Phospholipase A2 in the central nervous system
2004; Elsevier BV; Volume: 45; Issue: 2 Linguagem: Inglês
10.1194/jlr.r300016-jlr200
ISSN1539-7262
AutoresGrace Y. Sun, Jianfeng Xu, Michael Dam Jensen, Ágnes Simonyi,
Tópico(s)Protein Kinase Regulation and GTPase Signaling
ResumoPhospholipase A2 (PLA2) belongs to a family of enzymes that catalyze the cleavage of fatty acids from the sn-2 position of phospholipids. There are more than 19 different isoforms of PLA2 in the mammalian system, but recent studies have focused on three major groups, namely, the group IV cytosolic PLA2, the group II secretory PLA2 (sPLA2), and the group VI Ca2+-independent PLA2. These PLA2s are involved in a complex network of signaling pathways that link receptor agonists, oxidative agents, and proinflammatory cytokines to the release of arachidonic acid (AA) and the synthesis of eicosanoids. PLA2s acting on membrane phospholipids have been implicated in intracellular membrane trafficking, differentiation, proliferation, and apoptotic processes. All major groups of PLA2 are present in the central nervous system (CNS). Therefore, this review is focused on PLA2 and AA release in neural cells, especially in astrocytes and neurons. In addition, because many neurodegenerative diseases are associated with increased oxidative and inflammatory responses, an attempt was made to include studies on PLA2 in cerebral ischemia, Alzheimer's disease, and neuronal injury due to excitotoxic agents.Information from these studies has provided clear evidence for the important role of PLA2 in regulating physiological and pathological functions in the CNS. Phospholipase A2 (PLA2) belongs to a family of enzymes that catalyze the cleavage of fatty acids from the sn-2 position of phospholipids. There are more than 19 different isoforms of PLA2 in the mammalian system, but recent studies have focused on three major groups, namely, the group IV cytosolic PLA2, the group II secretory PLA2 (sPLA2), and the group VI Ca2+-independent PLA2. These PLA2s are involved in a complex network of signaling pathways that link receptor agonists, oxidative agents, and proinflammatory cytokines to the release of arachidonic acid (AA) and the synthesis of eicosanoids. PLA2s acting on membrane phospholipids have been implicated in intracellular membrane trafficking, differentiation, proliferation, and apoptotic processes. All major groups of PLA2 are present in the central nervous system (CNS). Therefore, this review is focused on PLA2 and AA release in neural cells, especially in astrocytes and neurons. In addition, because many neurodegenerative diseases are associated with increased oxidative and inflammatory responses, an attempt was made to include studies on PLA2 in cerebral ischemia, Alzheimer's disease, and neuronal injury due to excitotoxic agents. Information from these studies has provided clear evidence for the important role of PLA2 in regulating physiological and pathological functions in the CNS. Bazan (1Bazan N.G. Effects of ischemia and electroconvulsive shock on free fatty acid pool in the brain.Biochim. Biophys. Acta. 1970; 218: 1-10Crossref PubMed Scopus (671) Google Scholar) recognized the important role of arachidonic acid (AA) in the central nervous system (CNS) in the '70s when he observed the rapid and transient release of this fatty acid in the brain due to seizure and cerebral ischemia. The "Bazan effect" has since stimulated over 30 years of investigations attempting to unravel mechanisms regulating AA release from membrane phospholipids in the CNS. Phospholipids in CNS membranes are enriched in polyunsaturated fatty acids (PUFAs) (2Sun G.Y. Horrocks L.A. The acyl and alk-1-enyl groups of the major phosphoglycerides from ox brain myelin and mouse brain microsomal, mitochondrial and myelin fractions.Lipids. 