Hirazawa K, Tateyama M, Kubo Y, Shimomura T.

	Figure 1. Schematic presentation of the two hypothetical models. Molecular structure of TPC3 homodimer and PI(3,4)P2 are schematically presented based on the high resolution structure of Danio rerio TPC3 (PDBID: 6V1Q) (26). Two subunits in the homodimer are drawn in dark and pale colors, respectively. Upper panels, side view of TPC3. The flow of the signal induced by PI(3,4)P2 binding is indicated by red arrows. The target domain of this signal transmission could be located in the same and/or another subunit compared with the PI(3,4)P2 binding site, and thus the PDs from both subunits are highlighted by yellow ovals, showing the ambiguity of the pathway of the signal transmission. In ‘local modulation’ (left), the effect of PI(3,4)P2 binding is confined around the pore domain, and thus the gate-opening step is potentiated without any effect on the second VSD. In ‘global modulation’ (right), the voltage-dependent structural rearrangement of the second VSD, especially the movement of the second S4 which governs the gate-opening, is also remotely modulated by PI(3,4)P2 binding to the first repeat. Lower panels, bottom-up view of TPC3 from the intracellular side. PI(3,4)P2 is depicted by red ovals. The intra-subunit interaction between the first and the second PD, which is critical for the potentiation of the voltage-dependent gating by PI(3,4)P2 (25) is depicted by pink bars. PD, pore domain; S4, the fourth helix; TPC3, two-pore channel 3; VSD, voltage sensor domain.
	Figure 2. Characterization of D511C-TPC3 for Cys-accessibility analysis.A, a schematic presentation of the two repeats-type structure of TPC3 and the Cys-accessibility analysis using MTSES to detect structural change of the second S4 of TPC3. VSD and PD are colored in green and brown, respectively. The arginine residues in the second VSD are depicted as +. PI(3,4)P2 is also depicted around the binding site. B, a homology model of the second VSD in the XtTPC3 structure. It is based on the structure of mouse TPC1 (PDBID: 6C9A) (19). D511, which was mutated to Cys in this study is presented as sticks. C, representative TPC3 current traces recorded in the presence of 0.5 mM MTSES. These experiments were performed in the presence of PI(3,4)P2. The current traces at the beginning (black), in the middle (light green), and at the end of the experiment (green) are shown to represent the MTSES-dependent current change. The upper panel shows current traces of D511C-TPC3 and the lower panel shows those of TPC3 (WT). D, the G-V relationships of WT or D511C-TPC3 after incubation without or with 0.5 mM MTSES in the presence of PI(3,4)P2. The color codes are as follows. Gray: WT without MTSES, black: WT with MTSES, pink: D511C-TPC3 without MTSES, and red: D511C-TPC3 with MTSES. The V1/2 values and slope factors are as follows. WT without MTSES (V1/2: 64.1 ± 4.1 mV and slope factor: 25.5 ± 3.7 mV (n = 3)), WT with MTSES (V1/2: 63.1 ± 3.1 mV and slope factor: 21.3 ± 1.4 mV (n = 3)), D511C-TPC3 without MTSES (V1/2: 111.6 ± 24.3 mV and slope factor: 26.9 ± 12.1 mV (n = 8)), and D511C-TPC3 with MTSES (V1/2: 69.2 ± 12.8 mV and slope factor: 25.9 ± 10.0 mV (n = 5)). The results of the statistical analyses of the V1/2 values are as follows (One-way ANOVA with Tukey’s test): WT without MTSES versus WT with MTSES: p = 1.000, WT without MTSES versus D511C-TPC3 without MTSES: p = 0.012, and D511C-TPC3 without MTSES versus D511C-TPC3 with MTSES: p = 0.008. p < 0.05 was considered statistically significant. G-V relationship, conductance-voltage relationship; MTSES, 2-sulfonatoethyl methanethiosulfonate sodium salt; PD, pore domain; S4, the fourth helix; TPC, two-pore channel; V1/2, membrane voltage for half maximum activation; VSD, voltage sensor domain; XtTPC3, Xenopus tropicalis TPC3.
