Role of sphingomyelin and ceramide in the regulation of the activity and fatty acid specificity of group V secretory phospholipase A2

Singh, Devinder; Gesquiere, Laurence R.; Subbaiah, Papasani V.

doi:10.1016/j.abb.2006.11.014

Cited by 23 publications

(20 citation statements)

References 39 publications

(65 reference statements)

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“…Treatment with DTT or TEAPC, general inhibitors of secretory PLA 2 s, decreased the DMB-mC11S (GS13)-and DMB-mC9S (GS20)-induced release of AA (Table 3). It is reported that ceramide activated secretory PLA 2 s including types IIa, V, and X, and the enzymes with ceramide prefer AA-containing phospholipids (19,20). Under our conditions with type III secretory PLA 2 from bee venom, however, we could not detect direct activation of the enzyme by DMB-mC11S (GS13).…”

Section: Discussioncontrasting

confidence: 64%

“…Ca 2+ -independent PLA 2 (β-isofrom) is reported to participate in endoplasmic reticulum stress-induced apoptosis in insulinoma cells (36) and in macrophages (34). Secretory PLA 2 s play important roles in cell damage under pathological conditions including inflammation and atherogeneis (14,16,20). These findings including our data suggest the cytotoxicity induced by AA.…”

Section: Possible Role Of Release Of Aa In Cell Deathsupporting

confidence: 59%

“…C1P triggered the translocation of cPLA 2 α from the cytosol to the perinuclear region in cells via interaction with its C2 domain and increased the enzyme activity (17,18). Several reports including those from our laboratory showed that sphingolipid-related compounds such as sphingomyelin, ceramide, C1P, and S1P analogs regulated the activities of PLA 2 s, including secretory PLA 2 (19,20) and cPLA 2 α (9, 21 -23). Thus, synthetic analogs of S1P /C1P that can regulate the release of AA are potential therapeutic agents for AA-related diseases, including immunological disorders and neuronal death (13,16).…”

Section: Introductionmentioning

confidence: 93%

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Effects of Synthetic Sphingosine-1-Phosphate Analogs on Cytosolic Phospholipase A2α–Independent Release of Arachidonic Acid and Cell Toxicity in L929 Fibrosarcoma Cells: the Structure–Activity Relationship

et al. 2009

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Abstract. Sphingolipid metabolites including ceramide, sphingosine, and their phosphorylated products [sphingosine-1-phosphate (S1P) and ceramide-1-phosphate] regulate cell functions including arachidonic acid (AA) metabolism and cell death. The development of analogs of S1P may be useful for regulating these mediator-induced cellular responses. We synthesized new analogs of S1P and examined their effects on the release of AA and cell death in L929 mouse fibrosarcoma cells. Among the analogs tested, several compounds including DMB-mC11S [dimethyl (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate] and DMB-mC9S [dimethyl (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxy-3-(3'-nonyl)phenylpropyl phosphate] released AA within 1 h and caused cell death 6 h after treatment. The release of AA was observed in C12 cells [a L929 variant lacking a type α cytosolic phospholipase A 2 (cPLA 2 α)] and L929-cPLAα-siRNA cells (L929 cells treated with small interference RNA for cPLA 2 α). Treatment with pharmacological inhibitors of secretory and Ca 2+ -independent PLA 2 s decreased the DMB-mC11S-induced release of AA. The effect of the S1P analogs tested on the release of AA was comparable to that on cell death in L929 cells, and a high correlation coefficient was observed. Two analogs lacking a butoxycarbonyl moiety phenylpropyl phosphate] and DMAm-mC11S [dimethyl (2S,3R)-2-amino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate)] had inhibitory effects on the release of AA and cell toxicity induced by DMB-mC11S. Synthetic phosphorylated lipid analogs may be useful for studying PLA 2 activity and its toxicity in cells.[ Supplementary Fig. 1: available only at http://dx

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Section: Discussioncontrasting

confidence: 64%

Section: Possible Role Of Release Of Aa In Cell Deathsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 93%

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Effects of Synthetic Sphingosine-1-Phosphate Analogs on Cytosolic Phospholipase A2α–Independent Release of Arachidonic Acid and Cell Toxicity in L929 Fibrosarcoma Cells: the Structure–Activity Relationship

et al. 2009

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“…Subbaiah and Liu ( 25 ) reported that lecithin-cholesterol acyltransferase, a specialized phospholipase A responsible for the esterifi cation of cholesterol in plasma, was inhibited by SM. The activities of lipoprotein lipase and secretory PLA2 have also been shown to be inhibited by SM in vitro (26)(27)(28)(29)(30). Dawson et al ( 31 ) reported that diacylglycerol-stimulated intracellular phospholipases were strongly inhibited by SM.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the activity of cytosolic phospholipase A2α (cPLA2α) by cellular sphingolipids and inhibition of cPLA2α by sphingomyelin