1970; 5: 1006-1012Crossref PubMed Scopus (73) Google Scholar). Metabolism of PUFA is stringently controlled by phospholipase A2 (PLA2) and acyltransferases—known as the "deacylation-reacylation cycle" (3Farooqui A.A. Horrocks L.A. Farooqui T. Deacylation and reacylation of neural membrane glycerophospholipids: a matter of life and death.J. Mol. Neurosci. 2000; 14: 123-135Crossref PubMed Google Scholar, 4Lands W.E.M. Crawford C.G. Enzymes of membrane phospholipid metabolism in animals.in: Martonosi A. The Enzymes of Biological Membranes. Vol. 2. Plenum Press, New York1979: 3-85Google Scholar, 5Sun G.Y. MacQuarrie R.A. Deacylation-reacylation of arachidonoyl groups in cerebral phospholipids.Ann. N.Y. Acad. Sci. 1989; 559: 37-55Crossref PubMed Google Scholar). Under normal conditions, free fatty acids (FFAs) released by PLA2 are rapidly taken up by membrane phospholipids through an energy-dependent process involving CoA and ATP (6Corbin D.R. Sun G.Y. Characterization of the enzymic transfer of arachidonoyl groups to 1-acyl-phosphoglycerides in mouse synaptosome fraction.J. Neurochem. 1978; 30: 77-82Crossref PubMed Scopus (74) Google Scholar). To date, limited information is available on the structure and functions of acyltransferases. However, recent advances in molecular biological techniques have aided in the identification of many genes encoding different groups of PLA2 and have provided new information on the properties and functions of these molecules. PLA2 (EC3.1.1.4.) belongs to a family of enzymes that catalyze the cleavage of fatty acids from the sn-2 position of phospholipids. These enzymes are not only important for maintenance of cell membrane phospholipids; they also play a key role in regulating the release of AA, a precursor for synthesis of eicosanoids. In the mammalian system, more than 19 different isoforms of PLA2 have been identified, and different PLA2s have been shown to participate in physiological events related to cell injury, inflammation, and apoptosis (7Cummings B.S. Mchowat J. Schnellmann R.G. Phospholipase A2s in cell injury and death.J. Pharmacol. Exp. Ther. 2000; 294: 793-799PubMed Google Scholar, 8Murakami M. Nakatani Y. Atsumi G. Inoue K. Kudo I. Regulatory functions of phospholipase A2.Crit. Rev. Immunol. 1997; 17: 225-283Crossref PubMed Google Scholar). Recent studies have focused on three major groups of PLA2: the group IV calcium-dependent cytosolic PLA2 (cPLA2), the group II secretory PLA2 (sPLA2), and the group VI Ca2+-independent PLA2 (iPLA2) (9Murakami M. Kudo I. Phospholipase A2.J. Biochem. (Tokyo). 2002; 131: 285-292Crossref PubMed Google Scholar). During the past decade, excellent reviews describing the structure and properties of these PLA2s in non-neural systems have appeared (7Cummings B.S. Mchowat J. 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Expression and function of phospholipase A2 in brain.FEBS Lett. 2002; 531: 12-17Crossref PubMed Scopus (0) Google Scholar, 13Farooqui A.A. Yang H-C. Rosenberger T.A. Horrocks L.A. Phospholipase A2 and its role in brain tissue.J. Neurochem. 1997; 69: 889-901Crossref PubMed Google Scholar). The present review is devoted to PLA2 in neural cells in the CNS, especially the signaling pathways regulating different PLA2s in neurons and astrocytes (see Fig. 1). Because PLA2s have been implicated in the pathology of a number of neurodegenerative diseases, an attempt was also made to include recent studies describing the different groups of PLA2s in cerebral ischemia, Alzheimer's disease (AD), and neuronal injury due to excitotoxic agents. To facilitate updated information, a website linking data concerning PLA2s in different neural cells and their involvement in neurodegenerative diseases has been created: http://www.pla2.com. The authors plan to update the information in this site periodically. cPLA2 