De Silva AM , Manville RW , Abbott GW .

R01 GM115189 NIGMS NIH HHS

	Fig. 1. Two components of M. oppositifolius leaf extract activate KCNQ1 channels.(A) M. oppositifolius (Geiseler) Mull. Arg. Photo by E. Bidault. Source: Tropicos.org. Missouri Botanical Garden (http://tropicos.org/Image/100521734). (B) KCNQ1 topology (two of four subunits shown). (C) Structure and electrostatic surface potential (blue, positive; green, neutral; red, negative) of M. oppositifolius leaf extract components. (D) Averaged KCNQ1 current traces in response to voltage protocol (upper inset) when bathed in the absence (control) or presence of M. oppositifolius leaf extract components (n = 5 to 8). Dashed line indicates zero current level in these and all following current traces. (E) Mean effects of leaf extract components [as in (D); n = 5 to 8] on KCNQ1 raw tail currents at −30 mV after prepulses as indicated (left); G/Gmax calculated from tail currents (right). Error bars indicate SEM. Ctrl, control.
	Fig. 2. MTX and CPT1 each activate KCNQ1 channels.All error bars indicate SEM. (A) Voltage dependence of KCNQ1 current fold increase by MTX (30 μM), plotted from traces as in Fig. 1 (n = 7). (B) Dose response of KCNQ1 channels at −40 mV for MTX (calculated EC50 = 10 μM; n = 7). (C) Dose response for mean ΔV0.5 of activation induced by MTX for KCNQ1 (n = 7). (D) Voltage dependence of KCNQ1 current fold increase by CPT1 (100 μM), plotted from traces as in Fig. 1 (n = 4 to 6). (E) Dose response of KCNQ1 channels at −60 mV for CPT1 (n = 4 to 6). (F) Dose response for mean ΔV0.5 of activation induced by CPT1 for KCNQ1 (n = 4 to 6).
	Fig. 3. KCNEs alter MTX effects on KCNQ1.All error bars indicate SEM. (A) Averaged KCNQ1-KCNE1 current traces in response to voltage protocol (upper left inset) in the absence (control) or presence of 30 μM MTX (n = 5). Dashed line indicates zero current level in this and all following current traces. (B) Mean effects of 30 μM MTX on KCNQ1 and KCNQ1-KCNE1 raw tail currents at −30 mV after prepulses as indicated [as in (A); n = 5]. (C) Mean instantaneous (inst) current compared to current after 3 s (both at +40 mV) for KCNQ1-KCNE1 channels in the absence (control) versus presence of MTX (30 μM). **P < 0.01 (n = 5). Left: Raw currents. Right: Instantaneous current/3-s current. (D) Mean KCNQ1-KCNE1 channel deactivation rate versus voltage in the absence (control) and presence of MTX (30 μM). (E) Mean dose response for effects of MTX on KCNQ1-KCNE1 current magnitude at −40 mV (n = 5). (F) Averaged KCNQ1-KCNE3 current traces in response to voltage protocol [as in (A)] in the absence (control) or presence of 30 μM MTX (n = 8). (G) Mean effects of 30 μM MTX on KCNQ1 and KCNQ1-KCNE3 raw tail currents at −30 mV after prepulses as indicated [as in (F); n = 8]. (H) Averaged KCNQ1-KCNE4 current traces in response to voltage protocol [as in (A)] in the absence (control) or presence of 30 μM MTX (n = 5). (I) Mean effects of 30 μM MTX on KCNQ1 and KCNQ1-KCNE4 raw tail currents at −30 mV after prepulses as indicated [as in (H); n = 5).
	Fig. 4. Summation of effects of MTX and SMIT1 on KCNQ1 activation.All error bars indicate SEM. (A) Topology of vSGLT, a eukaryotic SLC5A family ortholog bearing predicted structural similarity to SMIT1. (B) High-resolution structures of KCNQ1 and vSGLT (extracellular view) to illustrate relative sizes. (C) Averaged KCNQ1-SMIT1 traces in the absence (control) or presence of 30 μM MTX (n = 5). Dashed line indicates zero current level. (D) Mean effects of 30 μM MTX on KCNQ1-SMIT1 raw tail currents at −30 mV after prepulses as indicated [as in (C); n = 5]. (E) Mean effects of 30 μM MTX on KCNQ1-SMIT1 G/Gmax calculated from tail currents at −30 mV after prepulses as indicated [as in (C); n = 5]. (F) MTX dose response for mean ΔV0.5 of activation of KCNQ1-SMIT1 (blue) and KCNQ1 (red) (n = 5 to 7). (G) Comparison of mean effects of 30 μM MTX on KCNQ1 (red) and KCNQ1-SMIT1 (blue) G/Gmax calculated from tail currents at −30 mV after prepulses as indicated [as in (C); n = 5 to 7].
	Fig. 5. MTX and CPT1 compete for binding to R243 on the KCNQ1 S4-S5 linker.All error bars indicate SEM. (A) KCNQ1 topology (two of four subunits shown) indicating the position of R243 on the S4-S5 linker. (B) SwissDock result showing predicted binding of MTX to KCNQ1 via hydrogen bonding (green line) to R243. (C) Close-up of docking shown in (B). (D) Mean current augmentation by MTX versus voltage of wild-type and KCNQ1-R243A and KCNQ1-KCNE1 channels (n = 5 to 8). (E) SwissDock result showing predicted binding of CPT1 to KCNQ1-R243. (F) Mean current augmentation by CPT1 versus voltage of wild-type (from Fig. 2) and KCNQ1-R243A channels (n = 10). (G) SwissDock result showing predicted binding pose overlap in KCNQ1 of MTX and CPT1. (H) Mean effects of 30 μM MTX + 10 μM CPT1 on KCNQ1 raw tail currents (upper) and G/Gmax (lower) at −30 mV after prepulses as indicated (n = 5). (I) Mean current augmentation versus voltage of KCNQ1 by 30 μM MTX + 10 μM CPT1 (blue) [from (H)] compared to effects for MTX alone (red) or CPT1 alone (orange) (from Fig. 2) (n = 4 to 7). (J) Mean effects of M. oppositifolius leaf extract cocktail on KCNQ1 raw tail currents (upper) and G/Gmax (lower) at −30 mV after prepulses as indicated (n = 6).
	Fig. 6. MTX binds to the R243 equivalents on KCNQ2/3 channels.All error bars indicate SEM. (A) KCNQ2/3 topology (two of four subunits shown) indicating the position of R243 equivalents (R213/242) and of KCNQ2-W236/KCNQ3-W265 (orange pentagons). (B) SwissDock result showing predicted binding of MTX to KCNQ3 via hydrogen bonding (green line) to R242. (C) Close-up of docking shown in (B). (D) Left: Averaged wild-type and arginine mutant KCNQ2/3 traces as indicated in the absence (control) or presence of 30 μM MTX. Dashed line indicates zero current level. Mean tail currents (center). Mean G/Gmax (right) from traces as in left (n = 5 to 6). (E) Analysis of MTX effects recorded from wild-type and mutant KCNQ2/3 traces as in (D). Left: Current fold change in response to MTX (30 μM). Center: MTX dose responses for channel V0.5 activation shifts. Right: MTX dose responses for channel current augmentation at −60 mV (n = 5 to 6).

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