreatment of the cells with actinomycin D or cycloheximide did not prevent the increase in the cell membrane associated serine esterase and phospholipase A2 activities, and arachidonic acid release caused by A23187. These results suggest that (i) a membrane-associated serine esterase plays an important role in stimulating the smooth muscle cell membrane associated phospholipase A2 activity (ii) in addition to the presence of extracellular Ca2+, release of Ca2+ from intracellular storage site(s) by A23187 also appears to play a role in stimulating the cell membrane-associated serine esterase and phospholipase A2 activities, and (iii) the increase in the cell membrane-associated serine esterase and phospholipase A2 activities does not appear to require new RNA or protein synthesis.Abbreviations A23187 calcium ionophore - AA arachidonic acid - PMSF phenylmethyl sulfonylfuoride - DFP diisopropyl-fluorophosphate - DMEM Dulbecco's modified Eagles medium - FCS fetal calf serum - PBS phosphate buffered saline - HBPS Hank's buffered physiological saline - PLA2 phospholipase A2  相似文献   

14.
Previous studies have shown that micromolar concentrations of calmodulin inhibitor calmidazolium induce fast activation of nonselective Ca2+ channels in plasma membranes of Ehrlich ascites carcinoma cells (Zinchenko, V.P., Kasymov, V.A., Li, V.V., and Kaimachnikov, N.P., Biofizika (Rus.), 2005, vol. 50 (6), pp. 1055–1069). In order to detect this type of Ca2+ channels in other cells and to establish common regulatory mechanisms, we studied calmidazolium effects on rat thymocytes. It was found that calmidazolium induces biphasic increases in Ca2+ content in cytosol of rat thymocytes due to Ca2+ entry from external medium and reflects the activity of nonselective Ca2+ channels permeable for Mn2+ and Ni2+ ions. The rate and the amplitude of the fast phase are decreased, while those of the slow phase are increased in the presence of specific inhibitors of Ca2+-independent phospholipase A2 (bromoenol lactone and palmitoyl trifluoromethyl ketone). The rate and the amplitude of the fast phase are also inhibited by arachidonic acid and the lipoxygenase inhibitor nordihydroguaiaretic acid, while the Ca2+-dependent phospholipase A2 inhibitor bromophenacyl bromide, the cyclooxygenase inhibitor indomethacin, the specific store-operated Ca2+ channel inhibitor gadolinium and the phospholipase C inhibitor U73122 have no such effect. The rate of the fast phase only slightly depends on temperature, while that of the slow phase shows a strong temperature dependence and increases with a rise in temperatures (Q 10 = 2). The amplitude of the fast phase of the Ca2+ signal increases with a decrease of temperatures due to prolongation of the maximum activity of the Ca2+ channel. The data obtained suggest that iPLA2 is an intermediate link in the activation of calmidazolium-induced nonselective Ca2+ channels. The iPLA2 products lysophospholipids and arachidonic acid activate and inhibit Ca2+ channels, respectively. The fact that these compounds manifest different affinities for Ca2+ channels shed additional light on the mechanisms of biphasic Ca2+ elevation in thymus cell cytosol and prolongation of the active state of Ca2+ channels at low temperatures.  相似文献   

15.
Essential fatty acids (EFA) play a critical role in the brain and regulate many of the processes altered in Alzheimer's disease (AD). Technical advances are allowing for the dissection of complex lipid pathways in normal and diseased states. Arachidonic acid (AA) and specific isoforms of phospholipase A2 (PLA2) appear to be critical mediators in amyloid-β (Aβ)-induced pathogenesis, leading to learning, memory, and behavioral impairments in mouse models of AD. These findings and ongoing research into lipid biology in AD and related disorders promise to reveal new pharmacological targets that may lead to better treatments for these devastating conditions.  相似文献   

16.
—Lipid-free extracts of rat and human brain have been prepared and shown to contain phospholipase A1 and A2 activities and a lysophospholipase. The phospholipase Aj activity has pH optima of 4·2 and 4·6 in rat and human brain, respectively; it can be partially purified and isolated in high yields by dialysing the extracts at low pH. The purified preparations hydrolyse the ester bond at the 1-position in lecithin, phosphatidyl-ethanolamine and phosphatidylserine, but have little or no action on triglyceride or cholesterol ester. An assay system for the enzyme is described. Phospholipase A2 activity is optimal at pH 5·5 in rat brain extracts and at pH 5·0 in extracts of human brain. The phospholipase A2 activity of human cerebral cortex is largely unaffected by heating extracts at 70°C for 5 min, whereas this treatment substantially inactivates phospholipase A1 and completely destroys lysophospholipase. Phospholipase A1 is widely distributed in both grey and white matter of human brain and is also present in peripheral nerve. Phospholipase A2 activity is lower than A1 in all regions of the CNS examined so far, and is absent from peripheral nerve. Neither enzyme appears to require Ca2+ but both are inhibited by di-isopropylfluorophosphate (DFP, 2 × 10?6 m) and thus differ from phospholipase A of pancreas. These studies confirm that the phospholipase A1 and A2 activities in brain are due to separate enzymes.  相似文献   

