Cytosolic phospholipase A2 (cPLA2) and lipid mediator release in the brain.
The Ca(2+)-sensitive 85 kDa cytosolic PLA2 (cPLA2) is a receptor-regulated enzyme that may initiate the cascade of events leading to the production of free fatty acids and lysophospholipids for subsequent conversion to eicosanoids and PAF. At least two early events are necessary for full activation of cPLA2: (1) increased concentration of cytosolic free Ca2+ promoting association of cPLA2 with its membrane phospholipid substrate and (2) phosphorylation by stimulated proline-directed kinases converting cPLA2 into an enzyme of enhanced catalytic efficiency. Moreover, pro-inflammatory cytokines, such as IL-1 and TNF may induce de novo synthesis of cPLA2 thus further potentiating the mobilization of arachidonic acid and subsequent production of eicosanoids and PAF. Increased levels of fatty acids and PLA2-derived products, including eicosanoids and PAF are amongst the hallmarks of cerebral ischemia and reperfusion, and thought to mediate pathophysiological alterations and cellular processes which may lead to cell injury and death. There is substantial evidence to indicate that cPLA2 is present in the brain and appears most abundant in astrocytes. Therefore, cPLA2 may be an important component in the cascade of events leading to acute and delayed destructive cellular processes in the brain and accordingly represents an attractive target for the development of novel therapies to prevent brain damage triggered by ischemic and inflammatory insults.
Kramer
R M
RM
Lilly Research Laboratories, Indianapolis, IN 46285-0444, USA. kramer_ruth_m@lilly.com
Stephenson
D T
DT
Roberts
E F
EF
Clemens
J A
JA
D000818:Animals; D001921:Brain / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2
D010741:Phospholipases A; D054467:Phospholipases A2