Understanding the molecular mechanism underlying the presynaptic toxicity of secreted phospholipases A2

An important group of toxins, whose action at the molecular level is still a matter of debate, is secreted phospholipases A2 (sPLA2s) endowed with presynaptic or β-neurotoxicity. The current belief is that these β-neurotoxins (β-ntxs) exert their toxicity primarily due to their extracellular enzymatic action on the plasma membrane of motoneurons at the neuromuscular junction. However, the discovery of several extra- and intracellular proteins, with high binding affinity for snake venom β-ntxs, has raised the question as to whether this explanation is adequate to account for all the observed phenomena in the process of presynaptic toxicity. The purpose of this review is to critically examine the various published studies, including the most recent results on internalization of a β-ntx into motor nerve terminals, in order to contribute to a better understanding of the molecular mechanism of β-neurotoxicity. As a result, we propose that presynaptic neurotoxicity of sPLA2s is a result of both extra- and intracellular actions of β-ntxs, involving enzymatic activity as well as interaction of the toxins with intracellular proteins affecting the cycling of synaptic vesicles in the axon terminals of vertebrate motoneurons.