Enzymes belonging to the PLA(2) superfamily catalyze the hydrolysis of
unsaturated fatty acids from the sn-2 position of
glycerol moiety of neural membrane
phospholipids. The PLA(2) superfamily is classified into cytosolic PLA(2) (cPLA(2)),
calcium-independent PLA(2) (
iPLA(2)),
plasmalogen-selective PLA(2) (PlsEtn-PLA(2)) and secretory PLA(2) (
sPLA(2)). PLA(2) paralogs/splice variants/
isozymes are part of a complex signal transduction network that maintains cross-talk among
excitatory amino acid and
dopamine receptors through the generation of second messengers. Individual paralogs, splice variants and multiple forms of PLA(2) may have unique enzymatic properties, tissue and subcellular localizations and role in various physiological and pathological situations, hence tight regulation of all PLA(2)
isoforms is essential for normal brain function. Quantitative RT-PCR analyses show significantly higher relative level of expression of
iPLA(2) than cPLA(2) in all regions of the rat brain. Upregulation of the cPLA(2) family is involved in degradation of neural membrane
phospholipids and generation of
arachidonic acid-derived
lipid metabolites that have been implicated in nociception,
neuroinflammation, oxidative stress and neurodegeneration. In contrast, studies using a selective
iPLA(2) inhibitor,
bromoenol lactone, or
antisense oligonucleotide indicate that
iPLA(2) is an important "housekeeping"
enzyme under basal conditions, whose activity is required for the prevention of vacuous chewing movements, a rodent model for
tardive dyskinesia, and deficits in the prepulse inhibition of the auditory startle reflex, a common finding in
schizophrenia. These studies support the view that PLA(2) activity may not only play a crucial role in neurodegeneration but depending on the
isoform, could also be essential in prevention of neuropsychiatric diseases. The findings could open new doors for understanding and treatment of neurodegenerative and neuropsychiatric diseases.