Phospholipase A2 receptor: a regulator of biological functions of secretory phospholipase A2

Prostaglandins & other Lipid Mediators 68–69 (2002) 71–82

Phospholipase A2 receptor: a regulator of biological functions of secretory phospholipase A2 Kohji Hanasaki∗ , Hitoshi Arita Shionogi Research Laboratories, Shionogi and Co., Ltd., Sagisu 5-12-4, Fukushima-ku, Osaka 553-0002, Japan

Abstract The phospholipase A2 receptor (PLA2 R) is a type I transmembrane glycoprotein related to the C-type animal lectin family that includes the mannose receptor. PLA2 R regulates a variety of biological responses elicited by specific types of secretory PLA2 s (sPLA2 s). Group IB sPLA2 (sPLA2 -IB) acts as an endogenous PLA2 R ligand to induce cell proliferation, cell migration, and lipid mediator production. Analysis of PLA2 R-deficient mice has suggested a potential role of the sPLA2 IB/PLA2 R pathway in the production of pro-inflammatory cytokines in endotoxic shock. PLA2 R is also involved in the clearance of sPLA2 s, including group X sPLA2 (sPLA2 -X) and a particular type of snake venom sPLA2 , and clearance suppresses their potent enzymatic activities. In the circulation, the soluble form of PLA2 R is constitutively present as an endogenous inhibitor of sPLA2 s. This review will focus on recent findings on the roles of PLA2 R in regulating sPLA2 functions and summarize what is known about the other binding proteins for mammalian and snake venom sPLA2 s. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Secretory phospholipase A2 ; Phospholipase A2 receptor; Lipid mediators; Knockout mouse; Endotoxic shock

1. Introduction Phospholipase A2 (PLA2 ) is an enzyme that catalyzes the hydrolysis of the sn-2 ester bond of glycerophospholipids [1,2]. A number of intracellular and extracellular PLA2 s have now been identified and classified into different families according to their biochemical features [3]. Among them, secretory PLA2 s (sPLA2 s) have several common characteristics including a relatively low molecular mass (13–18 kDa), the presence of six to eight disulfide bridges, and an absolute catalytic requirement for millimolar concentrations of Ca2+ . Mammalian sPLA2 s are classified into ten different groups (IB, IIA, IIC, IID, IIE, IIF, III, ∗

Corresponding author. Tel.: +81-6-6455-2104; fax: +81-6-6458-0987. E-mail address: [email protected] (K. Hanasaki).

0090-6980/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII: S 0 0 9 0 - 6 9 8 0 ( 0 2 ) 0 0 0 2 2 - 9

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V, X, XII) depending on the primary structure characterized by the number and positions of cysteine residues as well as their characteristic domain structures [3–5]. To date, most of the biological activities of sPLA2 s have been attributed to their enzymatic capacity to hydrolyze membrane phospholipids. For example, group IIA sPLA2 (sPLA2 -IIA) plays a critical role in the hydrolysis of lung surfactant phospholipids during the progression of acute lung injury [6]. However, the discovery of the PLA2 receptor (PLA2 R) has expanded our concept of the functions of the sPLA2 family [7]. In addition to the digestive function, sPLA2 can exert various biological responses by binding to the cell surface PLA2 R [8]. In this review, we describe the regulatory roles of PLA2 R for sPLA2 functions and summarize the properties of other sPLA2 binding proteins.

