Edmond MA , Hinojo-Perez A , Wu X , Perez Rodriguez ME , Barro-Soria R .

R01NS110847 NINDS NIH HHS , R01 NS110847 NINDS NIH HHS

                epilepsy

	Figure 1. State-dependent modification of KCNQ2-R198C by external methanethiosulfonate (MTSET) is consistent with outward S4 motion. (A) Cartoons showing cysteine accessibility method with MTSET and two-electrode voltage clamp setup. (B) Sequence alignment of homologous S4 residues in KCNQ2, KCNQ3, KCNQ1, and Shaker channels. (C, E, and G) Currents from oocytes expressing (C) KCNQ2-N190C, (E) R198C, and (G) F202C channels in response to 20 mV voltage steps from –140 mV to +40 mV (left panels) before and after applications of MTSET (after washout, gray) in the closed and (after washout, color-coded) open states. MTSET is first applied (‘closed state’-middle panels) at –80 mV for 5 s in between 25 s washouts for 8–15 cycles and the change in current is measured at +20 mV. On the same cell and after MTSET is washed out of the bath, MTSET is reapplied (‘open state’-middle panels) at +20 mV using a similar protocol. We used 100 μM MTSET in (C) and (G), and 50 μM MTSET in (E). (D, F, and H) Steady-state conductance/voltage relationships, G(V)s, (lines from a Boltzmann fit) of (D) KCNQ2-N190C, (F) R198C, and (H) F202C channels normalized to peak conductance before MTSET application (black). The G(V) relationships after MTSET application in the closed (–80 mV, gray) and open (+20 mV, color-coded) states are obtained from recordings of panels (C), (E), and (G), (‘closed- and open state’-middle panels, respectively); mean ± SEM, n=3–24. (I) The rate of MTSET modification of R198C channels at +20 mV (red squares) or –80 mV (gray squares) was measured using the difference in current amplitudes taken at 400 ms after the start of the +20 mV voltage step, vertical dashed arrows in (E) between the first sweep (before MTSET application, which is represented by #0 along the vertical dashed arrows in (E) and normalized to zero) and the subsequent sweeps (after several MTSET application which are represented by #1, 2, …8–9 along the vertical dashed arrows in (E)) from the ‘closed-state and open-state’-middle panels. The normalized delta current amplitude was plotted versus the cumulative MTSET exposure and fitted with an exponential. The fitted second-order rate constant in the open state protocol is shown in red. kopen = 3230 ± 3.8 M–1 s–1 (n=8). (J) Cartoon representing the voltage-dependent cysteine accessibility data. MTSET modifies N190 in both the closed and open states. While F202 remains unmodified in both states (seemingly buried in the membrane), R198 becomes accessible only in the open state. Dashed line indicates the proposed outer lipid bilayer boundary.
	Figure 2. Labeled KCNQ2-F192C channels track S4 movement. (A) Cartoon showing the topology of one KCNQ2 subunit and the residues in the S3–S4 linker that were sequentially mutated to cysteine. (B) Currents from oocytes expressing a series of cysteine mutants in the S3–S4 linker of KCNQ2 channel. Cells are held at –80 mV and stepped to potentials between −140 mV and +40 mV in 20 mV steps for 2 s followed by a tail to –40 mV. (C) Normalized G(V) (lines from a Boltzmann fit) curves from (open symbols) unlabeled and (filled symbols) Alexa-488-maleimide labeled wt and cysteine mutations shown in (B). The midpoints of activation for the fits are shown in Supplementary file 1. Data are mean ± SEM, n=5–24; see Materials and methods. (D) Summary of G(V)1/2 values for the wt and cysteine mutants (open symbols) before and (filled symbols) after Alexa-488-maleimide labeling. (E) Cartoon representing the voltage clamp fluorometry (VCF) technique. A cysteine is introduced at position 192 (close to the voltage sensor [S4]) and labeled with a fluorophore tethered to a maleimide group (Alexa-488–5 maleimide). Upon voltage changes, labeled-S4s move and the environment around the tethered fluorophore