FIGURE 2.

Mechanism and possible implications of membrane lipid peroxidation and phospholipase A₂ activation. PUFAs are highly susceptible to (per)oxidation. Peroxidized PUFAs are prone to excision by members of the PLA₂ family of enzymes. The products of PLA₂’s enzymatic activity, free fatty acids (FFAs) and lysophospholipids (LPLs), have a wide range of extracellular, intracellular, and intramembranal biological activities. This highly simplified diagram indicates a few of the mechanisms and targets with special relevance to the nervous system. FFAs and LPLs can themselves act as signaling molecules and modify gating behavior of various types of ion channels. In addition they can act as substrate for other lipid-based intra- and extracellular signaling cascades, including signaling systems regulating inflammation. Moreover, through their effect on membrane microarchitecture they may change functions of integral membrane proteins such as stretch-activated ion channels, alter lipid micro domain organization, disrupt organization of transmembrane signaling complexes, or alter other cellular processes such as membrane fission and fusion that are important in the regulation of intrinsic neuronal excitability, synaptic transmission, and molecular mechanisms underlying neuronal plasticity. See Figure 6 for details on mechanisms involved in PUFA peroxidation.