June 1, 1997Open Access

Function and Inhibition of Intracellular Calcium-independent Phospholipase A2

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Abstract

Our previous Minireview (1Dennis E.A. J. Biol. Chem. 1994; 269: 13057-13060Abstract Full Text PDF PubMed Google Scholar) considered the three main kinds of phospholipase A2(PLA2) 1The abbreviations used are: PLA2, phospholipase A2; sPLA2, secretory Ca2+-dependent phospholipase A2; cPLA2, 85-kDa Ca2+-dependent cytosolic phospholipase A2; iPLA2, Ca2+-independent cytosolic phospholipase A2; BEL, bromoenol lactone; PAP-1, Mg2+-dependent phosphatidic acid phosphohydrolase; PAF, platelet-activating factor; AA, arachidonic acid; DAG, 1,2-diacylglycerol; CHO, Chinese hamster ovary. : the well characterized Groups I, II, and III small Ca2+-dependent secretory phospholipase A2s (sPLA2), the 85-kDa Group IV Ca2+-dependent cytosolic phospholipase A2 (cPLA2), and the 80-kDa Ca2+-independent cytosolic phospholipase A2(iPLA2). In the ensuing years, it has become clear that PLA2 represents a growing superfamily of enzymes with many additional sPLA2s (Groups IIC, V, and IX), further definition of the 80-kDa iPLA2 (Group VI), and two Ca2+-independent PLA2s specific for platelet-activating factor (PAF) (Groups VII and VIII) (2Dennis E.A. Trends Biochem. Sci. 1997; 22: 1-2Abstract Full Text PDF PubMed Scopus (758) Google Scholar). All of the well studied sPLA2s appear to use a His-Asp catalytic mechanism and require Ca2+ to be bound tightly in the active site of the enzyme. The well characterized iPLA2appears to require a central Ser for catalysis and of course, no Ca2+. Interestingly, the Group IV cPLA2 does not use Ca2+ for catalysis, but rather the Ca2+dependence seems to relate to a calcium lipid-binding domain (CaLB or C-2 domain) at the N-terminal end responsible for association of the enzyme with the membrane. Thus, the catalytic mechanism and active site Ser do not involve Ca2+ (3Reynolds L.J. Hughes L.L. Louis A.I. Kramer R.M. Dennis E.A. Biochim. Biophys. Acta. 1993; 1167: 272-280Crossref PubMed Scopus (151) Google Scholar, 4Sharp J.D. Pickard R.T. Chiou X.G. Manetta J.V. Kovacevic S. Miller J.R. Varshavsky A.D. Roberts E.F. Strifler B.A. Brems D.N. Kramer R.M. J. Biol. Chem. 1994; 269: 23250-23254Abstract Full Text PDF PubMed Google Scholar, 5Pickard R.T. Chiou X.G. Strifler B.A. DeFelippis M.R. Hyslop P.A. Tebbe A.L. Yee Y.K. Reynolds L.J. Dennis E.A. Kramer R.M. Sharp J.D. J. Biol. Chem. 1996; 271: 19225-19231Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar); therefore a mechanistic distinction between the Group IV cPLA2 and the iPLA2s may not be warranted at this time. This is relevant because most of the inhibitors that work on the Group IV cPLA2 also act on the Group VI iPLA2 (6Conde-Frieboes K. Reynolds L.J. Lio Y.C. Hale M.R. Wasserman H.H. Dennis E.A. J. Am. Chem. Soc. 1996; 118: 5519-5525Crossref Scopus (85) Google Scholar, 7Lio Y.C. Reynolds L.J. Balsinde J. Dennis E.A. Biochim. Biophys. Acta. 1996; 1302: 55-60Crossref PubMed Scopus (15) Google Scholar). Inhibitor specificity will be discussed in the next section. We (8Ackermann E.J. Dennis E.A. Biochim. Biophys. Acta. 1995; 1259: 125-136Crossref PubMed Scopus (129) Google Scholar) recently surveyed all of the reported Ca2+-independent PLA2 activities. While there exists a group of lysosomal iPLA2s and a group of characterized ectoenzymes with broad specificity, which may actually be general lipases (8Ackermann E.J. Dennis E.A. Biochim. Biophys. Acta. 1995; 1259: 125-136Crossref PubMed Scopus (129) Google Scholar), sequenced and well characterized intracellular iPLA2s are limited to the 80-kDa Group VI iPLA2and the 29-kDa Group VIII enzyme, which is a PAF acetyl hydrolase (9Hattori M. Adachi H. Tsujimoto M. Arai H. Inoue K. J. Biol. Chem. 1994; 269: 23150-23155Abstract Full Text PDF PubMed Google Scholar). The latter hydrolyzes the acetyl chain present at the sn-2position of PAF and perhaps