	Figure 3. Modification of D511C by MTSES is state-dependent.A, a schematic view of the possible voltage dependence of the MTSES-modification rate due to the movement of the second S4. B, representative TPC3 current traces recorded in the presence of 0.5 mM MTSES using two protocols with different lengths of depolarization (depicted as ‘less depo’ and ‘more depo’). These experiments were performed in the presence of PI(3,4)P2. The traces are shown in the same manner as Figure 2C. C, upper panel, time-lapse change of the activation rates. The activation rates of TPC3 were obtained, as described in Experimental procedures. The data in black are the results by the ‘less depo’ protocol, and the ones in red are those by the ‘more depo’ protocol. The arrows indicate the points in which the traces in Figure 3B were recorded (indicated by the same colors). Lower panel, time-lapse change of the normalized MTSES effect. The color codes are the same as those in the upper panel. The solid lines show the results of single exponential fit. The data points around 50 s for ‘more depo’ protocol slightly deviate from the fitting curve due to the contamination of gradual decrease in the activation rates observed in the late phase of the recording. This is presumably because of the slight decrease in the PI(3,4)P2 concentration caused by extensively repeated depolarizations. The error bars only show the upper side of the S.D. values for clarity (n = 5). For both plots, the data at the very beginning of the MTSES application are omitted because of their current instability. D, statistical comparison of the MTSES-modification rates obtained using two protocols. ‘Less depo’ protocol: 0.018 ± 0.006/s (n = 5) and ‘more depo’ protocol: 0.054 ± 0.017/s (n =5) (p = 0.004 by unpaired t test. ∗∗ means a statistically significant difference of p < 0.01). MTSES, 2-Sulfonatoethyl methanethiosulfonate sodium salt; S4, the fourth helix; TPC, two-pore channel.
	Figure 4. Analysis of the effect of R187Q mutation in D511C-TPC3.A, the model of the binding mode of PI(3,4)P2 in the first repeat in XtTPC3. This model is based on the structure of mouse TPC1 (PDBID: 6C9A) (19). Arg187, which is mutated to Gln in this experiment and the modeled PI(3,4)P2 are depicted as sticks. The positions of the carbon atoms bound to phosphate groups are indicated (C3 and C4). B, the G-V relationships of D511C-TPC3 (black) and R187Q&D511C-TPC3 (blue) without modification by MTSES in the presence of PI(3,4)P2. The V1/2 values and slope factors are as follows. D511C-TPC3 (V1/2: 100.5 ± 4.8 mV and slope factor: 22.9 ± 2.8 mV (n = 10)) and R187Q&D511C-TPC3 (V1/2: 180.0 ± 50.1 mV and slope factor: 46.1 ± 20.9 mV (n = 8)). The difference of the V1/2 values was statistically significant (p < 0.001 by unpaired t test). C, representative TPC3 current traces recorded in the presence of 0.5 mM MTSES. These experiments were performed in the presence of PI(3,4)P2. The traces are shown in the same manner as Figure 2C. The upper panel shows current traces of D511C-TPC3 (D511C), and the lower panel shows those of R187Q&D511C-TPC3 (+R187Q). D, upper and lower panels are shown in the same manner as Figure 3C. Upper panel, time-lapse change of the activation rates. The activation rates of TPC3 were obtained, as described in Experimental procedures. The data in black are the results of D511C-TPC3 and the ones in blue are those of R187Q&D511C-TPC3. Lower panel, time-lapse change of the normalized MTSES effect. The color codes are the same as those in the upper panel. The data points around 50 s for D511C-TPC3 slightly deviate from the fitting curve due to the contamination of gradual decrease in the activation rates observed in the late phase of the recording, similar to the result shown in Figure 3C. The error bars only show the upper side of the S.D. values for clarity (n = 4). For both plots, the data at the very beginning of the MTSES application are omitted because of their current instability. E, statistical comparison of the MTSES-modification rates of two constructs. D511C-TPC3: 0.043 ± 0.014/s (n = 4); R187Q&D511C-TPC3: 0.011 ± 0.005/s (n = 4) (p = 0.011 by unpaired t test. ∗ means a statistically significant difference of p < 0.05). G-V relationship, conductance-voltage relationship; MTSES, 2-Sulfonatoethyl methanethiosulfonate sodium salt; TPC, two-pore channel; V1/2, membrane voltage for half maximum activation; XtTPC3, Xenopus tropicalis TPC3.