2. Biochemical properties and expression of PLA2 R We identified PLA2 R as the binding protein for group IB sPLA2 (sPLA2 -IB), which had long been thought, given its abundance in digestive organs [9,10], to play a role in the digestion of glycerophospholipids in nutrients. We purified the bovine sPLA2 -IB binding protein and cloned its cDNA [11,12]. At almost the same time, Lambeau et al. [13] cloned its rabbit homologue based on findings of the purified binding protein recognized by snake venom Oxyuranus scutellatus toxin 1 sPLA2 (OS1 ). They called this site the M-type (muscle-type) receptor in order to discriminate it from another binding site for neurotoxic snake sPLA2 , the N-type receptor [14]. However, mammalian sPLA2 s can only bind to the former site, which is not restricted to muscles but also expressed in various mammalian tissues [8]. The molecular structure and biological roles of the N-type receptor have not yet been clarified. Under these circumstances, we decided to name the sPLA2 binding protein that we cloned “PLA2 R.” Although different subtypes of sPLA2 binding proteins have been identified in the last 10 years [15], PLA2 R is the only membrane “receptor” that can be linked to signal transduction systems leading to the induction of biological responses following occupation by sPLA2 ligands [8]. The amino acid sequence identity of the PLA2 R among bovine, rabbit, mouse, and human types is over 70%, and the human PLA2 R gene is located on chromosome 2 [16]. Genomic DNA blotting analysis indicated that the PLA2 R is encoded by a single copy gene, and there is no other closely related gene in the mammalian genome [17]. PLA2 R is a type I transmembrane glycoprotein with a molecular mass of 180–200 kDa and is composed of a large extracellular portion consisting of an N-terminal cysteine-rich region, a fibronectin-like type II domain and a tandem repeat of eight carbohydrate-recognition domains (CRDs), as well as a short intracellular C-terminal region. Its overall molecular organization is related to a unique member of the C-type animal lectin family (subgroup VI) [7], which includes the macrophage mannose receptor, DEC-205 in dendritic cells, and the endothelial cell lectin-like lambda protein [8,14]. The level of sequence identity between PLA2 R and the mannose receptor is only 29%, and sPLA2 -IB does not bind the macrophage mannose receptor or the lectin-like lambda protein [8]. Most of the extracellular portion of PLA2 R is composed of eight CRD-like domains, which are responsible for sPLA2 binding [12]. In particular, the three CRD-like domains from CRD3 to CRD5 are sufficient for conferring sPLA2 -IB binding activity [17]. However,

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the critical residues required for the sugar/Ca2+ binding found in the mannose receptor are not conserved in the CRD-like domains of the PLA2 R [7]. In fact, PLA2 R does not possess Ca2+ -dependent lectin activity, as mannose does not interfere with sPLA2 -IB binding to the PLA2 R. It should also be noted that the sPLA2 binding to PLA2 R is completely Ca2+ -independent. PLA2 R contains 15 potential N-glycosylation sites and thus is highly glycosylated. In mouse and bovine PLA2 R, the N-linked sugar moiety is essential for the optimum recognition of sPLA2 -IB [18,19]. The intracellular region of human PLA2 R consists of approximately 40 amino acids including a consensus sequence site for casein-kinase II phosphorylation [16], although there is no evidence for its involvement in signal transduction events. The cytoplasmic domain also carries a consensus sequence motif (Asn–Pro–Xxx–Tyr; the NPXY motif) of coated-pit-mediated endocytosis originally identified in the LDL receptor and also found in the mannose receptor [7]. In fact, PLA2 R undergoes internalization upon sPLA2 binding [10,20]. In mouse PLA2 R, however, the internalization can also occur in spite of the absence of the NPXY motif in its sequence [17]. In mice, PLA2 R mRNA as well as the sPLA2 binding activity have been detected in several tissues including the lung, spleen, and kidney [17]. Immunohistochemical analysis as well as in situ hybridization analysis has revealed PLA2 R expression in alveolar type II epithelial cells and a subset of splenic lymphocytes [21]. In rats, PLA2 R mRNA was detected in the lung, liver, and testis [10]. Extensive analysis of the cellular distribution of the sPLA2 -IB binding site in rats also demonstrated the presence of PLA2 R in glomerular mesangial cells, vascular smooth muscle cells, vascular endothelial cells, synovial cells, and chondrocytes, but its absence from platelets and erythrocytes [7]. Notably, PLA2 R mRNA is not expressed in the peritoneal macrophages where its homologue mannose receptor is abundantly expressed. In humans, the receptor mRNA is detected in the lung, kidney, and pancreas [16], and our preliminary immunohistological analysis has revealed the presence of PLA2 R in alveolar type II pneumocytes (Hanasaki, Nakano, and Kawamoto, unpublished observations). Thus, PLA2 R is expressed in strictly limited cell types in particular organs, including alveolar type II epithelial cells that are known to play a crucial role in the secretion of lung surfactant and various types of cytokines and growth factors [22].