acts on oxidized phospholipids as well but not on normal phospholipids carrying unoxidized long chain fatty acids at the sn-2 position (9Hattori M. Adachi H. Tsujimoto M. Arai H. Inoue K. J. Biol. Chem. 1994; 269: 23150-23155Abstract Full Text PDF PubMed Google Scholar). This enzyme and a secreted Group VII PAF acetyl hydrolase, both of which are really iPLA2s with a particular substrate specificity, have been considered elsewhere (2Dennis E.A. Trends Biochem. Sci. 1997; 22: 1-2Abstract Full Text PDF PubMed Scopus (758) Google Scholar). The Group VI 80-kDa iPLA2 was first identified in P388D1 macrophages (10Ross M.I. Deems R.A. Jesaitis A.J. Dennis E.A. Ulevitch R.J. Arch. Biochem. Biophys. 1985; 238: 247-258Crossref PubMed Scopus (38) Google Scholar), purified (11Ackermann E.J. Kempner E.S. Dennis E.A. J. Biol. Chem. 1994; 269: 9227-9233Abstract Full Text PDF PubMed Google Scholar), further characterized (12Ackermann E.J. Conde-Frieboes K. Dennis E.A. J. Biol. Chem. 1995; 270: 445-450Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar), and then cloned and sequenced by Jones and co-workers (13Tang J. Kriz R.W. Wolfman N. Shaffer M. Seehra J. Jones S.S. J. Biol. Chem. 1997; 272: 8567-8575Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar) from CHO cells. The CHO iPLA2 has been shown to represent a species variant of that present in P388D1 macrophage-like cells, where the iPLA2 has also been cloned and sequenced (14Balboa M.A. Balsinde J. Jones S.S. Dennis E.A. J. Biol. Chem. 1997; 272: 8576-8580Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). The sequence of the Group VI iPLA2 reveals the presence of eight ankyrin-like domains and the G-X-S-X-G motif commonly found in other lipases. Interestingly, no known consensus sequences for posttranslational modification, such as phosphorylation sites, are apparent in the Group VI iPLA2 (13Tang J. Kriz R.W. Wolfman N. Shaffer M. Seehra J. Jones S.S. J. Biol. Chem. 1997; 272: 8567-8575Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 14Balboa M.A. Balsinde J. Jones S.S. Dennis E.A. J. Biol. Chem. 1997; 272: 8576-8580Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). This is compatible with the possibility that the Group VI iPLA2 acts to remodel membrane phospholipids as a sort of housekeepingenzyme as will be discussed later. The functional significance of intracellular iPLA2 can most easily be investigated using selective inhibitors. Unfortunately, no specific iPLA2 inhibitors currently exist. As indicated above, the apparent presence of an active site Ser residue in Group VI iPLA2 is similar to that of the Group IV cPLA2. Thus, the cPLA2 inhibitors currently available, which were designed as site-directed inhibitors, all inhibit the Group VI iPLA2 as well. These include arachidonyl trifluoromethyl ketone (6Conde-Frieboes K. Reynolds L.J. Lio Y.C. Hale M.R. Wasserman H.H. Dennis E.A. J. Am. Chem. Soc. 1996; 118: 5519-5525Crossref Scopus (85) Google Scholar), arachidonyl tricarbonyl (6Conde-Frieboes K. Reynolds L.J. Lio Y.C. Hale M.R. Wasserman H.H. Dennis E.A. J. Am. Chem. Soc. 1996; 118: 5519-5525Crossref Scopus (85) Google Scholar), and methyl arachidonyl fluorophosphonate (7Lio Y.C. Reynolds L.J. Balsinde J. Dennis E.A. Biochim. Biophys. Acta. 1996; 1302: 55-60Crossref PubMed Scopus (15) Google Scholar). These three compounds contain an arachidonyl tail and function as transition-state analogues in a reversible or irreversible manner. The arachidonyl tail was intended to confer selectivity to the inhibitors and to facilitate their access to the cPLA2 active site (15Street I.P. Lin H.K. Laliberté F. Ghomashchi F. Wang Z. Perrier H. Tremblay N.M. Huang Z. Weech P.K. Gelb M.H. Biochemistry. 1993; 32: 5935-5940Crossref PubMed Scopus (419) Google Scholar, 16Huang Z. Payette P. Abdullah K. Cromlish W.A. Kennedy B.P. Biochemistry. 1996; 35: 3712-3721Crossref PubMed Scopus (86) Google Scholar), as this enzyme selectively hydrolyzes arachidonate-containing phospholipids (17Clark J.D. Milona N. Knopf J.L. