Troncone Lanfranco R P, Georgiou John, Hua Shao-Ying, Elrick Donald, Lebrun Ivo, Magnoli Fabio, Charlton Milton P
Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
J Neurophysiol. 2003 Nov;90(5):3529-37. doi: 10.1152/jn.00155.2003. Epub 2003 Jul 30.
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, omega-phonetoxin-IIA (omega-Ptx-IIA, 8360 MW), which blocks Ca2+ channels. At frog neuromuscular junctions (NMJ) bathed in normal Ca2+ (1.8 mM) saline, omega-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 omega-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 omega-Ptx-IIA. Therefore omega-Ptx-IIA blocks N-type Ca2+ channels, which admit Ca2+ that triggers transmitter release at the frog NMJ. Additional evidence predicts that omega-Ptx-IIA binds to N-type Ca2+ channels at a different site from that of omega-Conotoxin-GVIA. omega-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 omega-agatoxin-IVA. The Ca2+-dependent reversibility and promiscuity of this toxin may make it highly useful experimentally and therapeutically.
在许多食肉动物毒液中发现的肽通道阻滞剂是有用的药理学工具和潜在的治疗剂。巴西黑腹栉足蛛的毒液中含有一种成分，ω-Phoneutria毒素-IIA（ω-Ptx-IIA，分子量8360），它能阻断Ca2+通道。在正常Ca2+（1.8 mM）盐溶液浸泡的青蛙神经肌肉接头（NMJ）处，ω-Ptx IIA不影响自发递质释放，但在12和24 nM时分别可逆地将诱发递质释放减少75%和95%。相比之下，在低Ca2+（0.5 mM）盐溶液中毒素的作用是不可逆的。在正常Ca2+盐溶液中的Ca2+成像显示，ω-Ptx-IIA部分阻断了刺激依赖性突触前Ca2+信号，并且这种阻断几乎完全可逆。高细胞外K+诱导的自发释放频率增加被ω-Ptx-IIA阻断。因此，ω-Ptx-IIA阻断N型Ca2+通道，该通道允许Ca2+进入，从而触发青蛙NMJ处的递质释放。其他证据预测，ω-Ptx-IIA与N型Ca2+通道的结合位点与ω-芋螺毒素-GVIA不同。在小龙虾NMJ处，P型通道被ω-阿加毒素-IVA阻断，ω-Ptx-IIA对递质释放和突触前Ca2+信号也有低亲和力的部分阻断作用。这种毒素的Ca2+依赖性可逆性和混杂性可能使其在实验和治疗方面非常有用。