3. Endogenous ligands of PLA2 R There is strict species specificity in the relationship between sPLA2 ligands and PLA2 R [23]. In mice, sPLA2 -IB is one of the endogenous ligands of PLA2 R with a Kd of approximately 1 nM [23]. sPLA2 -IB has a characteristic intramolecular disulfide bond between Cys-11 and -77 and the pancreatic loop structure. Mutations of amino acid residues within or close to the Ca2+ -binding loop of sPLA2 -IB result in a dramatic decrease in the affinity for the PLA2 R [24,25]. In contrast, sPLA2 -IIA possesses a different type of intramolecular disulfide bond between Cys-50 and -124, as well as an amino acid C-terminal extension structure. Inhibition studies on snake venom OS1 binding have revealed that sPLA2 -IIA can also act as a natural ligand for mouse PLA2 R, but its affinity is 6–10-fold lower than sPLA2 -IB [23]. However, some inbred mouse strains have a natural frameshift

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mutation in the sPLA2 -IIA gene that leads to a non-functional enzyme [26], and even in sPLA2 -IIA-expressing mouse strains, its expression is restricted in the small intestine. In addition, group IID sPLA2 cannot act as a PLA2 R ligand despite its structural similarities to sPLA2 -IIA [27]. These findings suggest that the contribution of sPLA2 -IIA as a PLA2 R ligand could be much lower in mice. Recently, a novel type of group X sPLA2 (sPLA2 -X) has been identified as another high-affinity ligand for mouse PLA2 R [28]. sPLA2 -X possesses 16 cysteine residues located at positions characteristic for both sPLA2 -IB and -IIA, and also has an amino acid C-terminal extension that is typical of group II sPLA2 subtypes [29]. The binding of sPLA2 -X to mouse lung membranes is completely abolished by the deficiency of PLA2 R, demonstrating that PLA2 R represents the only binding component of sPLA2 -X in mice. The expression of sPLA2 -IB and X were detected in alveolar type II epithelial cells and splenic cells in mice [21,30,31], where they can work as functional PLA2 R ligands in vivo. Intriguingly, both sPLA2 ligands are produced as inactive pro-enzymes that have a propeptide sequence attached at the NH2 -terminals of the mature form [30], and the structural change during conversion from the pro-form by proteolytic cleavage of the propeptide is essential for optimum binding to the receptor [31]. Therefore, the PLA2 R-mediated responses are regulated by the activation of sPLA2 ligands with proteolytic enzymes such as trypsin and proprotein convertases [32]. In rats, sPLA2 -IB also acts as a high-affinity ligand for PLA2 R to induce various biological responses [10]. In contrast to rodents, the natural ligands for human PLA2 R remain obscure at present. From the inhibitory potency against OS1 binding in PLA2 R-overexpressing COS cells, the binding affinity of human sPLA2 -IB was calculated to be approximately 400 nM [16], which is rather weak compared to those calculated in rodents. However, the binding affinity of OS1 itself was also 20–40-fold lower than that estimated in the PLA2 R of other animal species [23], demonstrating a different recognition mode of human PLA2 R for the sPLA2 ligands. In the human pancreatic cancer cell line MIAPaCa-2 cells, human sPLA2 -IB was shown to bind to a single class of high-affinity binding sites [33], suggesting a possible contribution of some accessory molecules to the high-affinity recognition of sPLA2 -IB in the native human PLA2 R. In humans, sPLA2 -IB and PLA2 R are co-expressed in the pancreas, lung, and kidney [16,17], suggesting that sPLA2 -IB is, at least in part, a natural ligand for human PLA2 R. In contrast, sPLA2 -IIA does not bind to the PLA2 R in rats and humans [23], and there is no information regarding the potency of sPLA2 -X as a ligand for human PLA2 R. Recent advances in molecular biology as well as accumulating DNA sequence information have led to discoveries of a number of novel types of human sPLA2 s, including group III, V, and XII [3]. As these sPLA2 s have different structural features from sPLA2 -IB and -IIA, their possible roles as endogenous ligands of human PLA2 R should be evaluated in future studies. Snake and insect venoms contain a variety of sPLA2 s that have a similar catalytic mechanism and the same overall structural organization as mammalian sPLA2 s [15], and thus can act as exogenous ligands for PLA2 R. However, PLA2 R can recognize only a limited number of Taipan snake venom sPLA2 s including OS1 and OS2 , whereas other types of snake venom sPLA2 s and bee venom sPLA2 do not bind to the receptor [14]. Since OS1 is the ligand with the highest affinity for PLA2 R in various animal species [23], it has been used as a powerful probe for detecting PLA2 R in spite of the lack of the data on biological responses following receptor binding.

