Lin MC , Abramson J , Papazian DM .

R01 GM43459 NIGMS NIH HHS , R01 GM043459-19 NIGMS NIH HHS , R01 GM043459 NIGMS NIH HHS , R01 GM078844 NIGMS NIH HHS

	Figure 1. Alignment of S2 and S3 sequences from Shaker, the Kv1.2/Kv2.1 chimera, Drosophila eag, and rat CNG4 (A) (Tempel et al., 1987; Warmke et al., 1991; Chandy and Gutman, 1995; Nelson et al., 1999; Long et al., 2007). Acidic residues conserved throughout the voltage-gated channel superfamily are shown in bold; positions of acidic residues conserved only in the eag and CNG subfamilies are underlined and shown in bold italics. The asterisk (*) above the conserved proline in S3 indicates the division between S3a and S3b (Alabi et al., 2007). Numbers corresponding to the Shaker and eag sequences are provided above and below the alignment, respectively. (B) Cartoon of the membrane topology of a voltage-gated K+ channel subunit shows the approximate locations of the binding site residues (filled circles) (Silverman et al., 2000). Circled negative signs indicate positions occupied by acidic residues throughout the voltage-gated channel superfamily (Chandy and Gutman, 1995). Circled positive signs indicate charge-moving arginine residues in the S4 segment (Aggarwal and MacKinnon, 1996; Seoh et al., 1996). Filled circles indicate positions occupied by acidic residues only in the eag and CNG channel subfamilies (Kaupp et al., 1989; Dhallan et al., 1990; Warmke and Ganetzky, 1994).
	Figure 2. Shaker-IR is insensitive to extracellular Mg2+. (A) Shaker-IR currents were recorded in the absence (left) or presence (middle) of 10 mM of extracellular Mg2+. From a holding potential of −100 mV, 50-ms test pulses to voltages between −60 and +90 mV were applied in 10-mV increments. In this and subsequent figures, traces obtained by pulses ranging from −60 to +40 mV are shown. (Right) Currents recorded at −10 mV in the absence (solid trace) or presence (dashed) of Mg2+ have been scaled and overlaid. (B) Mg2+ shifts the voltage dependence of activation in Shaker-IR channels. Conductance values were calculated from steady-state current amplitudes during a 50-ms test pulse. Normalized conductance values (g/gmax) obtained in the absence (■) or presence (•) of Mg2+ were plotted versus voltage. Datasets were fitted with single Boltzmann functions. Values of V1/2 in the absence and presence of Mg2+ were −19 ± 1 and −7 ± 2 mV, respectively. Values of the apparent valence were 2.5 ± 0.2 and 2.5 ± 0.1 without and with Mg2+, respectively. To correct for the field effect of Mg2+, g/gmax values obtained in Mg2+ were shifted by −12 mV and replotted (○). Data are provided as mean ± SEM; n = 6. (C) Current traces have been scaled and overlaid after approximate correction for the surface charge effect of Mg2+. Representative current traces were recorded at +20 mV in the absence (dashed trace) or at +30 mV in the presence (dotted trace) of Mg2+. Fitted exponential functions (solid lines) have been superimposed. Values of τact in the absence (+20 mV) or presence (+30 mV) of Mg2+ were 1.2 ± 0.1 and 1.1 ± 0.1 ms, respectively, and did not differ significantly (P ≥ 0.05). (D) Activation kinetics are unaffected by Mg2+. τact in the absence (■) or presence (•) of Mg2+ were obtained by fitting single-exponential functions to the current traces and plotted versus voltage. To correct for the field effect of Mg2+, τact values obtained in Mg2+ were shifted by −12 mV and replotted (○). Data are shown as mean ± SEM; n = 6. (E) Tail current traces have been scaled and overlaid after approximate correction for the surface charge effect of Mg2+. Representative tail currents were recorded at −100 mV in the absence (dashed trace) or at −90 mV in the presence (dotted trace) of Mg2+. Fitted exponential functions (solid lines) have been superimposed. The values of τdeact in the absence (−100 mV) and presence (−90 mV) of Mg2+ did not differ significantly and were 1.4 ± 0.1 and 1.5 ± 0.1 ms, respectively. (F) Mg2+ does not affect deactivation kinetics. The membrane was depolarized to +40 mV, followed by repolarization to tail potentials ranging from −50 to −125 mV. Tail currents recorded in the absence (■) or presence (•) of Mg2+ were fitted with a single-exponential component to obtain values for τdeact, which were plotted versus repolarization voltage. Data are provided as mean ± SEM; n = 9. To correct for the field effect of Mg2+, values of τdeact obtained in the presence of Mg2+ were shifted by −12 mV and replotted (○).