changes, altering fluorescence intensity. Both current and fluorescence are recorded simultaneously using a VCF set up. (F) Representative current (black) and fluorescence (cyan) traces from Alexa-488-labeled KCNQ2-F192C channels (KCNQ2*) for the indicated voltage protocol (top). A sweep to 0 mV is depicted in red to facilitate comparison of time courses in (H–I). (G) Normalized G(V) (black solid lines from Boltzmann fit) and F(V) (cyan circles and cyan solid line from a Boltzmann fit) curves from (black circles) F192C-Alexa-488 ‘KCNQ2*’, (black squares) unlabeled F192C, and (gray squares) wt channels. The midpoints of activation for the fits are: GV1/2F192C-Alexa-488 = –77.1 ± 2.7 mV, (n=9), FV1/2F192C-Alexa-488 = –87.1 ± 3.9 mV, (n=8), GV1/2 unlabeled-F192C = –55.8 ± 0.8 mV, (n=9), and GV1/2wt = –43 ± 0.7 mV, (n=21), Supplementary file 1. Data are mean ± SEM; see Materials and methods. (H) Representative current time courses of (gray) wt, (black) F192C, and (red) F192C-Alexa-488 channels in response to the protocol shown on top. The dashed line represents 50% of the maximum current level at the end of the depolarizing pulse. (I) The time courses of current activations are quantified as the time to reach half the maximum current level at the end of the depolarizing pulse in (H, dashed line). Data are presented as mean ± SEM, n=9–21. Statistical significance was determined using ANOVA and Tukey’s post hoc test, and significance level was set at p<0.05. Asterisks denote significance: p<0.05*. V: voltage; PD in this cartoon represents: photodiode photodetector.
	Figure 3. Fluorescence from KCNQ2* correlates with channel opening. (A–D) Representative current (black) and fluorescence (cyan) traces from KCNQ2* channels for the activation (A) and deactivation (C) voltage protocols (top). In response to the prepulse to −120 mV, the fluorescence signal decreases (cyan dashed arrow), indicating that not all voltage sensors were in their resting position at the holding potential (−80 mV). Representative experiments showing time courses of (B) activation and (D) deactivation of current (black) and fluorescence (cyan) signals from KCNQ2* channels at different voltages as in (A) and (C), respectively. Note that the current and the fluorescence signals correlate during both channel activation and deactivation.
	Figure 4. Accessibility of residue A193C supports voltage-dependent motion of S4 segment. (A) Cartoon representing extracellular cysteine accessibility of residue A193C as in Figure 1A. (B) Currents in response to +20 mV voltage steps before (gray trace #0) and during several 5 s applications of methanethiosulfonate (MTSET) at +20 mV (green traces #1–7), –100 mV (blue traces #1–12), and –140 mV (black traces #1–19) on A193C channels for the indicated voltage protocol. We repeat MTSET applications (10 μM at +20 and –100 mV, and 20 μM at –140 mV) in between 25 s washouts as shown in each voltage protocol. (C) Normalized current of A193C during MTSET exposure at +20 mV (green), 0 mV (orange), – 80 mV (pink), –100 mV (blue), and – 140 mV (black). (D and E) Normalized G(V) curves (squares and black line from a Boltzmann fit) of A193C channels and voltage dependence of the modification rate (mod. rate [V], green circles and green line from a Boltzmann fit) for MTSET to residue A193C. In (E), dashed lines represent ‘wt’ KCNQ2* (black) G(V) and (cyan) F(V) curves for comparison. (E’) Summary of G(V)1/2 for (open squares) A193C and (open gray circles) labeled F192C-Alexa channels. Data are presented as mean ± SEM, n=9–12. Statistical significance was determined using paired Student t-test and significance level was set at p<0.05, p=0.062. The midpoints of activation for the fits are: GV1/2A193C = – 70 ± 2.4 mV, (n=12) and GV1/2F192C-Alexa = –77.1 ± 2.7 mV, (n=9); Mod. rate V1/2 A193C = –72.8 ± 24.5 mV, (n=3–8); GV1/2A193C = – 70 ± 2.4 mV, (n=12); see Figure 2G for KCNQ2* GV1/2 and FV1/2, values.