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4. PLA2 R-mediated biological responses PLA2 R has been shown to be involved in both positive and negative regulation of sPLA2 functions, as depicted in Fig. 1. The PLA2 R-mediated activation of cell functions has been studied in vitro in non-digestive organs and various cell types, as described in our previous reviews [7,8]. These responses are considered to be PLA2 R-mediated reactions, and are not a single consequence of increased extracellular PLA2 activity for the following reasons: (1) the responses are elicited only by an active form of sPLA2 -IB and not by pro-sPLA2 -IB and bee venom sPLA2 , which coincides well with their binding potency for PLA2 R; (2) the value of the half-maximum effective concentration of sPLA2 -IB is very close to the dissociation constant of the sPLA2 -IB/PLA2 R complex; (3) the sPLA2 -IB binding to PLA2 R is independent of Ca2+ , and there are some mutant sPLA2 -IB molecules that lose almost all enzymatic activity, but retain binding affinity for PLA2 R as well as a potency for eliciting biological responses [24]. In addition, the enzymatic activity of sPLA2 -IB is suppressed

Fig. 1. PLA2 R-mediated regulation of the biological functions of sPLA2 s. Active forms of sPLA2 -IB and -X, in addition to possessing enzymatic activity, can act as high-affinity ligands for the cell surface PLA2 R in mice, thus inducing a variety of biological responses through some signal transduction pathways, such as MAPK activation. On the other hand, PLA2 R can also play a negative role in sPLA2 functions (enzymatic activity and receptor-mediated responses) to suppress their exaggerated reactions, as it is involved in the internalization and degradation of sPLA2 ligands and also acts as a circulating endogenous inhibitor for sPLA2 s after shedding from the plasma membranes. The number (1–8) in the PLA2 R structures represents the CRD-like domains.

