HETEROPODATOXINS - PEPTIDES ISOLATED FROM SPIDER VENOM THAT BLOCK KV4.2 POTASSIUM CHANNELS

Toxins isolated from scorpion, snake, and spider venoms are valuable t ools to probe the physiologic function and structure of ion channels. In this study, we have isolated three new toxins (heteropodatoxins) fr om the venom of a spider, Heteropoda venatoria. These toxins are struc turally similar peptides of 29 to 32 amino acids and share sequence ho mology with hanatoxins isolated from the venom of a Chilean tarantula. The heteropodatoxins prolonged the action-potential duration of isola ted rat ventricular myocytes, suggesting that the peptides block K+ cu rrents. The effect of toxins on cardiac K+ currents were studied using voltage clamp techniques. The toxins blocked the transient outward K current but not other K+ currents in isolated rat cardiac myocytes. T he mechanism of block was studied further using Kv4.2, a cloned channe l believed to underlie transient outward KC current in rat myocytes. T he toxins blocked Kv4.2 current expressed in Xenopus laevis oocytes in a voltage-dependent manner, with less block at more positive potentia ls. In addition, the toxins slowed the time course of current activati on and inactivation and shifted the voltage dependence of current inac tivation to more positive potentials. The heteropodatoxins represent n ew pharmacologic probes to study the role of Kv4.2 channels in cardiac and neural tissue.