Xie C , Liu HW , Pan N , Ding JP , Yao J .

	Figure 1. Electrocardiogram (ECG) changes in rats with acute ethanol treatments. (A) ECG recordings in adult male Wistar rats. Representative tracings of ECG recorded from individual rat before and after injection with 0.3 mL of normal saline or a solution containing 3%, 10% or 50% ethanol (v/v). Each solution was injected into the abdomen of a different rat fixed by two cortical electrodes. The proper position of ECG leads was monitored by the telemetry signal quality using the recording software, and all of the ECG traces were recorded until the quality of the ECG signal was considered acceptable, usually approximately 40 min after each treatment for an individual rat. The ∼1-s ECG recordings were mainly used for average heart rate measurements, albeit the voltage amplitude values being remarkably reduced, especially in the rats that were injected with high concentrations of ethanol (eg, 50%). (B) Comparison of heart rate responses to different treatments (n=3–6). Mean±SEM. bP<0.05 vs control. EtOH, ethanol.
	Figure 2. Extending the alkyl chain length augments the inhibition efficiency of 1-alkanols on IKs currents as recorded in oocytes. (A) Representative currents were recorded from oocytes expressing wild-type KCNQ1/KCNE1 under two-electrode voltage–clamp by voltage steps from −60 to +60 mV in 10-mV increments lasting for 3 s in the presence and absence of 200 mmol/L ethanol (termed as EtOH; A1), 50 mmol/L 1-butanol (BuOH; A2) and 5 mmol/L 1-hexanol (HexOH; A3) as indicated. Voltage protocols included above current traces. (B) Summary plots of I–V curves before and after exposure to different concentrations of EtOH (B1; n=4), BuOH (B2; n=5) and HexOH (B3; n=5) as indicated. All of the currents at each concentration were normalized to their respective control values.
	Figure 3. 1-Alkanols inhibit IKs currents in both the open and closed state of wild-type KCNQ1/KCNE1 channels. (A) Dose-response curves for the open-channel block were plotted for EtOH (A1; n=4), BuOH (A2; n=5) and HexOH (A3; n=5) at +20 mV and were fitted to the Hill equation. Both the IC50 values and the corresponding Hill coefficient nH are indicated on each panel. (B) Voltage-dependence of IC50 values for EtOH (n=4), BuOH (n=4) and HexOH (n=3). The solid lines are the lines of best fit of the function k(V)=k(0)×exp(−zFV/RT), where k(0) represents the IC50 for 1-alkanols at 0 mV, and z is the fitted value for fractional charges moved during block reaction. The variables of F, R and T have their standard definitions. For EtOH, k(0)=0.0718 with z=−0.4749; k(0)=0.0338 with z=−0.6200 for BuOH; and k(0)=0.0021 with z=−0.5688 for HexOH. (C) Time courses and fractional inhibitions of KCNQ1/KCNE1 currents evoked at +60 mV in the presence of 200 mmol/L EtOH (n=4), 50 mmol/L BuOH (n=4) and 5 mmol/L HexOH (n=5). (D) Dose-dependence of three 1-alkanols effects on the closed state KCNQ1 channels. The inhibition values or ratios by 1-alkanols at the closed state were derived from the values at the intersection of the prolonged line of Idrug/Icontrol and the zero time axis (t=0 s), as shown in Figure 3C. The solid line represents a Hill equation fit. (E) Normalized conductance-voltage relationship. The conductances that were obtained from steady state currents at the end of the pulse in the presence of various concentrations of EtOH (E1), BuOH (E2) and HexOH (E3) were simultaneously fit to a four-state block model (Model I) as described in the main text (solid lines). The optimal fit for the open and closed-channel block (OB-CB) yielded KOB=90±8.2 mmol/L, KCB=60.8±7.0 mmol/L for EtOH (E1), KOB=20±5.2 mmol/L, KCB=17.6±6.1 mmol/L for BuOH (E2) and KOB=5.0±2.1 mmol/L, KCB=1.6±1.5 mmol/L for HexOH (E3). The error bars represent the SEM. EtOH, ethanol; BuOH, 1-butanol; HexOH, 1-hexanol.
	Figure 4. I257, the residue in the intracellular linker of transmembranes S4 and S5, is critical for the 1-alkanol inhibition of KCNQ1 channels. (A) Effects of ethanol on kqt-3 currents. Representative outward current in oocytes expressed with kqt-3 and KCNE1 were evoked by step depolarizations from −90 mV to +60 mV in 10-mV increments in the presence and absence of 200 mmol/L EtOH. The interpulse interval was 3 s. Voltage protocols are presented above current traces. (B) Summary plots of relative currents over voltage before and after exposure to different concentrations of EtOH (n=4), showing that ethanol (200 mmol/L) has a slight effect on kqt-3 currents. (C) An amino acid alignment of the linker of S4 and S5 between C elegans kqt-3 and human KCNQ1. (D) Representative current traces from oocytes that were injected with KCNQ1 (I257A) and KCNE1 in response to voltage steps from −60 to +60 mV in 10-mV increments for 3 s in the presence and absence of 400 mmol/L EtOH (D1), 200 mmol/L BuOH (D2) and 10 mmol/L HexOH (D3) as indicated. (E) Summary plots of relative current over voltage before and after exposure to different concentrations of EtOH (B1; n=4), BuOH (B2; n=5) and HexOH (B3; n=5) as indicated. All of the currents at each concentration were normalized to their respective control values. The error bars indicate the SEM. EtOH, ethanol; BuOH, 1-butanol; HexOH, 1-hexanol.
	Figure 5. Substitution of I257 by alanine abrogates the closed-state block of the KCNQ1 channel by 1-alkanols. (A) Dose-response curves for the open-channel block by 1-alkanols; best fitting by Hill's equation resulted in the following: IC50=634±0.8 mmol/L, nH=0.5 for EtOH (A1, n=5); IC50=414±7.0 mmol/L, nH=0.5 for BuOH (A2, n=5); and IC50=7.4±0.8 mmol/L, nH=0.7 for HexOH (A3, n=6). (B) Summary plots of the logarithm of IC50 versus voltage. Solid lines represent the best fits of the function k(V)=k(0)×exp(−zFV/RT), where k(0) represents the IC50 for 1-alkanols at 0 mV, and z is the fitted value for fractional charges moved during the block. The variables F, R and T have their standard definitions. The fits yield the following model parameters: k(0)=0.2053 with z=−0.4010 for EtOH; k(0)=0.0498 with z=−0.6217 for BuOH; and k(0)=0.0052 with z=−0.6999 for HexOH. (C) Normalized peak current amplitudes are plotted as a function of elapsed time. Currents that were encoded with the mutant I257A and KCNE1 were recorded in the presence of 400 mmol/L EtOH, 200 mmol/L BuOH and 10 mmol/L HexOH, respectively. The membrane potential was depolarized to +60 mV lasting for 3 s. (D) Each average C/Gmax vs voltage plot with simultaneous fits to the 3-state model for the open channel block (Model II) of I257A with KCNE1 in the presence of various concentrations of EtOH (D1), BuOH (D2) and HexOH (D3). See text for details. The fits correspond to the following parameter values: KOB=600±18.5 mmol/L for EtOH, KOB=400±20.1 mmol/L for BuOH and KOB=2.9±3.2 for HexOH. The error bars indicate the SEM. EtOH, ethanol; BuOH, 1-butanol; HexOH, 1-hexanol.

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