Disease relevance of Pla2g6

• iPLA2 inhibitor blocks negative inotropic effect of HIV gp120 on cardiac myocytes [1].
• Because islet beta-cell phospholipids are enriched in arachidonate, we have examined the role of iPLA2 in arachidonate incorporation into islets and INS-1 insulinoma cells [2].
• The rat CaIPLA2 cDNA, when expressed in a baculovirus expression system, and the purified rabbit kidney cortex protein exhibit both CaIPLA2 and lysophospholipase activities [3].
• Taken toghether, these studies have demonstrated that nuclear phospholipid mass decreases after myocardial ischemia by a mechanism that involves, at least in part, phospholipolysis mediated by iPLA2 [4].

High impact information on Pla2g6

• Mitochondrial iPLA2 activity modulates the release of cytochrome c from mitochondria and influences the permeability transition [5].
• Together, these results for the first time demonstrate that iPLA2 plays a role in thrombin-induced arachidonic acid release and growth in VSMC and that these responses are mediated by p38 MAPK [6].
• Down-regulation of iPLA2 activity by its specific inhibitor, bromoenol lactone, or its expression by antisense oligonucleotides, significantly reduced thrombin-induced arachidonic acid release and DNA synthesis in VSMC [6].
• Identification of calcium-independent phospholipase A2 (iPLA2) beta, and not iPLA2gamma, as the mediator of arginine vasopressin-induced arachidonic acid release in A-10 smooth muscle cells. Enantioselective mechanism-based discrimination of mammalian iPLA2s [7].
• Inhibition of iPLA2 with a bromoenol lactone (BEL) suicide substrate did not suppress and generally enhanced [3H]arachidonate incorporation into these cells in the presence or absence of extracellular calcium at varied time points and BEL concentrations [2].

Chemical compound and disease context of Pla2g6

• Pancreatic islets and insulinoma cells express a novel isoform of group VIA phospholipase A2 (iPLA2 beta) that participates in glucose-stimulated insulin secretion and is not produced by alternate splicing of the iPLA2 beta transcript [8].

Biological context of Pla2g6

• The present investigation provides the first indication that constitutive, calcium-independent phospholipase A2 activity (iPLA2) modulates phosphorylation of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) subtype of glutamate receptors [9].
• Pancreatic islets express a Ca2+-independent phospholipase A2 (CaI-PLA2) activity that is sensitive to inhibition by a haloenol lactone suicide substrate that also attenuates glucose-induced hydrolysis of arachidonic acid from islet phospholipids and insulin secretion [10].
• A cDNA has been cloned from a rat islet cDNA library that encodes a protein with a deduced amino acid sequence of 751 residues that is homologous to a CaI-PLA2 enzyme recently cloned from Chinese hamster ovary cells [10].
• Transient transfection of both COS-7 cells and Chinese hamster ovary cells with the cloned islet CaI-PLA2 cDNA resulted in an increase in cellular CaI-PLA2 activity, and this activity was susceptible to inhibition by haloenol lactone suicide substrate [10].
• The iPLA2 inhibitor by itself interfered with neither paired pulse facilitation nor N-methyl-D-aspartate (NMDA) receptor-mediated EPSCs, suggesting that its influence on synaptic transmission is postsynaptic in origin and specific to the AMPA subtype of glutamate receptors [11].

Anatomical context of Pla2g6

• The present study shows that the iPLA2 inhibitor bromoenol lactone, when introduced into hippocampal CA1 pyramidal cells through a patch pipette, generated a dose-dependent increase in the amplitude of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs) [11].
• The calcium-independent form of phospholipase A2 (iPLA2), an enzyme known to generate arachidonic acid (AA), was recently identified as the predominant constitutive phospholipase in the hippocampus [11].
• In glial cells, lipopolysaccharide (LPS) induced the activities of PLA2 (calcium-independent PLA2; iPLA2 and cytosolic PLA2; cPLA2) as well as gene expression of iNOS [12].
• Using quantitative-PCR, we found that Group IVA cPLA2 and Group VI iPLA2 are the predominant PLA2 messages in the spinal cord [13].
• We previously showed that in adult rat ventricular myocytes interleukin (IL)-1beta activates a membrane-associated, Ca2+-independent phospholipase A2 (iPLA2) [14].

Associations of Pla2g6 with chemical compounds

• Preincubation of frozen-thawed brain sections with two iPLA2 inhibitors, bromoenol lactone (BEL) or palmitoyl trifluoromethyl ketone (PACO), produced a dose-dependent enhancement in phosphorylation at both Ser831 and Ser845 sites on the GluR1 subunit of AMPA receptors [9].
• Arachidonyl trifluoromethyl ketone (AACOCF3), a PLA2 inhibitor, bromoenol lactone (BEL), a Ca2+-independent PLA2 (iPLA2) inhibitor, and EGTA suppressed the magnolol-induced AA release [15].
• These findings complement previous pharmacologic observations that suggest that CaI-PLA2 may participate in regulating transmembrane ion flux in glucose-stimulated beta-cells [10].
• Inhibition of p38 MAPK activity by SB203580 and SB202190 resulted in decreased iPLA2 activity, arachidonic acid release, and DNA synthesis induced by thrombin in VSMC [6].
• Comparable results were obtained with palmitoyl trifluoromethyl ketone, a second structurally distinct iPLA2 inhibitor [11].

Regulatory relationships of Pla2g6

• These results suggest that constitutive cPLA2 and iPLA2 systems may differentially influence AMPA receptor properties and function in the rat brain through mechanisms involving PKC activity [16].
• TNF-alpha-induced increases in cytosolic iPLA2 activity and arachidonic acid release were completely blocked by methyl arachidonyl fluorophosphonate (MAFP) but not by bromoenol lactone (BEL) [14].

Other interactions of Pla2g6

• Additional experiments indicated that calcium-mediated truncation of GluR1 subunits was reduced by iPLA2 inhibitors, an effect that was not correlated with overall changes in the distribution of AMPA receptors between intracellular and membrane compartments prepared from whole brain sections [9].
• The ability of iPLA2 inhibitors to increase AMPA receptor-mediated currents was also reproduced by MK-866, an inhibitor recognized to interfere with the generation of 5-lipoxygenase by-products of AA [11].
• Lithium chloride (LiCl), when fed to rats for 6 weeks, has been reported to decrease brain mRNA, protein, and activity levels of arachidonic acid (AA)-selective cytosolic phospholipase A2 (cPLA2), without affecting secretory sPLA2 or Ca2+-independent iPLA2 [17].
• With phosphatidylcholine as substrate, TNF-alpha decreased both cytosolic and membrane-associated iPLA2 activities [14].
• A23187- or thapsigargin-induced arachidonate release is prevented by a bromoenol lactone (BEL) inhibitor of a beta-cell phospholipase A2 (iPLA2), which does not require Ca2+ for catalytic activity and which is negatively modulated by and physically interacts with calmodulin by Ca2+-dependent mechanisms [18].

Analytical, diagnostic and therapeutic context of Pla2g6

• Western blotting and activity assays specific for Group IVA cPLA2 and Group VI iPLA2 verified the presence of these enzymes [13].
• Reverse transcriptase-polymerase chain reaction (RT-PCR) showed that NRK-52E cells express cPLA2 and iPLA2 mRNAs, but not sPLA2 [19].
• Several lines of evidence (DNA sequence comparison, Southern blot analysis, and examination of the expressed sequence tag database) show that CaIPLA2 enzymes are encoded by a multigene family in rats, mice, rabbits, and humans [3].

References