17.
Summary Treatment of human red cell membranes with pure phospholipase A2 results in a progressive inactivation of both Ca2+-dependent and (Ca2++K+)-dependent ATPase and phosphatase activities. When phospholipase C replaces phospholipase A2, Ca2+-dependent ATPase activity and Ca2+-dependent phosphorylation of red cell membranes are lost, while Ca2+-dependent phosphatase activity is enhanced and its apparent affinity for Ca2+ is increased about 20-fold. Activation of Ca2+-dependent phosphatase following phospholipase C treatment was not observed in sarcoplasmic reticulum preparation. Phospholipase C increases the sensitivity of the phosphatase to N-ethylmaleimide but has little effect on the kinetic parameters relating the phosphatase activity to substrate and cofactors, suggesting that no extensive structural disarrangement of the Ca2+-ATPase system has occurred after incubation with phospholipase C.  相似文献   

18.
The Ca2+-independent phospholipase A2 (iPLA2) subfamily of enzymes is associated with arachidonic acid (AA) release and the subsequent increase in fatty acid turnover. This phenomenon occurs not only during apoptosis but also during inflammation and lymphocyte proliferation. In this study, we purified and characterized a novel type of iPLA2 from bovine brain. iPLA2 was purified 4,174-fold from the bovine brain by a sequential process involving DEAE-cellulose anion exchange, phenyl-5PW hydrophobic interaction, heparin-Sepharose affinity, Sephacryl S-300 gel filtration, Mono S cation exchange, Mono Q anion exchange, and Superose 12 gel filtration. A single peak of iPLA2 activity was eluted at an apparent molecular mass of 155 kDa during the final Superose 12 gel-filtration step. The purified enzyme had an isoelectric point of 5.3 on twodimensional gel electrophoresis (2-DE) and was inhibited by arachidonyl trifluoromethyl ketone (AACOCF3), Triton X-100, iron, and Ca2+. However, it was not inhibited by bromoenol lactone (BEL), an inhibitor of iPLA2, and adenosine triphosphate (ATP). The spot with the iPLA2 activity did not match with any known protein sequence, as determined by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) analysis. Altogether, these data suggest that the purified enzyme is a novel form of cytosolic iPLA2.  相似文献   

19.
Activation of phospholipases A2 (PLA2s) leads to the generation of biologically active lipid mediators that can affect numerous cellular events. The Group VIA Ca2+-independent PLA2, designated iPLA2β, is active in the absence of Ca2+, activated by ATP, and inhibited by the bromoenol lactone suicide inhibitor (BEL). Over the past 10–15 years, studies using BEL have demonstrated that iPLA2β participates in various biological processes and the recent availability of mice in which iPLA2β expression levels have been genetically-modified are extending these findings. Work in our laboratory suggests that iPLA2β activates a unique signaling cascade that promotes β-cell apoptosis. This pathway involves iPLA2β dependent induction of neutral sphingomyelinase, production of ceramide, and activation of the intrinsic pathway of apoptosis. There is a growing body of literature supporting β-cell apoptosis as a major contributor to the loss of β-cell mass associated with the onset and progression of Type 1 and Type 2 diabetes mellitus. This underscores a need to gain a better understanding of the molecular mechanisms underlying β-cell apoptosis so that improved treatments can be developed to prevent or delay the onset and progression of diabetes mellitus. Herein, we offer a general review of Group VIA Ca2+-independent PLA2 (iPLA2β) followed by a more focused discussion of its participation in β-cell apoptosis. We suggest that iPLA2β-derived products trigger pathways which can lead to β-cell apoptosis during the development of diabetes.  相似文献   

20.
Amiodarone, an antiarrhythmic drug, like chloroquine and chlorpromazine, is a tertiary amine with amphiphilic properties. Chloroquine and chlorpromazine are known inhibitors of phospholipases. All three drugs produce characteristic microcorneal deposits consistent with lysosomal accumulations of phospholipid. Similar lysosomal bodies were found in leukocytes of 15 patients on chronic amiodarone treatment as well as 3 patients each on chloroquine and chlorpromazine, suggestive of widespread systemic inhibition of lysosomal phospholipases. These lysosomal inclusions were similar in morphology, irrespective of the drug given, and were of four types: multilamellar, amorphous dense, amorphous light, or a combination of 2 or more of the preceding types. There was no simple relationship between the number of inclusion bodies per cell and the cumulative dose of amiodarone (r=0.02) or amiodarone serum levels (r=0.11). An in vitro assay was used to compare the effects of the three drugs on Ca2+-dependent phospholipase A and C activities. Phospholipase A2 activity was inhibited in a dose-dependent fashion (1–8 mg/assay) by all three drugs in the order: chlorpromazine > amiodarone > chloroquine. The inhibitory effect on phospholipase C was more pronounced with all three drugs, producing almost total inhibition at 8 mg/assay. In a Ca2+-independent lysosomal phospholipase A system, amiodarone had a greater effect, producing 85% inhibition at 1.2 mg/assay. These observations suggest that amiodarone, like other cationic amphiphiles, induces a generalized phospholipidosis by inhibiting phospholipid catabolism. Its therapeutic and toxic effects may be due to its ability to modulate both Ca2+-dependent membrane phospholipases and Ca2+-independent acid phospholipases.  相似文献   

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