	Figure 3. Mg2+ significantly slows activation and increases the delay before pore opening in I287D+F324D channels. (A) I287D+F324D currents were recorded in the absence (left) or presence (middle) of Mg2+. (Right) After approximate correction for the nonspecific field effect of Mg2+ (see B), current traces have been scaled and overlaid. Representative current traces were recorded at +20 mV in the absence (dashed trace) or at +30 mV in the presence (dotted trace) of Mg2+. Fitted exponential functions (solid lines) have been superimposed. (B) Mg2+ shifts the voltage dependence of activation in I287D+F324D channels. Because the conductance of I287D+F324D channels did not saturate in the tested voltage range, un-normalized conductance values from a representative experiment are shown. Data were obtained in the absence (■) or presence (•) of Mg2+, plotted versus voltage, and fitted with a single Boltzmann function without constraining the maximum conductance value. Fitted parameters from individual experiments were averaged and are provided as mean ± SEM; n = 8. Values of V1/2 and apparent valence in the absence and presence of Mg2+ were 38 ± 2 mV and 0.7 ± 0.04, and 43 ± 1 mV and 1.0 ± 0.07, respectively. To correct for the field effect of Mg2+, conductance values obtained in Mg2+ were shifted by −5 mV and replotted (○). (C) Mg2+ slows activation kinetics in I287D+F324D. (Left) Values of τact obtained in the absence (■) or presence (•) of Mg2+ have been plotted versus voltage from 0 to +45 mV. To correct for the field effect of Mg2+, τact values obtained in Mg2+ were shifted by −5 mV and replotted (○). Data are provided as mean ± SEM; n = 7. Shifted τact values obtained with Mg2+ and τact values obtained without Mg2+ differed significantly; P < 0.05. (Right) Values of τact obtained at voltages from +50 to +95 mV are shown on an expanded scale; symbols as described above. To correct for the field effect of Mg2+, τact values obtained in Mg2+ were shifted by −5 mV and replotted (○). Shifted τact values obtained with Mg2+ and τact values obtained without Mg2+ differed significantly; P < 0.05. (D) Representative current traces recorded at +20 mV in the absence (solid trace) or at +25 mV in the presence (dashed trace) of Mg2+ are shown on an expanded time scale to highlight the delay before pore opening. The arrow indicates start of voltage pulse (t = 0). Values of τact obtained in the absence (+20 mV) and presence (+25 mV) of Mg2+ differed significantly and were 9.9 ± 0.3 and 20.2 ± 0.5 ms, respectively (n = 7; P < 0.05). Measured delay values were 4.6 ± 0.2 ms at +20 mV in the absence and 11.3 ± 0.8 ms at +25 mV in the presence of Mg2+ (n = 7; P < 0.05). (E) Mg2+ increases the delay before activation of the ionic conductance in I287D+F324D. The delay before pore opening was measured in the absence (■) or presence (•) of Mg2+ and plotted versus voltage. Data are provided as mean ± SEM; n = 10. To correct for the field effect of Mg2+, delays measured in the presence of Mg2+ were shifted by −5 mV and replotted (○). Shifted delay values obtained with Mg2+ and delay values obtained without Mg2+ differed significantly; P < 0.05. (F) Mg2+ does not affect deactivation kinetics. Representative tail currents evoked at −95 mV in the absence (dashed trace) or at −90 mV in the presence (dotted trace) of Mg2+ have been scaled and overlaid. Values of τdeact in the absence (−95 mV) and presence (−90 mV) of Mg2+ were 3.7 ± 0.5 and 3.9 ± 0.1 ms, respectively, and did not differ significantly. (G) The membrane was depolarized to +40 mV, followed by repolarization for 200 ms to tail potentials ranging from −40 to −115 mV. Tail current traces were fitted with single-exponential functions to obtain values for τdeact in the absence (■) or presence (•) of Mg2+, which were plotted versus repolarization voltage. Data are provided as mean ± SEM; n = 4. To correct for the field effect of Mg2+, τdeact values obtained in Mg2+ were shifted by −5 mV and replotted (○).
