Disease relevance of Pla2g4a

• Activated MAPK, in turn, may induce various functional changes of mesangial cells at least through the activation of cPLA2 and contribute to the development of diabetic nephropathy [1].
• The mRNA levels of cPLA2, COX-2 and mPGES-1 in the bladder papilloma and TCC were significantly higher than those in normal bladder (P<0.01), while the mRNA levels of COX-1 and mPGES-2 in TCC were unchanged compared with normal bladder [2].
• Understanding the regulation of cPLA2 expression induced by BK in astrocytes might provide a new therapeutic strategy of brain injury and inflammatory diseases [3].
• Molecular cloning of rat cDNA for cytosolic phospholipase A2 and the increased gene expression in the dentate gyrus following transient forebrain ischemia [4].
• These data indicate that hypercalcemia stimulates intrarenal cPLA2 and PGHS-2 protein expression [5].

Psychiatry related information on Pla2g4a

• These results indicate that the effect of lithium selectively involves the cPLA2/COX-2 pathway, which might be responsible for the therapeutic effect in bipolar disorder [6].

High impact information on Pla2g4a

• Losartan abolished the polydipsia associated with hypercalcemia, prevented the increase in cPLA2 protein in all regions of the kidney, and diminished PGHS-2 expression in the inner medulla [5].
• Immunoblot analysis of extracts derived from IL-1-treated (30 min) cells demonstrates a decreased mobility of cPLA2, and treatment of MC lysates with acid phosphatase significantly reduces cytokine-activated cPLA2 activity, further indicating that IL-1 stimulates phosphorylation of the enzyme [7].
• IL-1 does not alter either cPLA2 mRNA expression or mass in serum-stimulated MC, suggesting that cPLA2 activity is increased by a posttranslational modification [7].
• Interleukin 1 alpha causes rapid activation of cytosolic phospholipase A2 by phosphorylation in rat mesangial cells [7].
• CONCLUSIONS: Glucocorticoids are capable of markedly altering basal and cytokine-stimulated cPLA2 gene expression in intestinal epithelial cells, leading to a reduction in arachidonate pools in these cells [8].

Chemical compound and disease context of Pla2g4a

• To gain insights into the signal transduction pathways involved in glutamate release we examined the time course of changes in enzyme levels and activities of cPLA2, PKC and ERKs in the rat cerebral cortex after four vessel (4VO) ischemia followed by reperfusion [9].
• In rats fed dihydrotachysterol to induce hypercalcemia, Western blot analysis revealed significant upregulation of both cPLA2 and PGHS-2 in the kidney cortex and the inner and outer medulla [5].
• Increased cPLA2 and COX-2 immunoreactivities in astrocytes at 1, 2, 4 and 11 weeks after kainate injection indicate an adaptive astrocytic response that may be associated with gliosis [10].
• Interleukin-1 beta induces cytosolic phospholipase A2 gene in rats C6 glioma cell line [11].
• Release of arachidonic acid from membrane glycerophospholipids by cytosolic phospholipase A2 (cPLA2) is a key step in the generation of platelet-activating factor (PAF), recognized as the most proximal mediator of inflammatory events triggered by bacterial infection [12].

Biological context of Pla2g4a

• Elevation of intracellular Ca2+, the mechanism involving extracellular Ca2+ influx, might act partly through PKCalpha activation and in turn MAPK might be activated, leading to cPLA2 phosphorylation and AA release [13].
• 1alpha,25(OH)(2)D(3) and PTH modulation of cPLA2 activity may change membrane fluidity and permeability and thereby affecting intestinal cell membrane function [14].
• Then, the mRNA level of cytosolic phospholipase A2 (cPLA2), cyclooxygenases (COX)-1 and -2, membrane-bound PGE2 synthases (mPGES)-1 and -2 was detected using reverse transcription polymerase chain reaction (RT-PCR) [2].
• STAT-3-dependent cytosolic phospholipase A2 expression is required for thrombin-induced vascular smooth muscle cell motility [15].
• Agonists, including oxytocin, increase cPLA2 activity, in part, by elevating intracellular Ca2+ concentration, which causes cPLA2 to be translocated from the cytosol to intracellular membrane binding sites [16].

Anatomical context of Pla2g4a

• Cytosolic phospholipase A2 is required for cytokine-induced expression of type IIA secretory phospholipase A2 that mediates optimal cyclooxygenase-2-dependent delayed prostaglandin E2 generation in rat 3Y1 fibroblasts [17].
• In cultured rat GEC, sublytic C5b-9 injures plasma membranes and releases arachidonic acid (AA) and eicosanoids, due to activation of cytosolic phospholipase A2 (cPLA2) [18].
• Recruitment of both 5-LO and cPLA2 to the membranes was suppressed by EGTA [19].
• Enterocytes exposure to 1alpha,25(OH)(2)D(3) (1nM) or PTH (10 nM) also resulted in P-cPLA2 translocation from cytosol to nuclei and membrane fractions, where phospholipase subtrates reside [14].
• The effect of either hormone on enterocytes was totally reduced by preincubation with the intracellular Ca(2+) chelator BAPTA-AM (5 microM), suggesting that the release of AA following cell exposure to the calciotropic hormones occurs mainly through a Ca(2+)-dependent mechanism involving activation of Ca(2+)-dependent cPLA2 [14].