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upon binding to the receptor. This is quite a contrast to other receptors for enzyme ligands, such as the proteinase-activated receptors, in which the enzymatic activity is required for ligand recognition and induction of biological functions [34]. The cell growth promoting effects of sPLA2 -IB are observed at a relatively low concentration (1–10 nM) in a variety of cell types, including Swiss 3T3 cells, rat aortic smooth muscle cells, chondrocytes, and synovial cells [9,10]. In human MIAPaCa-2 cells, sPLA2 -IB was shown to activate the mitogen-activated protein kinase (MAPK) cascade to induce cell proliferation [33]. In rat vascular smooth muscle A7r5 cells, sPLA2 -IB induced chemokinetic migration [35], and in NIH3T3 cells, mouse fibrosarcoma cells, and mouse sarcoma cells, sPLA2 -IB stimulated cell invasion into the extracellular matrix [19]. Suppression of these responses by PLA2 R-specific antisense oligonucleotide suggests the involvement of the receptor. In rodent uterus and ovary, as well as in human gestational tissues, a considerable amount of PLA2 R mRNA is detected [17]. In rat corpora lutea, sPLA2 -IB induces the release of progesterone in a dose-dependent manner, and its expression correlates well with the estrous cycle and progesterone secretion from rat ovary [36]. In rat pancreatic islets, sPLA2 -IB and PLA2 R mRNAs are co-expressed, and stimulation of intact islets with insulin secretagogues results in the co-secretion of insulin and sPLA2 -IB [37]. These findings suggest a regulatory role of the sPLA2 -IB/PLA2 R system in hormone secretion in endocrine organs. The production of lipid mediators has also been identified as a PLA2 R-mediated response induced by sPLA2 -IB [8]. In guinea pig lung parenchyma, sPLA2 -IB induces a potent contractile response via the production of TXA2 . Notably, type-specific responses of sPLA2 s, homologous desensitization, and the existence of a high-affinity sPLA2 -IB binding site have strongly implicated the involvement of PLA2 R in this response [38]. Fonteh et al. [39] have shown the presence of PLA2 R in murine bone marrow-derived mast cells (BMMC) and in human monocytic THP-1 cells, where sPLA2 -IB induces the selective release of arachidonic acid (AA). They have recently reported that overexpression of PLA2 R causes a marked increase in AA and PGD2 release after stimulation of BMMC with sPLA2 -IB or antigen [40]. Notably, the sPLA2 -IB-induced AA release was coupled to a transient increase in the activity of cytosolic PLA2 and its translocation from the cytosol to the membrane fractions possibly via phosphorylation by p44/p42 MAPK. Since sPLA2 -IB has substrate specificity for anionic phospholipids such as phosphatidylglycerol and thus has a weak hydrolyzing activity toward intact cell membranes [30], the PLA2 R-mediated formation of lipid mediators is particularly important for this sPLA2 subtype. In mouse osteoblastic MC3T3-E1 cells that abundantly express PLA2 R, sPLA2 -IB induced the expression of cyclooxygenase-2 (COX-2) leading to elevated PGE2 production [41]. In rat renal glomerular mesangial cells, sPLA2 -IB can induce the expression of sPLA2 -IIA as well as PGE2 production [42]. The use of PLA2 R-deficient mice has enabled us to analyze the biological functions of PLA2 R in vivo [43]. The specific binding of sPLA2 -IB detected in the membrane fractions of lung, kidney, and ovary in wild-type mice was completely ablated in the knockout mice, although the mutant mice were fertile and healthy under normal conditions. In a model of endotoxic shock, PLA2 R-deficient mice showed significant resistance to lipopolysaccharide (LPS)-induced lethality [43]. In addition, the maximum plasma levels of pro-inflammatory cytokines, such as tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤), after LPS administration were significantly lower in PLA2 R-knockout mice than in wild-type mice.

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Similar reductions in the plasma cytokine levels were observed in mice treated with Indoxam, a specific sPLA2 inhibitor that can strongly block the sPLA2 -IB binding to the murine PLA2 R [44]. In situ hybridization analysis revealed a reduced expression level of TNF-␣ mRNA in type II alveolar epithelial cells in the mutant mice after LPS challenge. With the same treatment, the expression of PLA2 R as well as sPLA2 -IB were markedly enhanced in the same type of cells in wild-type mice [21]. In addition, protease activities essential for the processing of sPLA2 ligands are known to be elevated in the tissues and circulation during septic shock [45]. Taken together, these findings suggest that, upon endotoxin challenge, the active form of sPLA2 ligands could be elevated in the alveoli, which may act on the PLA2 R present in type II epithelial cells to induce the production of lipid mediators involved in the regulation of TNF-␣ synthesis. Since alveolar macrophages are located predominantly at alveolar septal junctions in close proximity to type II epithelial cells, the signals evoked by the augmented sPLA2 -IB/PLA2 R pathway might also regulate cellular functions of alveolar macrophages, such as the production of various inflammatory cytokines. The elevated expressions of sPLA2 -IB and PLA2 R during endotoxemia have also been detected in the splenic lymphocytes [21]. Since enhanced conversion from the pro-form to active sPLA2 -IB has also been demonstrated in patients of acute lung injury [46], the potential involvement of PLA2 R in human disorders deserves evaluation in future studies.

