PLA2 activity

H, receptors also can stimulate the activity of phospholipase A2 (PLA2), with the subsequent release of arachido-nate and its metabolites. In platelets, this response does not require activation of the phosphoinositide cycle and is inhibited by pertussis toxin, suggesting a second, distinct Gj/o-protein-mediated transduction mechanism. In cells transfected with the H, receptor, PLA2 activation is partially inhibited by pertussis toxin, also suggesting at least two transduction systems [30,34],... 

Synaptic stimulation, ischemia or seizure activates phospholipase A2 and releases arachidonic and docosahexaenoic acids. Ischemia or seizure triggers accumulation of free AA, DHA and other FFA in the brain( see also Chs 32, 37). This reflects PLA2 activation in excitable membranes [24]. While little is known about the mechanisms that control its activity, the importance of cPLA2 in ischemic brain injury is strongly supported by the recent finding that cPLA2-knockout mice have substantially reduced infarcts and neurologic deficits in a model of stroke [25],... 

Shifts in intracellular pH may be another mechanism by which intracellular PLA2 activity can be regulated. Glutamate-induced AA release in mouse cortical neuronal cultures is mediated in part by a membrane-associated PLA2 activity, which is upregulated in alkaline pH and is therefore sensitive to the shifts in pH induced by excitatory neurotransmission. 

There are also mechanisms in the brain for the down-regulation of intracellular PLA2 activity by lipocortins, a... 

Free arachidonic acid, along with diacylglycerols and free docosahexaenoic acid, is a product of membrane lipid breakdown at the onset of cerebral ischemia, seizures and other forms of brain trauma. Because polyunsaturated fatty acids are the predominant FFA pool components that accumulate under these conditions, this further supports the notion that fatty acids released from the C2 position of membrane phospholipids are major contributors to the FFA pool, implicating PLA2 activation as the critical step in FFA release [1,2] (Fig. 33-6). 

Reports that AA is released primarily by G-protein-mediated PLA2 activation remain to be confirmed [84, 85]. In addition, modulation of PLA2 by Ca2+ and protein kinase needs to be better defined. It is clear that NMDA receptor activation promotes the release of AA [86], and that a variety of eicosanoids are then generated (Fig 33-2,33-3). The modulatory events that channel AA towards specific eicosanoids are not understood. The endocannabinoid family of lipid messengers will remain an active focus of interest because of the growing evidence of their actions in synaptic function, learning, memory, and other forms of behavior [56,87]. 

In addition to the importance of Ca2+, PLA2 activity is also regulated by lipocortin (also termed lipomodulin), which is a 40-kDa protein. The inhibitory effect of lipocortin is regulated by its phosphorylation status, acting as an inhibitor of the enzyme when in the dephosphorylated state. Upon cell activation (e.g. by fMet-Leu-Phe), the lipocortin becomes phosphorylated, and PLA2 activity (usually detected as the release of arachidonic acid) increases. Protein kinase C can cause this phosphorylation, and so activation of this kinase may lead to the relief of PLA2 inhibition via phosphorylation of lipocortin. Thus, elevations in the levels of intracellular Ca2+ and production of DAG (required for protein kinase C activation) may co-ordinately activate PLA2. 

From the marine alga Stypopodium flabelliforme, several diterpenoids with interesting biological properties were isolated. The diterpenoid epitaondiol exhibited a potent anti-inflammatory activity related to inhibition of human PLA2 activity and leukocyte accumulation [64], Additionally, epitaondiol has been shown as a potent calcium antagonist in... 

Presynaptic snake neurotoxins endowed with PLA2 activity (SPANs) are major components of the venom of four families of venomous snakes (Crotalidae, Elapidae, Hydrophiidae, and Viperidae). These neurotoxins play a crucial role in envenomation of the prey (Harris 1997) by causing a persistent blockade of neurotransmitter release from nerve terminals with a peripheral paralysis very similar to that of botulism (Connolly et al. 1995 Gutidrrez et al. 2006 Kularatne 2002 Prasampun et al. 2005 Theakston et al. 1990 Trevett et al. 1995 Warrell et al. 1983). 

Numerous studies have suggested that PLA2 activity changes in neural disorders [12-17], cancer [18-21], inflammatory disorders [8,22-24], and parturition [25,26], In addition, lysophosphatidylcholine (LPC) causes demyelination [27], Recent studies suggested that LPC, converted from oxidized low-density lipoprotein (ox-LDL), induces endothelium-dependent vasoconstriction [28] and abolishes the formation of the receptor G-protein complex [29],... 

G Rordorf, Y Uemura, JV Bonventre. Characterization of phospholipase A2 (PLA2) activity in gerbil brain enhanced activities of cytosolic, mitochondrial, and microsomal forms after ischemia and reperfusion. JNeurosci 11 1829-1836, 1991. 

Inhibits Ca2+ conductances Activates PLC, PC-PLC, and PLA2 Activates/inhibits NOS Activates NAD(P)H oxidase Activates NHE-1... 

Activates-inhibits adenylyl cyclase Activates PLA2 Activates Jak2/STAT3 Calmodulin... 

Studies of membrane-associated effects of a series of drugs on PLA2 have been undertaken to investigate the possibility that some proteins and drugs interact with the bilayer at phase boundaries or with defect structures necessary for PLA2 activity. The direct or indirect effect of drugs on such boundaries or defects could then affect membrane-protein interactions. 

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