Drug-induced ion channel opening tuned by the voltage sensor charge profile
2014 (English)In: The Journal of General Physiology, ISSN 0022-1295, Vol. 143, no 2, 173-182 p.Article in journal (Refereed) Published
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 mu M DHA at pH 9.0 increased the current greater than500 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.
Place, publisher, year, edition, pages
Rockefeller University Press , 2014. Vol. 143, no 2, 173-182 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-105035DOI: 10.1085/jgp.201311087ISI: 000330628500006OAI: oai:DiVA.org:liu-105035DiVA: diva2:703382