	Figure 5. Analysis of the effect of INPP4B coexpression with D511C-TPC3.A, the G-V relationships of D511C-TPC3 only and coexpressed with INPP4B without modification by MTSES after long depolarization. The color codes are as follows: black: D511C-TPC3 and blue: D511C-TPC3+INPP4B. The V1/2 values and slope factors are as follows: D511C-TPC3 (V1/2: 99.5 ± 3.4 mV and slope factor: 27.4 ± 2.9 mV (n = 6)) and D511C-TPC3+INPP4B (V1/2: 140.4 ± 3.5 mV and slope factor: 27.4 ± 2.4 mV (n = 6)). The difference of the V1/2 values was statistically significant (p < 0.001 by unpaired t test). B, representative TPC3 current traces recorded in the presence of 0.5 mM MTSES with or without coexpression of INPP4B. These experiments were performed after long depolarization. The traces are shown in the same manner as Figure 2C. C, upper panel, time-lapse change of the activation rates. The color codes are the same as those in Figure 5A. Lower panel, time-lapse change of the normalized MTSES effect (Experimental procedures). The color codes are the same as those in the upper panel. The upper and the lower panels are shown in the same manner as Figure 3C. The data points around 75 s for D511C-TPC3 deviate from the fitting curve due to the contamination of gradual decrease in the activation rates observed in the late phase of the recording, similar to the result shown in Figure 3C. The error bars only show the upper side of the S.D. values for clarity (n = 6 for D511C-TPC3, n = 8 for D511C-TPC3+INPP4B). For both plots, the data at the very beginning of the MTSES application are omitted because of their current instability. D, statistical comparison of the MTSES-modification rates between D511C-TPC3 only and D511C-TPC3 coexpressed with INPP4B. D511C-TPC3: 0.036 ± 0.014/s (n = 6) and D511C-TPC3+INPP4B: 0.018 ± 0.003/s (n = 8) (p = 0.006 by unpaired t test. ∗∗ means a statistically significant difference of p < 0.01). G-V relationship, conductance-voltage relationship; INPP4B, inositol polyphosphate 4-phosphatase type II; MTSES, 2-Sulfonatoethyl methanethiosulfonate sodium salt; TPC, two-pore channel; V1/2, membrane voltage for half maximum activation.
	Figure 6. VCF analysis using TPC3 with fluorescent label in the extracellular side of the second S4 and comparison with the PI(3,4)P2-binding deficient mutant.A, a schematic view of the position of Q507C. B, representative results showing TPC3 current and fluorescence traces of Q507C-TPC3 (left) and R187Q&Q507C-TPC3 (right). These experiments were performed in the presence of PI(3,4)P2. The traces shown in red are the current and fluorescent traces at +180 mV, respectively. C, the G-V (upper panel) and ΔF-V (middle panel) relationships of Q507C-TPC3 (black) and R187Q&Q507C-TPC3 (blue) in the presence of PI(3,4)P2. The V1/2 values and slope factors are as follows: Q507C-TPC3 (V1/2 of G-V: 82.1 ± 1.7 mV and slope factor of G-V: 20.4 ± 2.0 mV; V1/2 of ΔF-V: 96.1 ± 11.7 mV and slope factor of ΔF-V: 26.9 ± 5.2 mV (n = 7)) and R187Q&Q507C-TPC3 (V1/2 of G-V: 119.0 ± 3.1 mV and slope factor of G-V: 18.4 ± 1.4 mV; V1/2 of ΔF-V: 112.0 ± 5.6 mV and slope factor of ΔF-V: 20.1 ± 1.8 mV (n = 7)). In the ΔF-V relationships, the results of statistical comparison of the ΔF/ΔFmax values at each membrane voltage are indicated when they showed statistical significance. p values are shown in Table S1 (unpaired t test). The lower panel shows the expanded view of the middle panel (ΔF-V), focusing on the first phase. A slight increase in the ΔF/ΔFmax value at −80 mV suggests a possibility that holding potential (−60 mV) is within the range of the membrane voltage of the first phase. D, statistical comparison of the V1/2 values described above (G-V: p < 0.001, ΔF-V: p = 0.011 by unpaired t test. ∗ and ∗∗ mean statistically significant differences of p < 0.05 and p < 0.01, respectively). ΔF-V relationship, F change-voltage relationship; G-V relationship, conductance-voltage relationship; S4, the fourth helix; TPC, two-pore channel; V1/2, membrane voltage for half maximum activation; VCF, voltage clamp fluorometry.
