title: Drug-induced ion channel opening tuned by the voltage sensor charge profile.
abstract: 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.
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, SE-581 83 Linköping, Sweden.
authors.forename: Nina E
authors.initials: NE
authors.lastname: Ottosson
authors.forename: Sara I
authors.initials: SI
authors.lastname: Liin
authors.forename: Fredrik
authors.initials: F
authors.lastname: Elinder
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D005260:Female; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology*; D007473:Ion Channels / Q000737:chemistry / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D051637:Shaker Superfamily of Potassium Channels / Q000819:agonists* / Q000737:chemistry / Q000502:physiology*; D014982:Xenopus laevis
chemical_list: D007473:Ion Channels; D051637:Shaker Superfamily of Potassium Channels; D004281:Docosahexaenoic Acids