belongs to the group IV PLA2s. Although three isoforms, i.e., cPLA2α, -β, and -γ, have been identified, the 85 kDa cPLA2α has been studied most extensively. This protein is comprised of a C2 domain and multiple phosphorylation sites, including two consensus sites (S505 and S727) for phosphorylation by mitogen-activated protein kinases (MAPKs) (12Balboa M.A. Varela-Nieto I. Lucas K.K. Dennis E.A. Expression and function of phospholipase A2 in brain.FEBS Lett. 2002; 531: 12-17Crossref PubMed Scopus (0) Google Scholar) and an S515 site for Ca2+/calmodulin (9Murakami M. Kudo I. Phospholipase A2.J. Biochem. (Tokyo). 2002; 131: 285-292Crossref PubMed Google Scholar). The C2 domain confers a Ca2+-dependent translocation mechanism for this cPLA2 (14Evans J.H. Spencer D.M. Zweifach A. Leslie C.C. Intracellular calcium signals regulating cytosolic phospholipase A2 translocation to internal membranes.J. Biol. Chem. 2001; 276: 30151-30160Abstract Full Text Full Text PDF Scopus (201) Google Scholar, 15Gijon M.A. Spencer D.M. Kaiser A.L. Leslie C.C. Role of phosphorylation sites and the C2 domain in regulation of cytosolic phospholipase A2.J. Cell Biol. 1999; 145: 1219-1232Crossref PubMed Scopus (178) Google Scholar). Recent studies have provided evidence for translocation of cPLA2 from the cytosol to nuclear membranes (16Fatima S. Yaghini F.A. Ahmed A. Khandekar Z. Malik K.U. CaM kinase II alpha mediates norepinephrine-induced translocation of cytosolic phospholipase A2 to the nuclear envelope.J. Cell Sci. 2003; 116: 353-365Crossref PubMed Scopus (27) Google Scholar). Translocation of cPLA2 has also been shown to participate in intracellular membrane trafficking processes, such as those governing the Golgi and endocytic pathways (17Brown W.J. Chambers K. Doody A. Phospholipase A2 (PLA2) enzymes in membrane trafficking: mediators of membrane shape and function.Traffic. 2003; 4: 214-221Crossref PubMed Google Scholar). PLA2α seems to prefer hydrolysis of AA from phosphatidylcholine (9Murakami M. Kudo I. Phospholipase A2.J. Biochem. (Tokyo). 2002; 131: 285-292Crossref PubMed Google Scholar). In macrophages, as well as in other cell systems, agents including G protein-coupled receptor agonists, calcium ionophores, phorbol esters, and zymogens can activate cPLA2, resulting in AA release (12Balboa M.A. Varela-Nieto I. Lucas K.K. Dennis E.A. Expression and function of phospholipase A2 in brain.FEBS Lett. 2002; 531: 12-17Crossref PubMed Scopus (0) Google Scholar). Through its linkage to receptor-mediated signaling pathways, cPLA2 is an important PLA2 for rapid AA release in cells and for modulating a number of intracellular processes. The sPLA2 family consists of multiple groups (I, II, III, V, X, and XII) of enzymes characterized by a conserved Ca2+ binding loop and a conserved histidine residue in the catalytic domain (9Murakami M. Kudo I. Phospholipase A2.J. Biochem. (Tokyo). 2002; 131: 285-292Crossref PubMed Google Scholar). The group II sPLA2s, including IIA, IIC, IID, IIE, and IIF isoforms, are low-molecular-weight proteins (∼14 kDa) with secretory sequences. Genes for many of the group II sPLA2 isoforms are clustered in chromosome 1 (18Suzuki N. Ishizaki J. Yokota Y. Higashino K. Ono T. Ikeda M. Fujii N. Kawamoto K. Hanasaki K. Structures, enzymatic properties, and expression of novel human and mouse secretory phospholipase A2s.J. Biol. Chem. 2000; 275: 5785-5793Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). These enzymes do not have strict fatty acid specificity and tend to act on anionic phospholipids in the presence of high concentrations of Ca2+ (9Murakami M. Kudo I. Phospholipase A2.J. Biochem. (Tokyo). 2002; 131: 285-292Crossref PubMed Google Scholar). Of the group II sPLA2s, the IIA enzyme has been studied extensively because of its involvement in inflammatory processes in the peripheral systems (8Murakami M. Nakatani Y. Atsumi G. Inoue K. Kudo I. Regulatory functions of phospholipase A2.Crit. Rev. Immunol. 