How do presynaptic PLA(2) neurotoxins block nerve terminals?

Snake presynaptic neurotoxins with phospholipase A(2) activity block nerve terminals in an unknown way. Here, we propose that they enter the lumen of synaptic vesicles following endocytosis and hydrolyse phospholipids of the inner leaflet of the membrane. The transmembrane pH gradient drives the tra nslocation of fatty acids to the cytosolic monolayer, leaving lysophospholi pids on the lumenal layer. Such vesicles are highly fusogenic and release n eurotransmitter upon fusion with the presynaptic membrane, but cannot be re trieved because of the high local concentration of fatty acids and lysophos pholipids, which prevents vesicle neck closure.