	Figure 5. Disease-causing mutations in KCNQ2 channels differentially affect S4 and gate domains. (A) Cartoon representing the voltage-clamp fluorometry (VCF) technique as in Figure 2A. The localization of the two epilepsy-associated mutations - R198Q (red) and R214W (maroon) are shown. (B) Representative (black) current and (red) fluorescence traces from KCNQ2*-R198Q channels for the indicated voltage protocol (top). (B’) Comparison of the (black) time course of current activation and (red) fluorescence signals from KCNQ2*-R198Q channels in response to the voltage protocol shown. (C) Normalized G(V) (black triangles and black solid line from a Boltzmann fit) and F(V) (red triangles and red solid line from a Boltzmann fit) curves from KCNQ2*-R198Q. (D) Representative (black) current and (maroon) fluorescence traces from KCNQ2*-R214W channels for the indicated voltage protocol (top). (D’) Comparison of the (black) time course of current activation and (maroon) fluorescence signals from KCNQ2*- R214W channels in response to the voltage protocol shown. (E) Normalized G(V) (black squares and black solid line from a Boltzmann fit) and F(V) (maroon squares and maroon solid line from a Boltzmann fit) curves from KCNQ2*- R214W. (C and E) Dashed lines represent KCNQ2-F192C labeled with Alexa-488 (KCNQ2*) G(V) (black) and F(V) (cyan) curves for comparison. The same color code for the two KCNQ2 mutations is shown throughout the figure. The midpoints of activation of the fits are (GVR198Q 1/2 = –110.3 ± 3.5 mV, (n=10), FVR198Q 1/2 = –119.8 ± 4.2 mV, [n=4], GV214W 1/2 = –17.1 ± 0.9 mV, [n=8], and FVR214W 1/2 = – 77 ± 0.6 mV, [n=7]) and in Supplementary file 1. Data are mean ± SEM.
	Supplementary Figure 1. State-dependent modification of S4 residues by external methanethiosulfonate (MTSET) consistent with outward S4 motion. (A, C, D, E, F, and G) Currents from oocytes expressing (A) wild type (wt), (C) A193C, (D) S195C, (E) A196C, (F) S199C, and (G) L200C channels in response to 20 mV voltage steps from –140 mV to +40 mV (left) before and after applications of MTSET (middle) at hyperpolarized voltages (–80 mV for S195C and A196C, –100 mV for S199C and L200C, and –120 mV for A193C) and (right) a depolarized voltage at +20 mV. We repeat 5 s MTSET application in between 25 s washouts for 8–15 cycles, as shown in the open and closed protocols in Figure 1C. We used MTSET concentrations ranging from 10 to 100 μM, respectively. (B) Summary of G(V)1/2 values for the wt and cysteine mutants before MTSET application. Insets represent exemplar current traces of MTSET modification measured at +20 mV in both the (middle) closed and (right) open states. Scale bars: 1 s, 1μA. (A’, C’, D’, E’, F’, and G’) Normalized G(V) relations (lines from a Boltzmann fit) of recordings from panels (A), (C), (D), (E), (F), and (G), respectively, before (black) and after MTSET application in the (gray) closed and (color-coded) open states. The G(V)s after MTSET modification of recordings from panels (A), (C), (D), (E), (F), and (G) were normalized to peak conductance before MTSET application (black). mean ± SEM, n=3–21. Summary of (C’’, D’’, E’’, F’’, and G’’) relative change in current amplitude at +40 mV and (C’’’, D’’’, E’’’, F’’’, and G’’’) voltage dependence shift of MTSET-mediated modification of the cysteine mutants in (gray) the closed and (color-coded) open states. Mean ± SEM, n=3–15. Due to the non-saturating G(V) at negative voltages in A193C, S195C, and A196C after MTSET application in the open state, we used the voltages at the midpoint of the measured G(V) curves to calculate the estimated minimum shifts in voltage dependences in (C’’’, D’’’, E’’’), respectively. Statistical significance was determined using the paired Student’s t-test and significance level was set at p<0.05. Asterisks denote significance: p<0.05*, p<0.01**, p<0.001***. (H) Cartoon representing the voltage-dependent cysteine accessibility data from all residues assayed. Unlike residue N190 (yellow) that is modified by MTSET in both closed and open states (always exposed), residue F202 (brown) remains unmodified in both closed and open states (buried in the membrane). A stretch of eight to nine amino acids (193 to 200–201) moves from a membrane-buried position in the closed state to the extracellular solution during channel opening. Note that because R201C produces voltage-independent channels, we cannot test the state-dependent modification of MTS reagents. The dashed line indicates the proposed outer lipid bilayer boundary. Only two subunits of the tetrameric channel are shown.