5. Negative regulation for sPLA2 functions by PLA2 R In addition to the positive regulation of sPLA2 functions, PLA2 R has endocytic properties and rapidly internalizes sPLA2 ligands [10,20]. PLA2 R-mediated endocytosis is particularly important for the clearance of extracellular sPLA2 s to protect their potent enzymatic activities, as reported for snake venom OS1 [14]. Among the mammalian sPLA2 s, sPLA2 -X has been identified as one of the enzymes that possesses extremely potent hydrolyzing activity toward phosphatidylcholine in contrast to weak activities of sPLA2 -IB and -IIA [30,31]. In fact, sPLA2 -X can induce potent release of AA leading to COX-dependent PG formation, as well as marked production of lysophosphatidylcholine in various cell types, including macrophages and colon cancer cells. Given its high expression in macrophages and invasive colon cancers, sPLA2 -X is thought to play a crucial role in the progression of various disease states, including inflammation and colon tumorigenesis [31,47]. We have recently shown that mouse sPLA2 -X can be internalized and degraded after PLA2 R binding, thus resulting in a decrease in its potency for PGE2 production [48]. The internalization rate constant of PLA2 R for sPLA2 -X is comparable to the rates of other constitutively recycling receptors, including the mannose receptor [49]. Indirect immunocytochemical analysis revealed that internalized sPLA2 -X was co-localized with PLA2 R in lysosomes in PLA2 R-expressing CHO cells and MC3T3-E1 cells [48]. Since sPLA2 -X is expressed in the lung and spleen where PLA2 R is co-localized [30,31], PLA2 R may act as part of the endogenous defense system by withdrawing sPLA2 -X from the extracellular fluid. In other settings, the endosomal vesicles may serve as a vehicle delivering sPLA2 ligands to specific intracellular compartments where the enzyme can work before being degraded in the lysosomes, as sPLA2 -IB has been shown to be targeted to the nucleus after its binding

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to the cell surface [50]. Since PLA2 R-deficient mice exhibited normal degradation kinetics for sPLA2 -IB added exogenously to the circulation [43], vascular PLA2 R must not play a role in the clearance of circulating sPLA2 ligands. Negative regulation of sPLA2 functions also occurs with a circulating soluble-form of PLA2 R (sPLA2 R) that retains all of the extracellular domains of the membranebound receptor [51]. sPLA2 R possesses sPLA2 -binding properties identical to those of the membrane-bound receptor and blocks the biological functions of sPLA2 ligands, including the binding to the cell surface receptor and its enzymatic activity [21]. Analysis with a specific sandwich enzyme-immunosorbent assay revealed that the plasma sPLA2 R concentration is 0.13 nM in wild-type mice in contrast to its absence from the plasma of PLA2 R-deficient mice, and its circulating level in wild-type mice was significantly elevated to up to 1.5-fold after exposure to endotoxin [21]. Protease inhibitor tests with PLA2 R-overexpressing CHO cells suggested that sPLA2 R can be produced by cleavage of the membrane-bound receptor, at least in part, by the action of metalloproteinases, as reported for other membrane receptors and cell adhesion molecules including the mannose receptor [52]. It is known that venomous snakes have PLA2 inhibitory proteins (PLIs) in their plasma to protect themselves from their own venomous sPLA2 s, which elicit a wide variety of toxicities, such as neurotoxicity and myotoxicity [15]. In mammals, sPLA2 R is the first example of a circulating PLI that acts as an endogenous inhibitor of enzymatic activities and receptor-mediated functions of sPLA2 s. In the plasma of various snakes, three distinct types of PLIs (PLI␣, PLI␤, PLI␥) have been identified. Among them, PLI␣ is a 75-kDa glycoprotein composed of a trimer of 20-kDa subunits having sequence homology to the CRD of C-type lectins and preferentially blocks group II acidic PLA2 s [53]. Intriguingly, three CRD-like domains (CRD3, CRD4, CRD5) in sPLA2 R are representative of the sPLA2 binding activity [17]. In addition, the CRD of PLI␣ of the Habu snake Trimeresurus flavoviridis shows similarities with the CRD5 of PLA2 R (28%) [14]. Also, the soluble lung surfactant protein SP-A has a CRD which shares sequence homology with PLI␣ and blocks Habu snake venom sPLA2 activity [54]. SP-A can bind to guinea pig sPLA2 -IIA to suppress its enzymatic activity, although SP-A can also interact with carbohydrate ligands and its specific cell surface receptor [55]. These findings suggest that other members of the C-type lectin superfamily are good candidates for sPLA2 binding proteins. The potential production of sPLA2 R in human kidney was also suggested by the finding of an alternatively processed transcript encoding the ectodomains of PLA2 R [16], although its presence has not been confirmed in humans.

