The role of arachidonic acid in the secretion of the amyloid precursor protein (APP)

We have studied the activation of human ml-muscarinic receptors in a genetically engineered Chinese hamster ovary cell line (CHO-ml) to determine which second messenger systems affect the secretion of APP via the non-amyloidogenic route. Carbachol activation of the signaling pathways in CHO-ml cells promotes APP secretion by activation of both protein kinase C (PKC)dependent or Ca++-dependent second messenger pathways. Both pathways converge to increase the enzyme activity of phospholipase A(2) (PLA(2)), the enzyme that releases arachidonic acid from cellular stores. Directly activating PLA(2) with melittin, a peptide from bee venom, or by adding arachidonic acid directly to cultured cells increases the secretion of APP. Thus, our results indicate that arachidonic acid is yet another cellular second messenger involved in regulating the metabolism of APP in addition to PKC and cytoplasmic Ca++. Moreover, activation of PLA(2) appears to be an obligatory event in increasing the secretion of APP from CHO-ml cells by the various methods of activation that we have tried thus far.