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J Gen Physiol February 1, 2014; 143 (2): 173-82.

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

Ottosson NE , Liin SI , Elinder F .

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.

PubMed ID: 24420769
PMC ID: PMC4001773
Article link: J Gen Physiol

Species referenced: Xenopus
Genes referenced: kcna2 tbx2

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References [+] :
Billman, Prevention of ischemia-induced ventricular fibrillation by omega 3 fatty acids. 1994, Pubmed