	Figure 4. Single mutants I287D (A–C) and F324D (D–F) are insensitive to extracellular Mg2+. (A and D) Mg2+ shifts the voltage dependence of activation in (A) I287D and (D) F324D channels. Values of g/gmax obtained in the absence (■) or presence (•) of Mg2+ were plotted versus voltage. Data are provided as mean ± SEM; n = 6 (I287D) or 8–9 (F324D). Data were fitted with a single Boltzmann function. Values of V1/2 and apparent valence for I287D in the absence and presence of Mg2+ were −20 ± 2 mV and 1.7 ± 0.1, and 0 ± 1 mV and 1.5 ± 0.2, respectively. Values of V1/2 and apparent valence for F324D in the absence and presence of Mg2+ were 21 ± 1 mV and 2.1 ± 0.2, and 40 ± 1 mV and 2.5 ± 0.3, respectively. To correct for the field effect of Mg2+, g/gmax values obtained in Mg2+ were shifted by −20 mV and replotted (○). (B and E) Representative I287D (B) and F324D (E) currents recorded at +20 mV in the absence (solid trace) and +40 mV in the presence (dashed trace) of Mg2+ have been scaled and overlaid. Values of τact (I287D) or τact,fast (F324D) obtained in the absence (+20 mV) and presence (+40 mV) of Mg2+ did not differ significantly and were 2 ± 0.1 and 2 ± 0.1 ms for I287D, and 17 ± 2 and 14 ± 1 ms for F324D, respectively. (C and F) Mg2+ does not affect activation kinetics in (C) I287D or (F) F324D. I287D and F324D current traces recorded in the absence (■) or presence (•) of Mg2+ were fitted with single- (I287D) or double- (F324D) exponential functions. Values of τact were plotted versus voltage. In F, only the major, fast kinetic component of F324D activation is shown. Data are shown as mean ± SEM; n = 6 (I287D) or 3 (F324D). To correct for the field effect of Mg2+, τact values obtained in Mg2+ were shifted by −20 mV and replotted (○).
	Figure 5. E283 is not required for Mg2+ modulation of activation time course in I287D+F324D. (A) E283A+I287D+F324D currents were recorded in the absence (left) or presence (middle) of Mg2+. (Right) After approximate correction for the nonspecific field effect of Mg2+ (see B), representative current traces recorded at +20 mV in the absence (dashed trace) or at +30 mV in the presence (dotted trace) of Mg2+ have been scaled and overlaid. Single-exponential fits to the data are shown (solid curves). (B) Mg2+ shifts the voltage dependence of activation in E283A+I287D+F324D. Because the conductance of E283A+I287D+F324D channels did not saturate in the tested voltage range, un-normalized conductance values from a representative experiment are shown. Data were obtained in the absence (■) or presence (•) of Mg2+, plotted versus voltage, and fitted with a single Boltzmann function without constraining the maximum conductance value. Fitted parameters from individual experiments were averaged and are provided as mean ± SEM; n = 8. Values of V1/2 and apparent valence in the absence and presence of Mg2+ were 36 ± 3 mV and 0.8 ± 0.07, and 44 ± 4 mV and 0.9 ± 0.07, respectively. To correct for the field effect of Mg2+, conductance values obtained in Mg2+ were shifted by −8 mV and replotted (○). (C) Mg2+ slows activation kinetics. (Left) Values of τact obtained in the absence (■) or presence (•) of Mg2+ have been plotted versus voltage from 0 to +48 mV. Data are provided as mean ± SEM; n = 8. To correct for the field effect of Mg2+, τact values obtained in Mg2+ were shifted by −8 mV and replotted (○). Shifted τact values obtained with Mg2+ and τact values obtained without Mg2+ differed significantly; P < 0.05. (Right) Values of τact obtained at voltages from +50 to +98 mV are shown on an expanded scale; symbols as described above. To correct for the field effect of Mg2+, τact values obtained in Mg2+ were shifted by −8 mV and replotted (○). Shifted τact values obtained with Mg2+ and τact values obtained without Mg2+ differed significantly; P < 0.05. (D) Representative current traces recorded at +20 mV in the absence (solid trace) or at +28 mV in the presence (dashed trace) of Mg2+ are shown on an expanded time scale to highlight the delay before pore opening. The arrow indicates start of voltage pulse (t = 0). Values of τact measured in the absence (+20 mV) and presence (+28 mV) of Mg2+ were 11.3 ± 0.5 and 18.5 ± 1.2 ms, respectively, and differed significantly (P < 0.05; n = 8). Measured delay values were 3.3 ± 0.3 ms at +20 mV in the absence and 9.1 ± 0.2 ms at +28 mV in the presence of Mg2+ and differed significantly (P < 0.05; n = 8). (E) Mg2+ increases the delay before activation of the ionic conductance in E283A+I287D+F324D. The delay before pore opening was measured in the absence (■) or presence (•) of Mg2+ and plotted versus voltage. Data are provided as mean ± SEM; n = 10. To correct for the field effect of Mg2+, delays measured in the presence of Mg2+ were shifted by −8 mV and replotted (○). Shifted delay values obtained with Mg2+ and delay values obtained without Mg2+ differed significantly; P < 0.05.