	Supplementary Figure 2. Fast perfusion system delivers 5 s applications of external solution exchange to whole oocytes. Representative time course of solution exchange from 100 mM NaCl (Na) to 100 mM KCl (K). Currents from KCNQ2 channels in response to a +20 mV pulse from a holding potential of –80 mV followed by a tail potential of –80 mV. Extracellular solution was ND96 (100 mM NaCl) except for the 5 s application for which the 100 mM NaCl was exchanged for 100 mM KCl. Shown are three cycles of solution exchanging as shown in the protocol (top). The application of 100 mM KCl quickly reduces (τ=0.21 ± 3.6 s) the outward currents, and the reintroduction of the 100 mM NaCl quickly (τ=0.32 ± 1.5 s) restores the currents.
	Supplementary Figure 3. Summary of modification of N190C, R198C, and F202C in the closed and open states by external methanethiosulfonate (MTSET). Summary of (A, C, and E) relative change in current amplitude at +40 mV and (B, D, and F) voltage of half activation shift of MTSET-mediated modification of the cysteine mutants in (gray) the closed and (color-coded) open states. Mean ± SEM, n=3–24. Statistical significance was determined using the paired Student’s t-test and significance level was set at p<0.05. Asterisks denote significance: p<0.01**, p<0.001***.
	Supplementary Figure 4. Modification of N190C in the open state by external methanethiosulfonate (MTSET). (A) Currents from oocytes expressing KCNQ2-N190C channels in response to 20 mV voltage steps from –140 mV to +40 mV (black) before and (yellow) after application of MTSET in the open state. The middle panel in (A) shows currents in response to a +20 mV voltage step during MTSET application on N190C channels in the open state for the indicated voltage protocol. MTSET is applied at +20 mV for 5 s in between 25 s washouts for 8–15 cycles, and the change in current is measured at +20 mV. (B) Steady-state conductance/voltage relationships, G(V), (lines from a Boltzmann fit) of N190C channels normalized to peak conductance before MTSET application (black). The G(V) relationships of N190C channels before and after MTSET application in the open state (+20 mV, yellow) are obtained from recordings of (A, left and right panels, respectively). Summary of (C) relative change in current amplitude and (D) voltage dependence shift of MTSET-mediated modification of N190C channels in the open state. Mean ± SEM, n=5–24. Statistical significance was determined using the paired Student’s t-test (from before) and significance level was set at p<0.05. Asterisks denote significance: p<0.01**.
	Supplementary Figure 5. Proposed molecular motions of S4 residues in KCNQ2 channels. (A and C) KCNQ2 homology model in the closed resting state (S4 down) and (B and D) cryo-EM structure of KCNQ2 channel in the activated state of S4 (up) and closed pore. The homology model of KCNQ2 channels with S4 in the resting (down) state was created using the Swiss-model program (https://swissmodel.expasy.org/) with the model of KCNQ1 in the resting state (Kuenze et al., 2019), as template. The homology model of KCNQ2 channels with S4 in the activated (up) state (Li et al., 2021b): PDB code for KCNQ2: 7CR0. (A) In the resting state, R1 and R2 in S4 (cyan) localize above and below the gating charge transfer center F137 (red stick), respectively. (B) Upon S4 activation, R1 and R2 move about three helical turns outward from F137 into a position close to or within the extracellular space. One subunit is shown as ribbons and key amino acid residues as sticks. (C–D) Proposed molecular motions of S4 residues from (C) resting to (D) activated states from cysteine accessibility data. A buried (red spheres) stretch of eight to nine amino acids (193 to 200–201) in the resting state (C) becomes exposed to the extracellular space (green spheres) in the activated state (D). The four subunits are shown as ribbons and buried and extracellularly exposed residues in the S4 are shown as red and green spheres, respectively. Dotted lines indicate the proposed inner and outer lipid bilayer boundary. All images were generated using UCSF ChimeraX, version 1.1 (2020-10-07). VSD: voltage sensing domain; PD: pore domain.