6. Other sPLA2 binding proteins Several binding proteins for mammalian and snake venom sPLA2 s have recently been reported [15]. Lambeau and Lazdunski [14] have found N-type receptors that possess biochemical properties distinct from PLA2 R in terms of ligand specificity and molecular organization. The N-type receptors display a high affinity for neurotoxic sPLA2 s including OS2 and bee venom sPLA2 but very low affinity for OS1 , sPLA2 -IB and -IIA, and consist of several proteins of 36–88 kDa determined by cross-linking experiments. However, the N-type receptors have not yet been cloned, and their molecular structure,

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endogenous ligands, physiological role, and signal transduction systems remain uncertain. In this context, the nomenclature “receptor” is not yet appropriate for these binding proteins of neurotoxic sPLA2 s. In porcine cerebral cortex, Krizaj and Gubensek [56] have recently identified several binding proteins for ammodytoxin C (AtxC), a snake venom presynaptically neurotoxic group sPLA2 -IIA. Cross-linking experiments have identified that the molecular masses of these binding proteins are 25 kDa (R25) and 180 kDa (R180). The preliminary sequence analysis of R180 have suggested that this binding protein is a glycosylated PLA2 R [56]. In contrast, R25 was identified as calmodulin (CaM) [57], a Ca2+ -binding protein that participates in many fundamental physiological processes. However, since CaM is generally regarded as an intracellular protein, AtxC must be internalized to associate with CaM. Further studies are required to understand the pathological significance of the association of CaM with this particular type of exogenous neurotoxic sPLA2 . Several neuronal binding proteins for snake venom sPLA2 s have also been reported, including voltage-dependent K+ channels, pentraxins, and reticulocalbins [58]. With respect to mammalian sPLA2 s, factor Xa and several proteoglycans (glypican, decorin, and biglycan) have been shown to bind sPLA2 -IIA, although their interactions are fundamentally dependent on the basic residues in sPLA2 -IIA [58,59]. Since these electrostatic interactions are influenced by various extracellular components, such as salt concentration [59], the biological implications of the sPLA2 -IIA bindings should be carefully evaluated under physiological and pathological conditions.

7. Concluding remarks Since the discovery of PLA2 R, several types of sPLA2 s have been regarded as specific ligands that induce various biological responses. In particular, analysis of PLA2 R-deficient mice demonstrated a potential role of the sPLA2 -IB/PLA2 R pathway during the development of endotoxic shock. PLA2 R is also involved in the clearance of “toxic” sPLA2 s to protect their exaggerated reactions evoked by enzymatic activities and receptor-mediated signals. Identification of the endogenous ligand(s) of human PLA2 R is crucial to the understanding of its physiological and pathological functions. In addition to PLA2 R, different types of membrane and soluble proteins have now been identified as acceptors for sPLA2 s. Further elucidation of the biological implications for the interactions with these acceptor proteins should enable us to assign more precise biological functions to the growing family of mammalian sPLA2 s. References [1] Vadas P, Pruzanski W. Role of secretory phospholipases A2 in the pathobiology of disease. Lab Invest 1986;55:391. [2] Arita H, Nakano T, Hanasaki K. Thromboxane A2 : its generation and role in platelet activation. Prog Lipid Res 1989;28:273. [3] Six DA, Dennis EA. The expanding superfamily of phospholipase A2 enzymes: classification and characterization. Biochim Biophys Acta 2000;1488:1.

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