Phospholipase arachidonic acid release

Shanker G, Mutkus LA, Walker SJ, Aschner M. 2002. Methylmercury enhances arachidonic acid release and cytosolic phospholipase A2 expression in primary cultures of neonatal astrocytes. Brain Res Mol Brain Res 106 1-11. 

Free radicals are by-products of prostaglandin metabolism and may even regulate the activity of the arachidonate pathway. Arachidonic acid, released from lipids as a result of activation of phospholipases by tissue injury or by hormones, may be metabolized by the prostaglandin or leu-kotriene pathways. The peroxidase-catalysed conversion of prostaglandin G2 to prostaglandin H2 (unstable prostanoids) and the mechanism of hydroperoxy fatty acid to the hydroxy fatty acid conversion both yield oxygen radicals, which can be detected by e.s.r. (Rice-Evans et al., 1991). 

The G-protein that has been termed Gp, and that is linked to phospholipase C activation, may in fact be Gaj 2 or Gc. 3. Ga is designated as the G-protein responsible for activation of phospholipase A2, which results in arachidonic acid release. Some experimental evidence indicates that, at least in HL-60 cells, different agonists can preferentially activate different phospholipases, and some of these are responsible for the activation of secretion. In neutrophils, the two pertussis-toxin-sensitive Ga-proteins (Gaj-2 and G j 3) have been identified by peptide mapping of proteolytic digests of the proteins, by peptide sequencing and by immunoblotting. Complementary-DNA clones for the mRNA of these two molecules have also been isolated from an HL-60 cDNA library. Gai-2 is five to ten times more abundant than Gai.3, the former component comprising 3% of the total plasma membrane proteins. It is possible that these two different Ga-subunits are coupled to different phospholipases (e.g. phospholipases C and D). Pertussis toxin inhibits the secretion of O2 after stimulation of neutrophils by fMet-Leu-Phe, but pertussis-toxin-insensitive G-proteins are also present in neutrophils. These may be members of the Gq family and may be involved in the activation of phospholipase Cp (see 6.3.1). 

Pharmacological approaches include the inhibition of release of arachidonic acid by inhibition of phospholipase A2 and the inhibition of acylcarnitine transferase I by and oxfenicine, the latter of which has been shown to prevent or at least delay ischemia-induced uncoupling. There are at present no data available on the possible effects of inhibitors of arachidonic acid release on ischemia-induced uncoupling. 

Axelrod J. (1990). Receptor-mediated activation of phospholipase A2 and arachidonic acid release in signal transduction. Biochem. Soc. Trans. 18 503-507. 

Farooqui A. A., Ong W. Y., Lu X. R., Halliwell B., and Horrocks L. A. (2001). Neurochemical consequences of kainate-induced toxicity in brain involvement of arachidonic acid release and prevention of toxicity by phospholipase A2 inhibitors. Brain Res. Rev. 38 61-78. 

Monoamine oxidase, tyrosine hydroxylase, and L-amino acid oxidase generate hydrogen peroxide as their reaction product. Hydrogen peroxide is also produced by auto-oxidation of catecholamines in the presence of vitamin C. Moreover, phospholipase A2 (PLA2), cyclooxygenase (COX), and lipoxygenase (LOX), the enzymes associated with arachidonic acid release and the arachidonic acid cascade,... 

M Murakami, S Shimbara, T Kambe, H Kuwata, MV Winstead, JA Tischfield, I Kudo. The functions of five distinct mammalian phospholipase A2s in regulating arachidonic acid release. Type IIA and type V secretory phospholipase A2s are functionally redundant and act in concert with cytosolic phospholipase A2. J Biol Chem 273 14411-14423, 1998. 

The kinin-kallikrein system (kinin system) is a poorly delineated system of blood proteins that plays a role in inflammation, blood-pressure control, coagulation and pain. Kinins are small peptides produced from kininogen by kallikrein, which are subsequently degraded by kininases. They act on phospholipase and increase arachidonic acid release and thus prostaglandin (PGE2) production. 

Figure 12.2. Alternate pathways of arachidonic acid release (a), and cellular locations of enzymes involved in eicosanoid formation (b). a Arachidonic acid may be directly released by phospholipase (PLA2), or alternatively by the successive action of phospholipase C (PLC) and diacylglycerol (DAG) lipase, b The major mechanism of release involves a cytosohc phospholipase A2 (CPLA2). An increase of Ca in response to an extrinsic signal causes binding of cPL A2 to the nuclear membrane. Cyclooxygenase (COX) and Lipoxygenase (LOX) form their respective intermediates, which are further processed by cytosolic enzymes to prostaglandins (PG), thromboxanes (TG), and leukotrienes (LT), respectively.

Calcitriol modulates the maturation of chondrocytes via a cell surface receptor linked to phospholipase and protein kinase C in response to calcitriol, there are rapid changes in arachidonic acid release from, and reincorporation into, membrane phospholipids, and increased synthesis of prostaglandins Ei and E2 (Boyan et al., 1999). 24-Hydroxycalcidiol also modulates the maturation of chondrocytes, acting via cell surface receptors linked to phospholipase D, causing inactivation of both protein kinase C and MAP kinases, thus... 

Lefkowitz, L.J., Smith, W.J. (2002). Sulfur mustard-induced arachidonic acid release is mediated hy phospholipase D in human keratinoc)4es. Biochem. Biophys. Res. Commun. 295 1062-7. 

Kambe T, Murakami M, Kudo I. Polyunsaturated fatty acids potentiate interleukin-1-stimulated arachidonic acid release by cells overexpressing type IIA secretory phospholipase A2. FEBS Lett. 1999 453 81-84. 

Oxalate is able to activate cytosolic phospholipase A2 (CPLA2) in Madin Darby Canine Kidney (MDCK) cells and thereby mediates arachidonic acid release [33]. Using a selective inhibitor of cPLAj cytotoxic effects of oxalate could be attenuated. 

Ruan Y, Kan H, Parmentier JH, Fatima S, Allen LF, Malik KU. a1A adrenergic receptor stimulation with phenylephrine promotes arachidonic acid release by activation of phospholipase D in rat-1 fibroblasts inhibition by protein kinase A. J Pharmacol Exp Therl998 284 576-585. 

Some evidence exists for phospholipase A2 (PLA2) activity that could be regulated by cannabinoid receptors. Cannabinoid-induced arachidonic acid release has been observed in several cell culture systems, and this is believed to be mediated both by phospholipase activity and G proteins (Burstein 1991 Burstein et al. 1994 Shivachar et al. 1996). 

Figure 3. Arachidonic acid release is mediated by phospholipase A2 or phospholipase C. Arachidonic acid esterified to the sn-2 position of phospholipids can be released directly by the action of phospholipase Aj or by the sequential actions of phospholipase C, diglyceride lipase, and monoglyceride lipase.

Fig. 6. Biochemical pathway of the metabolism of arachidonic acid into the biologically active leukotrienes. Arachidonic acid released from phospholipids by cytosolic (c) phospholipase Aja is metabolized by 5-lipoxygenase to 5-hydroperoxyeicosatetraenoic acid (5-HpETE) and leukotriene A4 (LTA4) which is then enzymatically converted into leukotriene B4 (LTB4) or conjugated by glutathione to yield leukotriene C4 (LTC4).

Ni, Z., Okeley, N.M., Smart, B.P., Gelb, M.H. 2006. Intracellular actions of group IIA secreted phospholipase A2 and Group IVA cytosolic phospholipase A2 contribute to arachidonic acid release and prostaglandin production in rat gastric mucosal cells and transfected human embryonic kidney cells. J. Biol. Chem. 281 16245-16255. 

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