	Figure 6. Low pH abolishes Mg2+ modulation of delay and activation kinetics in I287D+F324D channels. (A) Representative currents recorded at pH 5.5 (top) or pH 8.0 (middle) at +20 mV in the absence (solid trace) or at +30 mV (+20 mV at pH 5.5 only) in the presence (dashed trace) of Mg2+ have been scaled and overlaid. (Bottom) Representative currents recorded at pH 5.5 in the absence of Mg2+ (solid trace; +20 mV) or at pH 8.0 in the presence of Mg2+ (dashed trace; +30 mV) have been scaled and overlaid. Arrows indicate start of voltage pulse (t = 0). (B) Bar graph shows τact values measured at pH 5.5, 6.5, 7.5, or 8.0 in the absence (open bars; +20 mV) or presence (filled bars; +30 mV, except for +20 mV at pH 5.5) of Mg2+. Data are provided as mean ± SEM; n = 8–11. Asterisk (*), τact values measured in the presence and absence of Mg2+ differ significantly; P < 0.05 by ANOVA. Values of τact for I287D+F324D in the absence of Mg2+ were 15 ± 1 ms (pH 5.5), 7 ± 0.3 ms (pH 6.5), 9 ± 1 ms (pH 7.5), and 8 ± 0.4 ms (pH 8). Values of τact for I287D+F324D in the presence of Mg2+ were 14 ± 2 ms (pH 5.5), 14 ± 1 ms (pH 6.5), 16 ± 1 ms (pH 7.5), and 17 ± 1 ms (pH 8). (C) Bar graph shows delay before pore opening measured at pH 5.5, 6.5, 7.5, or 8.0 in the absence (open bars; +20 mV) or presence (filled bars; +30 mV, except for +20 mV at pH 5.5) of Mg2+. Data are provided as mean ± SEM; n = 9–15. Asterisk (*), delay values measured in the presence and absence of Mg2+ differ significantly; P < 0.05 by ANOVA. Values of the delay for I287D+F324D in the absence of Mg2+ were: pH 5.5, 5.7 ± 0.2 ms; pH 6.5, 1.5 ± 0.1 ms; pH 7.5, 3.5 ± 0.2 ms; pH 8.0, 2.9 ± 0.2 ms. Values of the delay for I287D+F324D in the presence of Mg2+ were: pH 5.5, 5.0 ± 0.4 ms; pH 6.5, 3.6 ± 0.2 ms; pH 7.5, 6.7 ± 0.4 ms; pH 8.0, 7.3 ± 0.3 ms.
	Figure 7. Low pH abolishes Mg2+ modulation of activation kinetics in E283A+I287D+F324D channels. (A) Representative currents recorded at pH 5.5 (top) or pH 8.0 (middle) at +20 mV in the absence (solid trace) or at +30 in the presence (+20 mV at pH 5.5 only) (dashed trace) of Mg2+ have been scaled and overlaid. (Bottom) Representative currents recorded at pH 5.5 in the absence of Mg2+ (solid trace; +20 mV) or at pH 8.0 in the presence of Mg2+ (dashed trace; +30 mV) have been scaled and overlaid. Arrows indicate start of voltage pulse (t = 0). (B) Bar graph shows τact values measured at pH 5.5, 6.5, 7.5, or 8.0 in the absence (open bars; +20 mV) or presence (filled bars; +30 mV, except for +20 mV at pH 5.5) of Mg2+. Data are provided as mean ± SEM; n = 8–11. Asterisk (*), τact values measured in the presence and absence of Mg2+ differ significantly; P < 0.05 by ANOVA. Values of τact for E283A+I287D+F324D in the absence of Mg2+ were 13 ± 1 ms (pH 5.5), 8 ± 1 ms (pH 6.5), 11 ± 1 ms (pH 7.5), and 10 ± 1 ms (pH 8). Values of τact for E283A+I287D+F324D in the presence of Mg2+ were 13 ± 2 ms (pH 5.5), 15 ± 1 ms (pH 6.5), 17 ± 1 ms (pH 7.5), and 17 ± 1 ms (pH 8). (C) Bar graph shows delay before pore opening measured at pH 5.5, 6.5, 7.5, or 8.0 in the absence (open bars; +20 mV) or presence (filled bars; +30 mV, except for +20 mV at pH 5.5) of Mg2+. Data are provided as mean ± SEM; n = 8–14. Asterisk (*), delay values measured in the presence and absence of Mg2+ differ significantly; P < 0.05 by ANOVA. Values of the delay for E283A+I287D+F324D in the absence of Mg2+ were: pH 5.5, 6.4 ± 0.2 ms; pH 6.5, 2.0 ± 0.2 ms; pH 7.5, 3.1 ± 0.3 ms; pH 8.0, 3.1 ± 0.2 ms. Values of the delay for E283A+I287D+F324D in the presence of Mg2+ were: pH 5.5, 5.8 ± 0.4 ms; pH 6.5, 3.7 ± 0.2 ms; pH 7.5, 6.9 ± 0.4 ms; pH 8.0, 7.0 ± 0.3 ms.
