Studies on mammalian Ca^<2+>-dependent phospholipase A_2s

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Phospholipase A_2 (PLA_2) represents a growing family of enzymes that catalyze the hydrolysis of phospholipids at the sn-2 position, liberating free fatty acids inducing arachidonic acid (AA), a precursor of bioactive eicosanoids, and lysophospholipids. PLA_2 has been implicated in diverse cellular responses, such as signal transduction, host defense, blood coagulation, cigestion, and membrane remodeling. Accorcing to an updated classification, PLA2_2 can be subdivided into several groups based upon their stnictures and enzymatic characteristics, inducing Ca^2-dependent cytosolic (cPLA_2) and secretory (sPLA_2) PLA_2 isozymes and Ca^<2+>-independent PLA_2 (iPLA_2). In the present study, the functional coupling of several clstinct PLA_2s and two cyclooxygenase (COX) isoforms during immediate and delayed PG-biosynthetic responses was examined cPIA_2, sPLA_2-IIA and sPLA_2-V were " signaling PLA-_2s" that promoted AA release from cells after stimulation with ionophore or bradykinin, which … More evoked the immediate response, and IL-1, which induced the delayed response. AA released by these signaling PLA_2s was converted to PGE_2 by both COXs during the immediate response and pretbminantly by COX-2 during the dulayed response. iPLA,, which plays a crucial role in "phospholipid remodeling', failed to couple with COX-2 during the delayed response, whereas it was linked to ionophore-induced immeciate PGE_2 generation via COX-l in preference to COX-2. sPLA_2-X induced fatty acid release in a manner similar to iPIA_2 rather than other sPLA2s. Extracellular sPLA_2s-IIA and -V.but neither intracellular cPLA_2 nor iPLA_2, augmented PGE_2 synthesis by neighboring COX-expressing cells, implying that these sPLA_2s play a particular role as paracrine amplifiers of the PG-biosynthetic response signal from one cell to another. After cell activation, signaling PLA_2s were localized around the nucleus where both COX isozymes were present. cPLA_2 bound to vimentin, a perinuclear intermeiziate filament protein, in Ca^<2+>-dependent manner and translocated from the cytosol to perinuclear membrane. sPLA_2-IIA bound a GPI-anchored heparan sulfate proteoglycan glypican, which &livered sPLA_2-IIA into caveolae and perinuclear sites and augmented sPLA_2-IIA-meciated A.A release and PGE_2 generation. Less