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The naturally occurred peptide toxins from animal venoms are valuable pharmacological tools in exploring the structure-function relationships of ion channels. Herein we have identified the peptide toxin κ-LhTx-1 from the venom of spider  Pandercetes sp  (the Lichen huntsman spider) as a novel selective antagonist of the K V 4 family potassium channels. κ-LhTx-1 is a gating-modifier toxin impeded K V 4 channels’ voltage sensor activation, and mutation analysis has confirmed its binding site on channels’ S3b region. Interestingly, κ-LhTx-1 differently modulated the gating of K V 4 channels, as revealed by toxin inhibiting K V 4.2/4.3 with much more stronger voltage-dependence than that for K V 4.1. We proposed that κ-LhTx-1 trapped the voltage sensor of K V 4.1 in a much more stable resting state than that for K V 4.2/4.3 and further explored the underlying mechanism. Swapping the non-conserved S3b segments between K V 4.1( 280 FVPK 283 ) and K V 4.3( 275 VMTN 278 ) fully reversed their voltage-dependence phenotypes in inhibition by κ-LhTx-1, and intensive mutation analysis has identified P282 in K V 4.1, D281 in K V 4.2 and N278 in K V 4.3 being the key residues. Furthermore, the last two residues in this segment of each K V 4 channel (P282/K283 in K V 4.1, T280/D281 in K V 4.2 and T277/N278 in K V 4.3) likely worked synergistically as revealed by our combinatorial mutations analysis. The present study has clarified the molecular basis in K V 4 channels for their different modulations by κ-LhTx-1, which have advanced our understanding on K V 4 channels’ structure features. Moreover, κ-LhTx-1 might be useful in developing anti-arrhythmic drugs given its high affinity, high selectivity and unique action mode in interacting with the K V 4.2/4.3 channels.

Variation of Two S3b Residues in KV4.1–4.3 Channels Underlies Their Different Modulations by Spider Toxin κ-LhTx-1