	Figure 8. Mg2+ shifts the voltage dependence of gating charge movement in I287D+F324D channels, but not in control (W434F) or I287D channels. Gating currents were recorded from (A) I287D+F324D, (B) W434F, or (C) I287D channels in the absence (left) or presence (middle) of Mg2+. From a holding potential of −90 mV, 60-ms (A), 40-ms (B), or 25-ms (C) test pulses to voltages between −120 and +18 mV were applied in 3-mV increments. Every third pulse is shown. (Right) ON gating currents recorded in the absence (■) or presence (○) of Mg2+ were integrated to obtain the gating charge (Q), which was normalized to the maximum charge obtained in the experiment, and plotted versus voltage. Data were fitted with the sum of two Boltzmann functions to obtain values for V1/2 and apparent valence (z) for the q1 and q2 components of gating charge. Fitted parameters are provided in Table I.
	Figure 9. Mg2+ slows gating charge movement in I287D+F324D channels, but not in control (W434F) or I287D channels. Gating currents were recorded from (A) I287D+F324D, (B) W434F, or (C) I287D channels in the absence or presence of Mg2+ using the pulse protocols described in the Fig. 8 legend. (Left) Representative ON gating current traces obtained at −9 mV in the absence (solid trace) or presence (dashed trace) of Mg2+ have been scaled and overlaid. (Right) Gating current traces recorded in the absence (■) or presence (○) of Mg2+ were fitted with a single-exponential component to obtain values for τon, which have been plotted versus voltage. In A, values of τon measured in the presence andabsence of Mg2+ differed significantly from −21 to +18 mV; P < 0.05 by ANOVA. Values of τon obtained at −9 mV are shown in Table II.
	Figure 10. Threaded models of Shaker-IR and I287D+F324D based on Kv1.2/Kv2.1 chimera structure. (A) I287 and F324 are closely apposed in threaded Shaker-IR model. Side (left) and top (right) views are shown. S1 (light blue), S2 (yellow), S3 (red), and S4 (dark blue) transmembrane segments are pictured in cartoon form. Selected side chains are shown: I287 in S2 and F324 in S3b (green); acidic residues E283 and E293 in S2 and D316 in S3 (yellow and red); basic residues R362, R365, R368, R371, K374, and R377 in S4 (gray and blue). A subset of side chains are labeled to provide landmarks. S4 positively charged residues are labeled with a generic nomenclature (R1–R6). Dotted black line connects atoms of I287 and F324 that are ∼4.0 Å apart. (B) Aspartate residues introduced at I287D and F324D are closely apposed and located at the interface between the voltage sensor domain and the hydrophobic core of the membrane. Side (left) and top (right) views of I287D+F324D double-mutant model. Color code and labeling are the same as in A, except that the mutations I287D and F324D are shown in green and red. Dotted black line connects oxygen atoms of D287 and D324 that are ∼3.8 Å apart. (C) I287D and F324D are able to simultaneously coordinate a Mg2+ ion. Side (left) and top (right) views of I287D+F324D double-mutant model. Transmembrane segments S1–S4 are shown in ribbon form using the same color code as in A. Bound Mg2+ ion is shown as a green sphere. Color code and labeling are the same as in B. The figure was made using PyMOL (DeLano, 2002).

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