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 7708-7712Crossref PubMed Scopus (422) Google Scholar, 18Kramer R.M. Roberts E.F. Manetta J. Putnam J.E. J. Biol. Chem. 1991; 266: 5268-5272Abstract Full Text PDF PubMed Google Scholar). Remarkably, even though the iPLA2 is not AA-specific (11Ackermann E.J. Kempner E.S. Dennis E.A. J. Biol. Chem. 1994; 269: 9227-9233Abstract Full Text PDF PubMed Google Scholar), these inhibitors work even better on the iPLA2 than on the cPLA2 (6Conde-Frieboes K. Reynolds L.J. Lio Y.C. Hale M.R. Wasserman H.H. Dennis E.A. J. Am. Chem. Soc. 1996; 118: 5519-5525Crossref Scopus (85) Google Scholar, 7Lio Y.C. Reynolds L.J. Balsinde J. Dennis E.A. Biochim. Biophys. Acta. 1996; 1302: 55-60Crossref PubMed Scopus (15) Google Scholar). Furthermore, palmityl trifluoromethyl ketone and palmityl tricarbonyl are as good inhibitors of both the Group IV cPLA2 and Group VI iPLA2 as their arachidonyl analogs (6Conde-Frieboes K. Reynolds L.J. Lio Y.C. Hale M.R. Wasserman H.H. Dennis E.A. J. Am. Chem. Soc. 1996; 118: 5519-5525Crossref Scopus (85) Google Scholar, 12Ackermann E.J. Conde-Frieboes K. Dennis E.A. J. Biol. Chem. 1995; 270: 445-450Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar). Due to the lack of selectivity of the aforementioned compounds, it is unlikely that they will find much use in defining the role of the iPLA2 in cell function, unless the process under study is truly Ca2+-independent. Inhibition studies employing the fatty acyl trifluoromethyl ketones, tricarbonyls, or fluorophosphonates in the absence of Ca2+ might selectively target the iPLA2, as this is the only one of the well studied cellular PLA2s that remains active under Ca2+-depleted conditions. One common feature of the two best characterized intracellular iPLA2s, namely the Group VI enzyme present in P388D1 macrophages (12Ackermann E.J. Conde-Frieboes K. Dennis E.A. J. Biol. Chem. 1995; 270: 445-450Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar) and CHO cells (14Balboa M.A. Balsinde J. Jones S.S. Dennis E.A. J. Biol. Chem. 1997; 272: 8576-8580Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar) and a 40-kDa iPLA2 present in myocardial tissue and pancreatic islets (19Hazen S.L. Zupan L.A. Weiss R.H. Getman D.P. Gross R.W. J. Biol. Chem. 1991; 266: 7227-7232Abstract Full Text PDF PubMed Google Scholar), is their complete and irreversible inhibition by the mechanism-based inhibitor BEL. This inhibitor was first introduced as a serine protease inhibitor (20Daniels S.B. Katzenellenbogen J.A. Biochemistry. 1986; 25: 1436-1444Crossref PubMed Scopus (49) Google Scholar) but has been shown to be specific for iPLA2 over Ca2+-dependent sPLA2s (19Hazen S.L. Zupan L.A. Weiss R.H. Getman D.P. Gross R.W. J. Biol. Chem. 1991; 266: 7227-7232Abstract Full Text PDF PubMed Google Scholar, 21Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 6758-6765Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar) and Group IV Ca2+-dependent cPLA2 (21Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 6758-6765Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar). In addition, BEL does not affect a number of enzyme activities directly involved in cellular AA metabolism (22Balsinde J. Bianco I.D. Ackermann E.J. Conde-Frieboes K. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8527-8531Crossref PubMed Scopus (256) Google Scholar). Thus BEL has received great attention because of its possible use as a selective iPLA2inhibitor in whole cell studies. As a matter of fact, much of what is currently believed to be mediated by iPLA2 enzymes has been derived from studies using BEL. Unfortunately, BEL has recently been found to inhibit another key enzyme in cellular phospholipid metabolism, the Mg2+-dependent phosphatidic acid phosphohydrolase (PAP-1) (23Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 31937-31941Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar). The