Phospholipases A2 from viperidae snake venoms: how do they induce skeletal muscle damage?

Phospholipases A2 (PLA2s) are abundant components in snake venoms, which play important toxic roles. This review focuses on group II PLA2s endowed with myotoxic effects, present in Viperidae venoms. These PLA2s are subdivided into catalytically-active (Asp49) PLA2s, and catalytically-inactive PLA2 homologues, the latter most frequently presenting the Lys49 substitution. Both protein subgroups induce skeletal muscle necrosis, although by different mechanisms. Current evidence indicates that phospholipid hydrolysis plays a central role in the necrotizing action of Asp49 myotoxins, whereas PLA2 homologues rely on the direct membrane-destabilizing actions of their cationic C-terminal region to achieve such effect, in the absence of catalysis. Both mechanisms converge in sarcolemmal permeabilization, triggering a series of intracellular events that lead to necrosis. Most viperid PLA2 myotoxins act only locally, but those forming heterodimeric complexes such as crotoxin spread to distant muscles and induce rhabdomyolysis. This divergence between local and systemic myotoxicity might be related to differences in binding specificity to cell targets. Nevertheless, the identity of molecular targets recognized by viperid PLA2 myotoxins remains elusive. Identification of their membrane target(s), and a deeper understanding of the catalytic-dependent and -independent mechanisms that result in membrane destabilization, are two crucial, but still unclarified aspects of their myotoxic action.