Work

Myotoxin II, a snake venom Lys49 phospholipase A2 homolog, induces activation of the ryanodine receptor in artificial bilayers

Year: 2025

Type: article

Abstract: Envenomation by viperid snakes causes acute muscle tissue injury (myonecrosis). An important group of myotoxic components comprises catalytically-inactive Lys49 phospholipase A 2 homologs, which disrupt the integrity of the plasma membrane of skeletal muscle fibers through a mechanism that does not involve phospholipid hydrolysis. However, it remains unknown whether other mechanisms are involved in the cytotoxic action of these myotoxins. In this work, isolated calcium release channels (ryanodine receptor, RyR1) incorporated into an artificial lipid bilayer were used to study the action of the Lys49 phospholipase A 2 homolog myotoxin II (Mt-II) from the venom of Bothrops asper . Mt-II induced a dose-dependent activation of the RyR1. The open probability of the channel increased with the dose of the toxin. The maximal conductance of the channel remained unchanged during the toxin treatment. Furthermore, the analysis of the open and closed states showed a slight toxin dependency of the latter. These findings suggest that, in addition to the calcium influx from the extracellular space through the disrupted plasma membrane, Ca 2+ release from the internal stores may also occur. However, incubation of C 2 C 12 myotubes in culture with the RyR1 antagonist dantrolene did not reduce the extent of cytotoxicity induced by Mt-II, suggesting that the RyR1-mediated increase in cytosolic Ca 2+ does not contribute to the overall myotoxicity of this toxin. • Myotoxin II activates the ryanodine receptor 1, the calcium release channel of sarcoplasmic reticulum in skeletal muscle. • Specifically, the open probability of the ryanodine receptor channel increased with myotoxin II concentration. • The open probability analysis suggests cooperative binding of Mt-II to RyR1. • Despite channel activation, the resulting cytosolic Ca 2+ increase from internal stores is not critical to the toxic action.

Source: Toxicon

DOI: 10.1016/j.toxicon.2025.108590