SELECTIVE ALTERATION OF SODIUM-CHANNEL GATING BY AUSTRALIAN FUNNEL-WEB SPIDER TOXINS

The actions of potent mammalian neurotoxins isolated from the venom of two Australian funnel-web spiders were investigated using both electr ophysiological and neurochemical techniques. Whole-cell patch clamp re cording of sodium currents in rat dorsal root ganglion neurons reveale d that versutoxin (VTX), isolated from the venom of Hadronyche versuta , produced a concentration-dependent slowing or removal of tetrodotoxi n-sensitive (TTX-S) sodium current inactivation and a reduction in pea k TTX-S sodium current. In contrast, VTX had no effect on tetrodotoxin -resistant (TTX-R) sodium currents or potassium currents. VTX also shi fted the voltage dependence of sodium channel activation in the hyperp olarizing direction and increased the rate of recovery from inactivati on. Ion flux studies performed in rat brain synaptosomes also revealed that robustoxin (RTX), from the venom of Atrax robustus, and VTX both produced a partial activation of Na-22(+) flux and an inhibition of b atrachotoxin-activated Na-22(+) flux. This inhibition of flux through batrachotoxin-activated channels was not due to an interaction with ne urotoxin receptor site 1 since [H-3]saxitoxin binding was unaffected. In addition, the partial activation of Na-22(+) flux was not enhanced in the presence of alpha-scorpion toxin and further experiments sugges t that VTX also enhances [H-3]batrachotoxin binding. These selective a ctions of funnel-web spider toxins on sodium channel function are comp arable to those of alpha-scorpion and sea anemone toxins which bind to neurotoxin receptor site 3 on the channel to slow channel inactivatio n profoundly. Also, these modifications of sodium channel gating and k inetics are consistent with actions of the spider toxins to produce re petitive firing of action potentials. Copyright (C) 1996 Elsevier Scie nce Ltd