1997; 17: 225-283Crossref PubMed Google Scholar, 11Gijon M.A. Spencer D.M. Leslie C.C. Recent advances in the regulation of cytosolic phospholipase A2.Adv. Enzyme Reg. 2000; 40: 255-268Crossref PubMed Scopus (0) Google Scholar). In the CNS, group IIA sPLA2 mRNA is expressed in cultured astrocytes and can be induced in response to proinflammatory cytokines [tumor necrosis factor alpha (TNFα), interleukin-1β (IL-1β), and interferon gamma (IFNγ)] (19Li W. Xia J. Sun G.Y. Cytokine induction of iNOS and sPLA2 in immortalized astrocytes (DITNC): response to genistein and pyrrolidine dithiocarbamate.J. 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Upregulation of group IIA sPLA2 mRNA expression was observed in brain as a result of global cerebral ischemia (23Lauritzen I. Heurteaux C. Lazdunski M. Expression of group II phospholipase A2 in rat brain after severe forebrain ischemia and in endotoxic shock.Brain Res. 1994; 651: 353-356Crossref PubMed Google Scholar). The iPLA2 family is comprised of group VIA and VIB. Group VIA enzyme has at least five splice variants, all with ankyrin repeats, whereas group VIB iPLA2 lacks ankyrin repeats but consists of a signal motif for peroxisome localization (9Murakami M. Kudo I. Phospholipase A2.J. Biochem. (Tokyo). 2002; 131: 285-292Crossref PubMed Google Scholar). Fractionation of bovine brain cytosol by column chromatography resulted in two fractions, a 110 kDa iPLA2 fraction, which prefers hydrolysis of diacyl-glycero-3-phosphoethanolamine, and a 39 kDa iPLA2 fraction, which selectively acts on 1-alkenyl-2-acyl-glycero-3-phosphoethanolamine (ethanolamine plasmalogen, PEpl) (13Farooqui A.A. Yang H-C. Rosenberger T.A. Horrocks L.A. Phospholipase A2 and its role in brain tissue.J. Neurochem. 1997; 69: 889-901Crossref PubMed Google Scholar). Although iPLA2s are generally regarded as housekeeping enzymes for the maintenance of membrane phospholipids, recent studies have revealed novel functional roles for this group of enzymes, i.e., regulation of vascular smooth muscle contraction (24Guo Z. Su W. Ma Z. Smith G.M. Gong M.C. Ca2+-independent phospholipase A2 is required for agonist-induced Ca2+ sensitization of contraction in vascular smooth muscle.J. Biol. 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Astrocytes are the major cell type in the CNS and play multiple functional roles in providing nutrient support to neurons, modulating Ca2+ homeostasis, and regulating neurotransmission, as well as mediating host defense functions. Astrocytes have been shown to contain all major groups of PLA2 (27Zanassi P. Paolillo M. Schinelli S. Coexpression of phospholipase A2 in rat striatal astrocytes.Neurosci. Lett. 1998; 247: 83-86Crossref PubMed Scopus (0) Google Scholar). Therefore, these cells have been used to study the roles of different groups of PLA2 in normal physiological and pathological functions. Although many G protein-coupled receptors are expressed in astrocytes, there is considerable interest in the P2Y nucleotide receptors in these cells. One reason for this interest is that in the brain, ATP is stored at high concentrations in synaptic vesicles and is coreleased with neurotransmitters during neuronal excitation (28Burnstock G. 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However, studies in NIH3T3 cells stably expressed with the serotonin 5HT2A receptor indicated that instead of the phospholipase C pathway, 5HT-stimulated PLA2 and AA release involved in both the Gi/o-associated G-mediated ERK1/2 and the G12/13-coupled, Rho-mediated p38 MAP kinase pathways (41Kurrasch-Orbaugh D.M. Watts V.J. Barker E.L. Nichols D.E. Serotonin 5-hydroxytryptamine (2A) receptor-coupled phospholipase C and phospholipase A2 signaling pathways have different receptor reserves.J. Pharmacol. Exp. Ther. 2003; 304: 229-237Crossref PubMed Scopus (0) Google Scholar, 42Kurrasch-Orbaugh D.M. Parrish J.C. Watts V.J. Nichols D.E. A complex signaling cascade links the serotonin2A receptor to phospholipase A2 activation: the involvement of MAP kinases.J. Neurochem. 