Drug-induced ion channel opening tuned by the voltage sensor charge profile

• Published in: The Journal of general physiology Vol. 143; no. 2; pp. 173 - 182
• Main Authors: Ottosson, Nina E, Liin, Sara I, Elinder, Fredrik
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 01-02-2014; The Rockefeller University Press
• Subjects: Amino Acid Sequence; Animals; Cells; Docosahexaenoic Acids - pharmacology; Fatty acids; Female; Ion Channel Gating - drug effects; Ion Channel Gating - physiology; Ion Channels - chemistry; Ion Channels - physiology; Ions; MEDICIN; MEDICINE; Molecular Sequence Data; Molecules; Mutation - physiology; Shaker Superfamily of Potassium Channels - agonists; Shaker Superfamily of Potassium Channels - chemistry; Shaker Superfamily of Potassium Channels - physiology; Xenopus laevis
• ISSN: 0022-1295; 1540-7748; 1540-7748
• DOI: 10.1085/jgp.201311087

Polyunsaturated fatty acids modulate the voltage dependence of several voltage-gated ion channels, thereby being potent modifiers of cellular excitability. Detailed knowledge of this molecular mechanism can be used in designing a new class of small-molecule compounds against hyperexcitability diseases. Here, we show that arginines on one side of the helical K-channel voltage sensor S4 increased the sensitivity to docosahexaenoic acid (DHA), whereas arginines on the opposing side decreased this sensitivity. Glutamates had opposite effects. In addition, a positively charged DHA-like molecule, arachidonyl amine, had opposite effects to the negatively charged DHA. This suggests that S4 rotates to open the channel and that DHA electrostatically affects this rotation. A channel with arginines in positions 356, 359, and 362 was extremely sensitive to DHA: 70 µM DHA at pH 9.0 increased the current >500 times at negative voltages compared with wild type (WT). The small-molecule compound pimaric acid, a novel Shaker channel opener, opened the WT channel. The 356R/359R/362R channel drastically increased this effect, suggesting it to be instrumental in future drug screening.