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Promiscuous and Reversible Blocker of Presynaptic Calcium Channels in Frog and Crayfish Neuromuscular Junctions From Phoneutria nigriventer Spider Venom

¹Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; ²Instituto Butantan, Laboratory of Pharmacology, Biochemistry and Immunochemistry, São Paulo, SP, 05503-900 Brazil; and ³Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada

Submitted 19 February 2003; accepted in final form 25 July 2003

Peptide channel blockers found in venoms of many predators are useful pharmacological tools and potential therapeutic agents. The venom of the Brazilian spider Phoneutria nigriventer contains a fraction, -phonetoxin-IIA (-Ptx-IIA, 8360 MW), which blocks Ca²⁺ channels. At frog neuromuscular junctions (NMJ) bathed in normal Ca²⁺ (1.8 mM) saline, -Ptx IIA did not affect spontaneous transmitter release but reversibly reduced evoked transmitter release by 75 and 95% at 12 and 24 nM, respectively. In contrast, toxin effects were irreversible in low-Ca²⁺ (0.5 mM) saline. Ca²⁺ imaging in normal-Ca²⁺ saline showed that -Ptx-IIA partially blocked stimulus-dependent presynaptic Ca²⁺ signals, and the blockade was almost completely reversible. Increases in spontaneous release frequency induced by high extracellular K⁺ were blocked by -Ptx-IIA. Therefore -Ptx-IIA blocks N-type Ca²⁺ channels, which admit Ca²⁺ that triggers transmitter release at the frog NMJ. Additional evidence predicts that -Ptx-IIA binds to N-type Ca²⁺ channels at a different site from that of -Conotoxin-GVIA. -Ptx-IIA also gave a low-affinity partial blockade of transmitter release and presynaptic Ca²⁺ signals at crayfish NMJs where P-type channels are blocked by -agatoxin-IVA. The Ca²⁺-dependent reversibility and promiscuity of this toxin may make it highly useful experimentally and therapeutically.

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