2003; 86: 980-991Crossref PubMed Scopus (0) Google Scholar). These results illustrate the complexity of different intracellular signaling pathways in the regulation of cPLA2. Reactive oxygen species (ROS) are produced in biological systems through both enzymatic and nonenzymatic mechanisms. Excessive generation of ROS in the CNS has been implicated in neuronal damage resulting from cerebral ischemia and in AD. Oxidant compounds such as H2O2 have been shown to cause perturbation of cell membrane integrity and alteration of mitochondrial function, resulting in an increase in [Ca2+]i (43Robb S.J. Robb-Gaspers L.D. Scaduto Jr., R.C. Thomas A.P. Connor J.R. Influence of calcium and iron on cell death and mitochondrial function in oxidatively stressed astrocytes.J. Neurosci. Res. 1999; 55: 674-685Crossref PubMed Scopus (0) Google Scholar, 44Rohrdanz E. Kahl E. Alterations of antioxidant enzyme expression in response to hydrogen peroxide.Free Radic. Biol. Med. 1998; 24: 27-38Crossref PubMed Scopus (0) Google Scholar). 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Astrocytes can readily respond to proinflammatory agents and lipopolysaccharides (LPS), causing the induction of a number of genes through activation of the nuclear factor κB pathway. In primary rat astrocytes, cytokines (TNFα, IL-1β, and IFNγ) stimulated the increase in prostaglandin E2 (PGE2) production, which was preceded by an increase in cyclooxygenase-2 (COX-2) and sPLA2 mRNA but not COX-1 and cPLA2 mRNA (22Xu J. Chalimoniuk M. Shu Y. Simonyi A. Sun A.Y. Gonzalez F.A. Weisman G.A. Wood W.G. Sun G.Y. Prostaglandin E2 production in astrocytes: regulation by cytokines, extracellular ATP, and oxidative agents.Prostaglandins, Leukot. Essent. Fatty Acids. 2003; 69: 437-448Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). In another study in rat astrocytes, LPS also increased expression of sPLA2 mRNA but not cPLA2 mRNA (27Zanassi P. Paolillo M. Schinelli S. Coexpression of phospholipase A2 in rat striatal astrocytes.Neurosci. Lett. 1998; 247: 83-86Crossref PubMed Scopus (0) Google Scholar). Although cytokines did not increase cPLA2 mRNA levels, an increase in cPLA2 phosphorylation was observed (22Xu J. Chalimoniuk M. Shu Y. Simonyi A. Sun A.Y. Gonzalez F.A. Weisman G.A. Wood W.G. Sun G.Y. Prostaglandin E2 production in astrocytes: regulation by cytokines, extracellular ATP, and oxidative agents.Prostaglandins, Leukot. Essent. Fatty Acids. 2003; 69: 437-448Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The study by Xu et al. (22Xu J. Chalimoniuk M. Shu Y. Simonyi A. Sun A.Y. Gonzalez F.A. Weisman G.A. Wood W.G. Sun G.Y. Prostaglandin E2 production in astrocytes: regulation by cytokines, extracellular ATP, and oxidative agents.Prostaglandins, Leukot. Essent. Fatty Acids. 2003; 69: 437-448Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) further indicated the role of sPLA2 in cytokine-induced production of PGE2. Because C57Bl/6 mice lack the group IIA sPLA2 gene due to a frame shift mutation (53Kennedy B.P. Payette P. Mudgett J. Vadas P. Pruzanski W. Kwan M. Tang C. Rancourt D.E. Cromlish W.A. A natural disruption of the secretory group II phospholipase A2 gene in inbred mouse strains.J. Biol. Chem. 1995; 270: 22378-22385Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar), astrocytes isolated from these mice were less responsive to cytokines in the production of PGE2 than were as
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