latter enzyme catalyzes the dephosphorylation of phosphatidic acid to yield 1,2-diacylglycerol (DAG), a central intermediate in glycerolipid synthesis as well as an important intracellular messenger molecule. Therefore, BEL cannot be used as a selective iPLA2 inhibitor in whole cell studies unless it is demonstrated that the process under study is independent of variations in cellular DAG levels as well as Ca2+; even then BEL is known to inhibit proteases and may affect other enzymes as well. The implications will be discussed in the next section. There exists in cells an ongoing deacylation/reacylation cycle of membrane phospholipids, the so-called Lands cycle, whereby a pre-existing phospholipid is cleaved by an intracellular PLA2 to generate a 2-lysophospholipid, which in turn may be re-acylated with a different fatty acid to generate a new phospholipid (22Balsinde J. Bianco I.D. Ackermann E.J. Conde-Frieboes K. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8527-8531Crossref PubMed Scopus (256) Google Scholar, 24Chilton F.H. Fonteh A.N. Surette M.E. Triggiani M. Winkler J.D. Biochim. Biophys. Acta. 1996; 1299: 1-15Crossref PubMed Scopus (211) Google Scholar). This remodeling cycle constitutes the major route for incorporation of free AA into the phospholipids of cells at nanomolar levels of the free fatty acid (Fig. 1) (22Balsinde J. Bianco I.D. Ackermann E.J. Conde-Frieboes K. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8527-8531Crossref PubMed Scopus (256) Google Scholar, 24Chilton F.H. Fonteh A.N. Surette M.E. Triggiani M. Winkler J.D. Biochim. Biophys. Acta. 1996; 1299: 1-15Crossref PubMed Scopus (211) Google Scholar). Thede novo route or Kennedy pathway constitutes, in addition, a second route for incorporation of AA into cellular phospholipids (Fig.1). However, the Kennedy pathway appears to be relevant in terms of AA incorporation only when high, micromolar levels of free AA are available (25Balsinde J. Dennis E.A. Eur. J. Biochem. 1996; 235: 480-485Crossref PubMed Scopus (29) Google Scholar). Thus, AA incorporation into phospholipids under normal conditions is strikingly dependent on a PLA2 that generates the 2-lysophospholipid used in the acylation reaction. Macrophages and macrophage cell lines possess a high capacity to incorporate AA into their membrane phospholipids (26Balsinde J. Fernández B. Solı́s-Herruzo J.A. Eur. J. Biochem. 1994; 221: 1013-1018Crossref PubMed Scopus (25) Google Scholar, 27Balsinde J. Barbour S.E. Bianco I.D. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 11060-11064Crossref PubMed Scopus (127) Google Scholar). This process occurs in a Ca2+-independent manner (22Balsinde J. Bianco I.D. Ackermann E.J. Conde-Frieboes K. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8527-8531Crossref PubMed Scopus (256) Google Scholar, 26Balsinde J. Fernández B. Solı́s-Herruzo J.A. Eur. J. Biochem. 1994; 221: 1013-1018Crossref PubMed Scopus (25) Google Scholar), suggesting the involvement of an iPLA2. Consistent with this observation, BEL inhibits AA esterification in a dose-dependent and saturatable manner, and the decrease in AA incorporation directly correlates with inhibition of both cellular iPLA2 activity and steady-state lysophospholipid levels (22Balsinde J. Bianco I.D. Ackermann E.J. Conde-Frieboes K. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8527-8531Crossref PubMed Scopus (256) Google Scholar). Although the lack of BEL specificity now raises some doubt about the firmness of this conclusion, it is important to stress here that AA esterification via phospholipid remodeling is independent of variations in DAG levels. Moreover, BEL does not reduce the cellular steady-state levels of DAG. 2J. Balsinde, M. A. Balboa, and E. A. Dennis, manuscript in preparation. Thus, the possible parallel inhibition of PAP-1 by BEL should not affect the basal rate of AA incorporation into phospholipids. The nucleotide sequence for the Group VI murine iPLA2 is now