Phospholipase A2 and Signaling Pathways in Pheochromocytoma PC12 Cells

Phospholipases A2 (PLA2s) (phosphatidylcholine 2-acylhydrolases, EC 3.1.1.4) are ubiquitous lipolytic enzymes. PLA2s are widely spread in nature; they have been found in many organisms including mammals, reptiles, invertebrates, plants, fungi, ameba, bacteria, and viruses as well as in snake and bee venom. The PLA2s include five distinct types of enzymes: the secreted PLA2s (sPLA2), the cytosolic PLA2s, the Ca2+ independent PLA2s, the platelet-activating factor acetylhydrolases, and the lysosomal PLA2s (Schaloske & Dennis 2006); a new type, so-called adipose-specific PLA2, has been described recently (Duncan et al., 2008). PLA2s form a numerous protein superfamily, which is divided into 15 groups and many subgroups basing on their amino acid sequences, molecular masses, origin, number of disulphide bonds, Ca2+-dependence and so on. “Conventional” sPLA2s belonging to groups I/II/V/X are closely related, 13–19-kDa secreted enzymes with a highly conserved Ca2+-binding loop, a catalytic site with a His–Asp dyad, six absolutely conserved disulfide bonds and up to two additional unique disulfide bonds, which contribute to the high degree of stability of these enzymes (Murakami et al., 2011). They require calcium at a level of extracellular environment for the lipolytic activity. For examples, PLA2s of group I are monomers of 13-15 kDa with 7 disulfide bridges. Among these, there are PLA2s of group IA found in Elapidae snake venom and those of group IB found mostly in mammalian pancreas. Group II of PLA2s comprises 6 sub-groups: sub-groups IIA and IIB are typical for Viperidae snake venom whereas sub-groups IIC-IIF are typical for mammalian tissues. Group III comprises sPLA2s from mammals, lizards, and bee venom (Schaloske & Dennis 2006). Cytosolic PLA2s have no apparent homology to sPLA2s and differ from the latter in molecular mass, which is in the range from 60 to 115 kDa, stability to thiol reagents and requirement in calcium at a cytosolic level which, in contrast to the sPLA2s, is required rather for translocation of the enzyme to intracellular membranes than for catalysis. Cytosolic PLA2s utilize the Asp-Ser catalytic dyad; phosphorylation of the Ser residue enhances lipolytic activity (Schaloske & Dennis 2006). These PLA2s are found only in vertebrates (Murakami et al., 2011). Ca2+-independent PLA2s are referred to so-called patatin-like phospholipase domaincontaining lipases (Murakami et al., 2011). Like cytosolic PLA2, they utilize a serine for catalysis (Schaloske & Dennis 2006).