The neuromuscular activity of paradoxin: A presynaptic neurotoxin from the venom of the inland taipan (Oxyuranus microlepidotus)

The inland taipan is the world's most venomous snake. However, little is known about the neuromuscular activity of the venom or paradoxin (PDX), a presynaptic neurotoxin from the venom. Venom (10 μg/ml) and PDX (65 nM) abolished indirect twitches of the chick biventer cervicis and mouse phrenic nerve diaphragm preparations. The time to 90% inhibition by PDX was significantly increased by replacing Ca2+ (2.5 mM) in the physiological solution with Sr2+ (10 mM). In the biventer cervicis muscle, venom (10 μg/ml), but not PDX (65 nM), significantly inhibited responses to ACh (1 mM) and carbachol (20 μM), but not KCl (40 mM). In the mouse diaphragm (low Ca2+; room temperature), the inhibitory effect of PDX (6.5 nM) was delayed and a transient increase (746 ± 64%; n = 5) of contractions observed. In intracellular recording experiments using the mouse hemidiaphragm, PDX (6.5–65 nM) significantly increased quantal content and miniature endplate potential frequency prior to blocking evoked release of acetylcholine. In extracellular recording experiments using the mouse triangularis sterni, PDX (2.2–65 nM) significantly inhibited the voltage-dependent K+, but not Na+, waveform. In patch clamp experiments using B82 mouse fibroblasts stably transfected with rKv 1.2, PDX (22 nM; n = 3) had no significant effect on currents evoked by 10 mV step depolarisations from −60 to +20 mV. PDX exhibits all the pharmacology associated with β-neurotoxins, and appears to be one of the most potent, if not the most potent β-neurotoxin yet discovered.