Nakamura

Wakita

Suganami

et al. 2010

Journal of Lipid Research

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This article is available online at http://www.jlr.org Arachidonic acid (AA) is a precursor of eicosanoids, including prostaglandins, thromboxanes, and leukotrienes, playing an important role in several physiological functions ( 1 ). The biosynthesis of these AA metabolites occurs mainly through the activation of phospholipase A2 (PLA2) in response to a wide variety of stimuli such as cytokines, growth factors, and neurotransmitters ( 2 ). PLA2 catalyzes hydrolysis of the sn-2 position of glycerophospholipids to release free AA. Mammalian cells have structurally diverse forms of PLA2 including secretory PLA2, Ca 2+ -independent PLA2, and cytosolic PLA2 (cPLA2) ( 3, 4 ). Among these PLA2s, the 85 kDa cPLA2, specifi cally cPLA2 ␣ , is highly selective for glycerophospholipids containing AA. cPLA2 ␣ is regulated mainly by an increase in the intracellular Ca 2+ concentrations ([Ca 2+ ]i) and by the phosphorylation on serine residues by mitogen-activated protein kinase (MAPK) ( 3, 4 ). The binding of Ca 2+ to the C2 domain of cPLA2 ␣ triggers translocation of cPLA2 ␣ from the cytosol to the perinuclear region including the Golgi apparatus, endoplasmic reticulum (ER), and nuclear envelope. cPLA2 ␣ can be phosphorylated at Ser 505 , Ser 515 , and Ser 727 , which increases its intrinsic enzymatic activity 2-to 3-fold in vitro ( 5-8 ). Abstract

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“…The inhibitory effect of added SM upon enzyme activity was relieved by the addition of free cholesterol (FC) (14). Similarly, addition of SM/ceramide to PtdCho liposomes (3,15) showed a clear preference for release of arachidonate by group X sPLA 2 , although at reduced activity, whereas the addition of SM to the group V sPLA 2 digestion mixture inhibited the release of arachidonate (16), resulting in greater release of linoleate.…”

mentioning

confidence: 99%

Phase composition of lipoprotein SM/cholesterol/PtdCho affects FA specificity of sPLA2s

Kuksis

Pruzanski

2008

Journal of Lipid Research

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We have previously reported preferential release of polyunsaturated FAs during hydrolysis of lipoprotein phosphatidylcholine (PtdCho) by group X secretory phospholipase A 2 (sPLA 2 ) and preferential release of oligounsaturated FAs during hydrolysis of lipoprotein PtdCho by group V sPLA 2 , but the mechanism of this selectivity has remained unknown. We now show that the rate and specificity of hydrolysis are affected by relative increases in endogenous SM and free cholesterol (FC) during the lipase digestion. The highest preference for arachidonate release from LDL and HDL by group X sPLA 2 was observed for residual SM/PtdCho molar ratio of 1.2 and 0.4, compared with the respective starting ratios of 0.4 and 0.2, as measured by liquid chromatography/electrospray ionization-mass spectrometry. Group V sPLA 2 showed preferential release of linoleate from LDL and HDL at SM/PtdCho ratio 1.5 and 0.6, respectively. We have attributed the change in FA specificity to segregation of molecular species of PtdCho and of sPLA 2 s between disordered and ordered SM/FC/ PtdCho lipid phases. The increases in SM and FC during digestion with group IIA sPLA 2 were more limited, and a preferential hydrolysis of any FAs was not observed. A preferential release of linoleate during hydrolysis of phosphatidylcholine (PtdCho) by group V secretory phospholipase A 2 (sPLA 2 ) was first reported in liposomal (1-3) and later in lipoprotein (4-6) incubations, but the mechanism of this selectivity has remained unknown. Early work (1, 2) attributed the selective enzyme activity to a difference in the physical state of substrate between the sonicate and the natural membranes that may contain a more optimum mixture of phospholipids. Alternatively, a preferential release of arachidonate by group V sPLA 2 exogenously added to cell cultures has been attributed to its combined action with cytosolic PLA 2 (7). Subsequent work with liposomes suggested a special role for ceramides (3) in regulation of group V sPLA 2 hydrolysis of plasma PtdCho, which, however, was difficult to reconcile with the apparent absence of sphingomyelinase activity from plasma lipoproteins (6,8,9). Likewise, the apparent preferential release of PtdCho arachidonate by group X sPLA 2 during liposomal (10, 11), lipoprotein (4-6), and cellular (10, 12) incubations has remained unexplained. In contrast, group IIA sPLA 2 apparently attacked liposomal and lipoprotein PtdCho without FA discrimination, although at a significantly lower rate than group V and group X sPLA 2 s (3,5,9,10,12). Therefore, the true differences in the activity and apparent FA specificity of PtdCho hydrolysis by the sPLA 2 s have remained obscure.In other studies, a preferential release of arachidonate by group IIA sPLA 2 from phosphatidylethanolamine/ phosphatidylserine (PtdEtn/PtdSer) micelles was observed (13,14) in the presence of added SM/ceramide and was attributed to phase separation and exclusion of polyunsaturates from the ordered liquid phase formed under these conditions. The inhibitory effect...

show abstract

Role of sphingomyelin and ceramide in the regulation of the activity and fatty acid specificity of group V secretory phospholipase A2

Cited by 23 publications

References 39 publications

Effects of Synthetic Sphingosine-1-Phosphate Analogs on Cytosolic Phospholipase A2α–Independent Release of Arachidonic Acid and Cell Toxicity in L929 Fibrosarcoma Cells: the Structure–Activity Relationship

Effects of Synthetic Sphingosine-1-Phosphate Analogs on Cytosolic Phospholipase A2α–Independent Release of Arachidonic Acid and Cell Toxicity in L929 Fibrosarcoma Cells: the Structure–Activity Relationship

Modulation of the activity of cytosolic phospholipase A2α (cPLA2α) by cellular sphingolipids and inhibition of cPLA2α by sphingomyelin

Phase composition of lipoprotein SM/cholesterol/PtdCho affects FA specificity of sPLA2s

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