Lipid Bilayer Perturbation by the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer does not Account for its Modulation of Voltage-Gated Potassium Channels

Abstract

The marine snail toxin BrMT, a 6-bromo-2-mercaptotryptamine dimer, is a powerful, hydrophobic modulator of Kv1 and Kv4 voltage-gated potassium channels. It remains unclear how BrMT modulates these diverse channels, and given BrMT's hydrophobicity, whether it alters potassium channel function by perturbing lipid bilayer properties. We synthesized BrMT and 11 analogs to determine structure-activity relationships, and create more chemically stable ion channel modulators. We found the biological activity was retained when the labile disulfide bond between BrMT's indole groups was replaced with an ether or alkane linkage.