	Supplementary Figure 6. Cysteine-scan mutagenesis of S3–S4 linker identifies F192C as the ideal position for fluorophore labeling. (A) Summary of the time courses of current activation for the wt and cysteine mutants quantified as the time to reach half the maximum current level at the end of the 0 mV pulse in Figure 2B. Data are presented as mean ± SEM, n=5–24. Statistical significance was determined using ANOVA and Tukey’s post hoc test; significance level was set at p<0.05. Asterisks denote significance: p<0.05*, p<0.001***. (B) Representative (black) current and (yellow) fluorescence traces from Dylight-488-labeled KCNQ2-F192C channels (KCNQ2*) for the indicated voltage protocol (top). (C, top panels) Comparison of time courses of (left) current activation and (right) fluorescence signals from (yellow) Dylight-488 and (cyan) Alexa-488-labeled KCNQ2* channels in response to the voltage protocol shown on top. The dashed lines represent 50% of the maximum (left) current and (right) fluorescence levels at the end of the normalized pulse. The time course of current activation (black solid line) curve of unlabeled F192C is shown. (C) The time courses of (left) current and (right) fluorescence are quantified as the time to reach half the maximum current and fluorescence levels at the end of the depolarizing pulse in (C, top). For comparison, the time courses of current for the (gray) wt and (black) unlabeled F192C are also shown. Data are presented as mean ± SEM, n=8–21. Statistical significance for the current and fluorescence was determined using ANOVA and Tukey’s post hoc test and paired-t test, respectively. Significance level was set at p<0.05. Asterisks denote significance: p<0.01**. (D) Normalized G(V) (open symbols and dashed lines from a Boltzmann fit) and F(V) (closed symbols and solid cyan and yellow lines from a Boltzmann fit) curves from (yellow) Dylight-488 and (cyan) Alexa-488-labeled KCNQ2* channels. For comparison, the G(V) relationships of (solid gray line) wt and (solid black line) unlabeled F192C channels are shown. Data are mean ± SEM, (n=8–21). The midpoints of activation for the fits are: GV1/2F192C-Alexa-488 = –77.1 ± 2.7 mV, (n=9) and FV1/2F192C-Alexa-488 = –87.1 ± 3.9 mV, (n=8), GV1/2F192C-Dylight-488 = –79.9 ± 1.4 mV, (n=11) and FV1/2F192C-Dylight-488 = –94.7 ± 1.8 mV, (n=8), GV1/2 unlabeled-F192C = –55.8 ± 0.8 mV, (n=9), and GV1/2wt = –43 ± 0.7 mV, (n=21), Supplementary file 1. (E–F) Representative (top panels) current and (bottom panels) fluorescence traces from (E) Dylight-488 and (F) Alexa-488-incubated wt-KCNQ2 channels.
	Supplementary Figure 7. Gating properties of the epilepsy-associated mutations - R198Q and R214W. (A, B) Representative normalized current time courses of (A) activation and (B) deactivation from labeled (black) F192C, (red) R198Q ,and (maroon) R214W mutated channels in response to the indicated voltage steps. The dashed lines in (A) and (B) represent 50% of the normalized current levels at the end of the pulse. (C) Summary of the time courses of (open symbols) current and (filled symbols) fluorescence is quantified as the time to reach 50% maximum level at the end of the depolarizing pulse as in (A and the fluorescence, inset). (D) Summary of Tau values for deactivation of current for (black) F192C, (red) R198Q, and (maroon) R214W, respectively. (E) Summary of (open symbols) G(V)1/2 and (filled symbols) F(V)1/2 values for the (cyan) F192C, (red) R198Q, and (maroon) R214W. Data is presented as mean ± SEM, n=8–11. Statistical significance was determined using ANOVA and Tukey’s post hoc test, and significance level was set at p<0.05. Asterisks denote significance: p<0.05*.
	Supplementary Figure 8. PIP2 tightly joints the loop connecting S4 and S4–S5 linker to facilitate channel opening. Cryo-EM structure of KCNQ2 channel in the activated state (S4 [up] and closed pore showing (A) the localization of residue R214 [sphere] in the loop connecting S4 [cyan] and S4–S5 linker, and (B) the position of PIP2 relative to R214 within the S4/S4–S5 interface of KCNQ2 channels). PDB code for KCNQ2: 7CR0. All images were generated using UCSF ChimeraX, version 1.1 (2020-10-07).

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