The Kv2.1 voltage-activated K+channel, a Shab-related K+channel isolated from rat brain, is insensitive to previously identified peptide inhibitors. We have isolated two peptides from the venom of a Chilean tarantula, G. spatulata, that inhibit the Kv2.1 K+channel. The two peptides, hanatoxin, (HaTx1) and hanatoxin2(HaTx2), are unrelated in primary sequence to other K+channel inhibitors. The activity of HaTx was verified by synthesizing it in a bacterial expression system. The concentration dependence for both the degree of inhibition at equilibrium (Kd= 42 nM) and the kinetics of inhibition (kon= 3.7 × 104M-1s-1; koff= 1.3 × 10-3s-1), are consistent with a bimolecular reaction between HaTx and the Kv2.1 K+channel. Shaker-related, Shaw-related, and eag K+channels were relatively insensitive to HaTx, whereas a Shal-related K+channel was sensitive. Regions outside the scorpion toxin binding site (S5-S6 linker) determine sensitivity to HaTx. HaTx introduces a new class of K+channel inhibitors that will be useful probes for studying K+channel structure and function. © 1995.
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