Cell Signaling and Neurotoxicity: 3H-Arachidonic Acid Release (Phospholipase A2) in Cerebellar Granule Neurons

Cell signaling is a complex process which controls basic cellular activities and coordinates actions to �maintain normal cellular homeostasis. Alterations in signaling processes have been associated with �neurological diseases, such as Alzheimer’s and cerebellar ataxia, as well as cancer, autoimmunitiy, and diabetes. Recent evidence also indicates a role for signaling molecules in the adverse effects associated with the exposure to environmental chemicals. One of these signaling molecules is arachidonic acid (AA). AA is abundant in the membrane phospholipids of the brain, where its release has been shown to be involved in synaptic plasticity processes, such as long-term potentiation. AA release is primarily produced by the activation of phospholipases, most commonly by phospholipase A₂ (PLA₂ ). The release of ³ H-AA is often used as a measure of PLA₂ activity in cell culture studies. In our laboratory, we have demonstrated the relationship between the stimulation of ³ H-AA release by persistent chemicals, such as polychlorinated biphenyls and polybrominated diphenyl ethers, and the associated cytotoxicity following in vitro exposure. Understanding the role of the AA signaling pathway in chemically-induced effects on the nervous system will provide specific mode of action information that can be used in assessing the compound risk.