Associations of Pla2g4a with chemical compounds

• These results suggest that certain metabolites produced by the cPLA2-dependent pathway are crucial for the subsequent induction of type IIA sPLA2 expression and attendant delayed PGE2 generation [17].
• Delayed PGE2 generation was also suppressed markedly by the cPLA2 inhibitor arachidonoyl trifluoromethyl ketone (AACOCF3), which attenuated induction of type IIA sPLA2, but not COX-2, expression [17].
• ATP, TPA, or A23187 induced an increase in the activity and tyrosine phosphorylation of p42 MAPK, as well as a molecular weight shift, consistent with phosphorylation, of cytosolic phospholipase A2 (cPLA2) [13].
• However, the detailed mechanisms underlying BK-induced cPLA2 expression in astrocytes remain unclear [3].
• ATV increased myocardial content of cytosolic phospholipase A2 (cPLA2) (174.8+/-0.5%), COX2 (446.2+/-0.9%), PGI2 synthase (201.8+/-1.1%) and PGE2 synthase (122+/-0.7%), whereas ATV+VAL did not (123.0+/-7.9%, 93.8+/-8.5%, 103.0+/-1.6% and 99.0+/-0%, respectively) [20].

Physical interactions of Pla2g4a

• The high-affinity CCK-AR appears to be coupled to the Gbeta/cPLA2/arachidonic acid (AA) cascade in mediating Ca2+ oscillations [21].

Regulatory relationships of Pla2g4a

• ERK was previously reported to stimulate cytosolic phospholipase A2 phosphorylation and activity [22].
• Furthermore, the cleavage of cytosolic phospholipase A2 during cell death induced by C2 ceramide and by TNF-alpha in the presence of CHX showed distinctive patterns [23].
• Taken together, DEHP suppresses cPLA2 activity and induces the AA metabolizing enzymes such as 12-LOX and CYP4A1, resulting in the reduction of AA level [24].
• Thus, SSTR4 appears to stimulate MAP kinase and cPLA2 in a Gi-dependent, and through a wortmannin-sensitive pathway [25].
• Overexpression of PKC-alpha or -epsilon specifically inhibited receptor-dependent cytosolic phospholipase A2 (cPLA2) activity, whereas this activity was enhanced in the PKC-betaI transfectant [26].

Other interactions of Pla2g4a

• The role of p42 MAPK in cPLA2 activation becomes redundant in the presence of relatively potent PKC activation [18].
• Alterations in renal cytosolic phospholipase A2 and cyclooxygenases in polycystic kidney disease [27].
• These proteins were identified as p42/p44 mitogen-activated protein (MAP) kinases by anti-MAP kinase immunoblots, which were known to activate cytosolic phospholipase A2 (cPLA2), a key enzyme in AA release [28].
• These results suggest that HGF as well as EGF causes AA release, probably through activation of cPLA2 mediated by MAP kinases, and that PGs, metabolites of AA, might play a pivotal role in hepatocyte proliferation in an autocrine mechanism [28].
• We examined the effects of IL-1beta on PGE2 production and changes in the relevant enzyme activities, and found that the activities of cytosolic phospholipase A2 (cPLA2), type II secretory PLA2 (sPLA2) and cyclooxygenase (COX)-2 in the day 21 cells were increased [29].

Analytical, diagnostic and therapeutic context of Pla2g4a

• To test whether this posttranslational effect involved the cytosolic phospholipase A2 (cPLA2) isoform, Western blots were probed for cPLA2 protein [30].
• PGE2 may be a biomarker for the development of bladder TCC. cPLA2 and mPGES-1 may be targets for development of novel chemoprevention strategies for bladder TCC [2].
• Immunoblotting analyses of cytosolic and particulate kidney fractions revealed that cPLA2 levels are significantly higher (by 34-131%) in the latter stages of the disease in both models [27].
• RT-PCR and Western blotting analysis showed that BK induced the expression of cPLA2 mRNA and protein, which was inhibited by Hoe140, suggesting the involvement of B2 BK receptors, confirmed by immunofluorescence staining using anti-B2 BK receptor antibody [3].
• By in situ hybridization, the gene expression for cPLA2 was detected in the hippocampus, olfactory bulb, and cerebellar granular cells at very low level of normal rats [4].

References