Ottosson NE , Wu X , Nolting A , Karlsson U , Lund PE , Ruda K , Svensson S , Konradsson P , Elinder F .

	Figure 1. The effect of several natural resin acids on the opening of the Shaker K channel.(a) Molecular structure (from left to right) for pimaric acid (PiMA) (1), isopimaric acid (Iso-PiMA) (2), abietic acid (AA) (3), dehydroabietic acid (DHAA) (4), and podocarpic acid (PoCA) (5). (b) Representative current traces for voltages corresponding to 10% of maximum conductance in control solution at pH 7.4 of the 3R Shaker K channel. Black traces indicate control, and red traces 100 μM compound (same order as in a). (c) Representative G(V) curves for DHAA effects, same cell as in b (control, black symbols; DHAA, red symbols. ∆VG(V) = −15.5. (d) Ring nomenclature of the general compound skeleton (blue) and modified carbons in derivates (grey). (e) Gating charge residues (362 = R1, and 365 = R2) and mutated residues (shown as R) of the 3R Shaker K channel (359R, and 356R) are marked on one VSD of the Shaker K channel in the active state. (f) Compound-induced G(V) shifts for the WT (blue) and 3R Shaker K channel (red). Mean ± SEM (n = 9, 15, 15, 6, 4, 4, 5, 5, 10, 6, 4, and 6 from left to right). Data for DHA (6) and PiMA (1) are from ref 17. The shifts of WT and 3R Shaker K channel are compared for each compound (one-way ANOVA together with Bonferroni’s multiple comparison test: *P < 0.05; ***P < 0.0001).
	Figure 2. The effect of modifications of C7 at the B-ring for the activation of the 3R Shaker K channel.Chemical side chain and molecular structure for the introduced side chain at C7 of DHAA (4) (middle) for the specific compound (left). Compound(100 μM)-induced G(V) shifts for the 3R Shaker K channel (right). The dashed line equals the DHAA-induced shift. Mean ± SEM (n = 4–6). The shifts are compared with DHAA (4) (one-way ANOVA together with Dunnett’s multiple comparison test: *P < 0.05; **P < 0.01; ***P < 0.001).
	Figure 3. Halogenation-dependent potency.Shift of G(V) (mean values) by the unhalogenated and halogenated DHAA (4) derivates (100 μM), arranged according to halogenation of the C-ring (horizontal) and side chains attached to C7 (vertical). Compounds are color coded according to their potency: dark green: ∆VG(V) ≤ −30.0 mV, green: −30.0 mV < ∆VG(V) ≤ −25.0 mV, light green: −25.0 mV < ∆VG(V) ≤ −20.0 mV, yellow: −20.0 mV < ∆VG(V) ≤ −15.0 mV, orange: −15.0 mV < ∆VG(V) ≤ −10.0 mV, light red: −10.0 mV < ∆VG(V) ≤ −5 mV, red: −5.0 mV < ∆VG(V) ≤ 0.0 mV, dark red: ∆VG(V) > +0.0 mV.
	Figure 4. Replacement of the isopropyl group at C13 with a chlorine.(a) Molecular structure for Compound 67 (upper) and Compound 77 (lower). (b) Representative current traces for voltages corresponding to 10% of maximum conductance in control solution at pH 7.4 of the 3R Shaker K channel. Black traces indicate control, and red traces 100 μM compound (upper, Compound 67; lower, Compound 77). (c) Representative G(V) curves. Same cells as in b (control, black symbols; compound, red symbols. ∆VG(V) = −6.1 mV by Compound 67 (upper), and −32.6 mV by Compound 77 (lower) in these examples.
	Figure 5. Concentration and pH dependent compound effects.(a) Concentration response curve for DHAA (4) (grey), Compound 33 (red), and Compound 77 (blue) at pH 7.4 for the 3R Shaker K channel. Error bars indicate SEM (n = 4–9). (b) Compound-induced G(V) shifts for the WT and 3R Shaker K channels. (c,d) pH dependence curves for WT (c) and 3R Shaker K channel (d) for 100 μM DHAA (4) (grey), 100 μM Compound 33 (red), and 100 μM Compound 77 (blue). Error bars indicate SEM (n = 4–9).
	Figure 6. The effect of compounds on the resting membrane potential (Vm) and excitability of DRG neurons.(a) Recordings of Vm during application of Compound 13 and 77. (b) Compound-induced hyperpolarizing shifts of Vm of DRGs (10 μM at pH 7.4) plotted versus the shifts for the 3R Shaker K channel expressed in Xenopus oocytes (100 μM at pH 7.4). Mean ± SEM (for DRG-recordings, n = 4–7; for oocyte recordings, n = 4–9). (c) Effects on single action potentials by Compound 13 and 77 (black is control and red is test compound). (d) Effects on repetitive firing elicited by a continuous current pulse. The effect of Compound 77 is clearly reversible. Compound 13 had almost no effect.

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