Ferrick-Kiddie EA , Rosenthal JJ , Ayers GD , Emeson RB .

U54 HD083211 NICHD NIH HHS , T32 DK007563 NIDDK NIH HHS , F31 NS087911 NINDS NIH HHS , R01 NS064259 NINDS NIH HHS , P20 GM103642 NIGMS NIH HHS , R01 NS087726 NINDS NIH HHS

	Figure 1. Quantitative analysis of in vitro RNA editing rates for wild-type and mutant Kv1.1 transcripts.(a) The predicted secondary structure for a portion of the wild-type (WT) Kv1.1 pre-mRNA is indicated with the positions of the A-to-I editing site (I400 V) and three non-synonymous mutations associated with EA1 shown with inverse lettering. (b) Wild-type and mutant Kv1.1 RNA minigenes, encompassing the duplex region required for editing, were in vitro transcribed and incubated with nuclear extracts prepared from HEK293 cells transiently expressing rat ADAR2. The extent of editing was quantified by high-throughput sequence analysis as described previously33 and used to calculate the editing rate. Single exponential curves were fitted to the data for emphasis. Statistical differences were determined for replicates at the 2 nM RNA concentration (mean ± SEM, n = 4 replicate reactions, *p ≤ 0.05; ****p ≤ 0.0001). Small error bars were obscured by the data symbols in some cases.
	Figure 2. Quantitative analysis of allele-specific Kv1.1 editing in V408A mutant mice.The extent of editing for the wild-type and mutant alleles in heterozygous V408A adult mice (V408A/+), compared to wild-type littermates, was determined for RNA isolated from dissected brain regions and spinal cord by high-throughput sequence analysis (mean ± SEM, n = 4, ***p ≤ 0.001, ****p ≤ 0.0001). Cbl, cerebellum; Hyp, hypothalamus; Hip, hippocampus; Ctx, cortex; Str, striatum; Olf, olfactory bulb; Sp C, spinal cord.
	Figure 3. Voltage-dependence of non-edited compared to edited mutant channels.Whole-cell K+ currents were recorded from oocytes expressing either the non-edited (N) or edited (E) isoforms of homotetrameric wild-type (WT), V404I, I407M, or V408A Kv1.1 channels. Test potentials were elicited in 10 mV voltage steps from −50 to 40 mV, from a holding potential of −80 mV. (a) Representative activating traces at −20 and 40 mV are shown for each construct. (b,c) Conductance (G) versus voltage plots are shown where data have been normalized to the maximal conductance (Gmax), demonstrating shifts in voltage dependence for (b) I407M and (c) V404I (mean ± SEM, n = 4–8 oocytes). Normalized conductance was measured from tail current amplitude. Small error bars were obscured by the data symbols.
	Figure 4. Editing alters gating kinetics of I407M and V404I channels.(a) Representative activation traces, depicting whole-cell currents, were recorded from oocytes expressing either the I407M N or I407M E channel. Test potentials were elicited in 10 mV voltage steps from −10 to 80 mV, from a holding potential of −80 mV. (b) Activation kinetics were measured as the time to reach half-maximal current amplitude (mean ± SEM, n = 3–7 oocytes). I407M N and I407M E channels were significantly slowed in their time to half-activation compared to each other, in the voltage range −10 to 70 mV (0.05 > p ≥ 0.0008). I407M N was significantly slower than WT N at all voltages (p ≤ 0.0001) and I407M E was significantly slower than WT E at all voltages (0.01 > p ≥ 0.0001). (c) Representative tail current traces, depicting whole-cell K+ currents, were recorded from oocytes expressing either the V404I N or V404I E channel. Following a holding potential of −80 mV and a depolarizing pulse to 20 mV, test potentials were elicited in 10 mV voltage steps from −120 to −60 mV. (d) Closing kinetics were determined by fitting the tail currents with single exponential curves to determine the associated τ value; (mean ± SEM, n = 3–6 oocytes). V404I N channels closed slower than V404I E from −120 to −100 mV (0.05 > p ≥ 0.0066). V404I N channels closed slower than WT N at all voltages (p < 0.0001) and V404I E channels closed significantly slower than WT E channels from −120 to −80 mV (0.01 ≥ p ≥ 0.0005). Small error bars were obscured by the data symbols in some cases.
	Figure 5. Editing slows Kvβ1.1-induced inactivation kinetics of I407M and V408A channels.(a,c) Representative β-inactivation traces, depicting whole-cell K+ currents, were recorded from oocytes co-expressing the Kvβ1.1 subunit and either the (a) I407M or (c) V408A channel, in the non-edited (N) or edited (E) isoform. Test potentials were elicited in 10 mV voltage steps from 10 to 80 mV, from a holding potential of −80 mV. (b,d) Inactivation kinetics were measured by fitting single exponential curves to the test pulse currents, to determine the associated τ value (mean ± SEM, n = 3–6 oocytes). (b) I407M E channels were significantly slower to inactivate than I407M N channels at every voltage (p ≤ 0.0001) and both I407M N and I407M E channels were slower than WT N and WT E channels, respectively, at every voltage (p ≤ 0.0001). (d) V408A E channels were significantly slower than V408A N channels from 10 to 50 mV (0.05 > p ≥ 0.0005). V408A E channels were slower than WT E channels from 10 to 60 mV (0.05 > p ≥ 0.0001). V408A N channels were significantly slower than WT N channels at all voltages (p ≤ 0.0001). Small error bars were obscured by the data symbols in some cases.
	Figure 6. Editing alters the recovery from Kvβ1.1-induced inactivation in V404I, I407M, and V408A channels.Whole-cell K+ currents were recorded from oocytes co-expressing the Kvβ1.1 subunit and either a non-edited (N) or edited (E) isoform of the wild-type (WT) or mutant Kv1.1 channel. (a) Representative I407M N and I407M E recovery traces are overlaid to depict the increased rate of recovery from β-inactivation, typical of an E isoform. A two-pulse protocol was used, eliciting a depolarizing pulse to 80 mV followed by a variable interpulse duration at −80 mV before a final depolarizing pulse at 80 mV. Recovery from β-inactivation was plotted as the time for the second pulse to regain the current amplitude of the first pulse. (b) τ values were determined by fitting single exponential curves to the recovery plots (mean ± SEM, n = 3–7 oocytes, ***p ≤ 0.001, ****p ≤ 0.0001).

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