A common hot spot confers hERG blockade activity to α-scorpion toxins affecting K+ channels

While alpha-KTx peptides are generally known for their modulation of the Shaker-type and the Ca2+-activated potassium channels, gamma-KTxs are associated with hERG channels modulation. An exception to the rule is BmTx3 which belongs to subfamily alpha-KTx15 and can block hERG channels. To explain the peculiar behavior of BmTx3, a tentative hot spot formed of 2 basic residues (R18 and K19) was suggestcd but never further studied [Huys I, et al. BmTx3, a scorpion toxin with two putative functional faces separately active on A-type K+ and HERG currents. Biochem J 2004;378:745-52]. In this work, we investigated if the hot spot is a commonality in subfamily alpha-KTx15 by testing the effect of (AmmTx3, Aa1, discrepin). Furthermore, single mutations altering the hot spot in discrepin, have introduced for the very first time a hERG blocking activity to a previously non-active a-KTx. Additionally, we could extend our results to other a-KTx subfamily members belonging to alpha-KTx1, 4 and 6, therefore, the hot spot represents a common pharmacophore serving as a predictive tool for yet to be discovered alpha-KTxs. (C) 2008 Elsevier Inc. All rights reserved.