available (14Balboa M.A. Balsinde J. Jones S.S. Dennis E.A. J. Biol. Chem. 1997; 272: 8576-8580Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). This has enabled us to utilize more convincing molecular biological approaches, such as antisense inhibition studies, to ascertain the role of the Group VI iPLA2 in cellular phospholipid metabolism. Antisense inhibition of the Group VI iPLA2 has confirmed that this enzyme does play a role in phospholipid remodeling as iPLA2-depleted cells show a significant reduction of their capacity to incorporate AA into membrane phospholipids.2 Moreover, the decreased incorporation of AA into phospholipids that iPLA2-depleted cells manifest is not further decreased by BEL,2 demonstrating that this compound is indeed targeting the iPLA2 in the previous experiments (22Balsinde J. Bianco I.D. Ackermann E.J. Conde-Frieboes K. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8527-8531Crossref PubMed Scopus (256) Google Scholar). Collectively, these findings suggest that the Group VI iPLA2 is responsible for phospholipid fatty acid remodeling under resting conditions. Hence this enzyme appears to regulate the main pathway through which the cells incorporate AA and other unsaturated fatty acids into their membrane phospholipids. In addition to its obvious importance in cellular metabolism, the rate of AA incorporation into phospholipids also determines the amount of free fatty acid available under resting conditions. This is relevant because free AA availability is a limiting factor for eicosanoid biosynthesis. By regulating basal AA esterification reactions, the Group VI iPLA2 may also play a key role in regulating the amount of prostaglandins by resting cells. the other there is now for the of different AA the cells (21Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 6758-6765Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar, A.N. F.H. J. 1993; Google Scholar) that can be by Ca2+-dependent PLA2s cell (21Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 6758-6765Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar). The role of in regulating the of AA different phospholipid has recently become F.H. Fonteh A.N. Surette M.E. Triggiani M. Winkler J.D. Biochim. Biophys. Acta. 1996; 1299: 1-15Crossref PubMed Scopus (211) Google Scholar). However, as the the of the it is possible that the both the of this fatty acid the different cellular and the amount of fatty acid present in further remodeling by the on BEL the iPLA2 has been to AA in different cells with S. Gross R.W. J. Biochemistry. 1993; 32: PubMed Scopus Google Scholar, S. J. Gross R.W. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar, R.W. Wang J. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). is that cell DAG levels and this may AA directly DAG substrate for the J. E. F. J. Biol. Chem. 1991; 266: Full Text PDF PubMed Google Scholar) or J. 1995; PubMed Scopus Google Scholar). As discussed above, BEL has recently been found to inhibit cellular PAP-1 activity (23Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 31937-31941Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar). is that PAP-1 a role in intracellular DAG levels in where the pathway is involved A. A. P.A. D.N. M. Scholar). Thus, the reported of BEL on AA might also be at in to inhibition of PAP-1 in addition to the iPLA2. The may better the of BEL on AA In studies with and pancreatic S. Gross R.W. J. Biochemistry. 1993; 32: PubMed Scopus Google Scholar) the iPLA2 as the major of AA on the of its inhibition by BEL. However, R.J. B.A. Biochemistry. 1994; PubMed Scopus Google Scholar) have that the DAG pathway constitutes the major route for AA in the The by these two be BEL was DAG in the work by S. Gross R.W. J. Biochemistry. 