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

• Published in: Biochemical pharmacology 2008-09, Vol.76 (6), p.805-815
• Main Authors: Abdel-Mottaleb, Yousra, Corzo, Gerardo, Martin-Eauclaire, Marie-France, Satake, Honoo, Céard, Brigitte, Peigneur, Steve, Nambaru, Praveen, Bougis, Pierre-Edouard, Possani, Lourival D., Tytgat, Jan
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Biochemistry; Biochemistry, Molecular Biology; Biological and medical sciences; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Ether-A-Go-Go Potassium Channels - genetics; Ether-A-Go-Go Potassium Channels - metabolism; Female; hERG channels; K + channels; Life Sciences; Medical sciences; Molecular Sequence Data; Mutagenesis, Site-Directed; Pharmacology. Drug treatments; Potassium Channel Blockers; Potassium Channel Blockers - chemistry; Potassium Channel Blockers - metabolism; Scorpion toxins; Scorpion Venoms; Scorpion Venoms - chemistry; Scorpion Venoms - genetics; Scorpion Venoms - metabolism; Scorpions; Xenopus laevis; α-KTx; γ-KTxs
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2008.07.008

While α-KTx peptides are generally known for their modulation of the Shaker-type and the Ca 2+-activated potassium channels, γ-KTxs are associated with hERG channels modulation. An exception to the rule is BmTx3 which belongs to subfamily α-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 suggested 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 α-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 α-KTx. Additionally, we could extend our results to other α-KTx subfamily members belonging to α-KTx1, 4 and 6, therefore, the “hot spot” represents a common pharmacophore serving as a predictive tool for yet to be discovered α-KTxs.