1993; 32: PubMed Scopus Google Scholar). the other it is to that in where AA appears not to on such as P388D1 macrophages J. M.A. P.A. Dennis E.A. Biochem. J. 1997; PubMed Scopus Google Scholar), BEL is in this (21Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 6758-6765Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar). of an iPLA2 in AA has also been by and M.R. E.J. J. Biol. 1993; PubMed Scopus Google Scholar, K. M.R. J. 1995; Google Scholar) in studies with AA in a Ca2+-independent manner M.R. E.J. J. Biol. 1993; PubMed Scopus Google Scholar). Consistent with the possible involvement of an iPLA2, AA in this is by BEL M.R. E.J. J. Biol. 1993; PubMed Scopus Google Scholar). The process was found to be dependent on K. M.R. J. 1995; Google Scholar). Thus, the BEL be to on DAG, the that the process in the absence of Ca2+ to the possible involvement of an iPLA2. is to the involvement of a Ca2+-independent enzyme in such as AA which in most is and Gross Gross R.W. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus (86) Google Scholar) have recently reported that a 40-kDa myocardial iPLA2 with in a Ca2+-dependent manner, a mechanism through which Ca2+ may regulate a Ca2+-independent enzyme. to these myocardial iPLA2 is when with of the to in the Ca2+ or addition of the iPLA2 to phospholipids and AA Gross R.W. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus (86) Google Scholar). This mechanism has been to the in of AA Gross R.W. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus (86) Google Scholar). the reported association with the 40-kDa iPLA2 activity from myocardial tissue and pancreatic islets was reported to to or an S.L. Gross R.W. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar, S. Z. B. Wang J. Gross R.W. J. Biochemistry. 1996; 35: PubMed Scopus Google Scholar). Due to their and molecular it appears clear that the 40-kDa iPLA2 activity identified in and pancreatic islets is different from the Group VI enzyme present in P388D1 macrophages and CHO cells S. Z. B. Wang J. Gross R.W. J. Biochemistry. 1996; 35: PubMed Scopus Google Scholar). However, as a common the two as catalytic of about (11Ackermann E.J. Kempner E.S. Dennis E.A. J. Biol. Chem. 1994; 269: 9227-9233Abstract Full Text PDF PubMed Google Scholar). The Group VI iPLA2 has been shown to possess eight which may or with other (13Tang J. Kriz R.W. Wolfman N. Shaffer M. Seehra J. Jones S.S. J. Biol. Chem. 1997; 272: 8567-8575Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar). is possible that the 40-kDa myocardial iPLA2 activity similar that its with other such as and the sequence of the 40-kDa has not been Thus, its with the Group VI iPLA2, cannot be at this time. However, to the Group VI iPLA2 (11Ackermann E.J. Kempner E.S. Dennis E.A. J. Biol. Chem. 1994; 269: 9227-9233Abstract Full Text PDF PubMed Google Scholar), the 40-kDa activity is by in S.L. Gross R.W. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar). by have shown rather than enzyme and the iPLA2 from the activity is found in the presence than in the absence of and other (14Balboa M.A. Balsinde J. Jones S.S. Dennis E.A. J. Biol. Chem. 1997; 272: 8576-8580Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). Thus there is no that a role for the Group VI iPLA2 in The importance of the intracellular iPLA2 in of cell function has not been at the that iPLA2s have been found to in all cells and many new iPLA2s are purified and characterized (8Ackermann E.J. Dennis E.A. Biochim. Biophys. Acta. 1995; 1259: 125-136Crossref PubMed Scopus (129) Google Scholar, J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, L.A. 1995; PubMed Scopus Google Scholar, M.A. Biochem. J. 1995; PubMed Scopus Google Scholar). The of iPLA2s that this of enzymes may play important in cell acid remodeling of membrane phospholipids in macrophages appears to be an most mediated by intracellular much of the available on cellular iPLA2 function on the use of inhibitors that have been shown not to be selective for this of However, these inhibitors may for the of more selective that may to new for intracellular iPLA2s in cellular

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