	Figure 7. VCF analysis of Q507C-TPC3 coexpressed with INPP4B.A, representative results showing the TPC3 current and fluorescence traces of Q507C-TPC3 (left) and Q507C-TPC3 coexpressed with INPP4B (right). These experiments were performed after long depolarization. The traces shown in red are the current and fluorescent traces at +180 mV, respectively. B, the G-V (upper panel) and ΔF-V (middle panel) relationships of Q507C-TPC3 (black) and Q507C-TPC3 coexpressed with INPP4B (blue) after long depolarization. The V1/2 values and slope factors are as follows: Q507C-TPC3 (V1/2 of G-V: 79.8 ± 3.5 mV and slope factor of G-V: 20.4 ± 2.2 mV; V1/2 of ΔF-V: 98.3 ± 5.7 mV and slope factor of ΔF-V: 19.5 ± 1.4 mV (n = 8)) and Q507C-TPC3 + INPP4B (V1/2 of G-V: 100.8 ± 8.0 mV and slope factor of G-V: 22.0 ± 1.1 mV; V1/2 of ΔF-V: 111.0 ± 5.2 mV and slope factor of ΔF-V: 19.1 ± 2.3 mV (n = 10)). In the ΔF-V relationships, the results of statistical comparison of the ΔF/ΔFmax values at each membrane voltage are indicated when they showed statistical significance. p values are shown in Table S2 (unpaired t test). The lower panel shows the expanded view of the middle panel (ΔF-V), focusing on the first phase. A slight increase in the ΔF/ΔFmax value at −80 mV suggests a possibility that holding potential (−60 mV) is within the range of the membrane voltage of the first phase. C, statistical comparison of the V1/2 values described above (G-V: p < 0.001, ΔF-V: p < 0.001 by unpaired t test. ∗∗ means a statistically significant difference of p < 0.01). ΔF-V relationship, F change-voltage relationship; G-V relationship, conductance-voltage relationship; INPP4B, inositol polyphosphate 4-phosphatase type II; TPC, two-pore channel; V1/2, membrane voltage for half maximum activation.
	Figure 8. Gating charge recordings of WT TPC3 and R187Q-TPC3.A, representative results showing the ‘pore current’ (upper panels) and ‘gating current’ (lower panels) of WT TPC3 (left panels) and R187Q-TPC3 (right panels). These traces were recorded from the transfected HEK293T cells by whole cell-patch clamp technique. The protocol for voltage step pulses is shown on the top. The traces shown in red are the current traces at +160 mV. The pipette solution did not contain Na+, which is the major permeating ion of TPC3. For the recordings of ‘pore current’, bath solution contained Na+ to detect TPC3 tail current attributed to the permeation through TPC3 channel pore. For the recordings of ‘gating current’, bath solution did not contain Na+ to detect gating current attributed to the S4 movement without contamination by pore current upon the repolarization to −80 mV from the step pulses. The traces in the time range marked by red bars are expanded in the insets. These experiments were performed with an assumption of the presence of remaining PI(3,4)P2 according to a previous report (38). B, G-V and Q-V relationships of WT TPC3 and R187Q-TPC3 (R187Q). The color codes are as follows: Black: WT G-V, blue: R187Q G-V, gray: WT Q-V, and pale blue: R187Q Q-V. The V1/2 values and slope factors are as follows: WT TPC3 (V1/2 of G-V: 96.7 ± 5.8 mV and slope factor of G-V: 25.6 ± 1.2 mV (n = 3); V1/2 of Q-V: 101.7 ± 16.5 mV and slope factor of Q-V: 29.6 ± 4.8 mV (n = 6)) and R187Q-TPC3 (V1/2 of G-V: 110.3 ± 3.0 mV and slope factor of G-V: 20.4 ± 1.4 mV (n = 4); V1/2 of Q-V: 120.3 ± 7.9 mV and slope factor of Q-V: 31.9 ± 2.0 mV (n = 6)). C, statistical comparison of the V1/2 values described above (G-V: p = 0.020, Q-V: p = 0.046 by unpaired t test. ∗ means a statistically significant difference of p < 0.05). G-V relationship, conductance-voltage relationship; Q-V relationship, gating charge-voltage relationship; S4, the fourth helix; TPC, two-pore channel; V1/2, membrane voltage for half maximum activation.
	Figure 9. VCF analysis using TPC3 with fluorescent label in the intracellular side of the second S4.A, a schematic view of the position of S527Anap. B, a representative result showing TPC3 current and fluorescence traces of S527Anap-TPC3. These experiments were performed in the presence of PI(3,4)P2. The traces shown in red are the current and fluorescent traces at +180 mV, respectively. C, the G-V (black) and ΔF-V (red) relationships of S527Anap-TPC3 in the presence of PI(3,4)P2. The V1/2 values and slope factors are as follows: V1/2 of G-V: 89.7 ± 7.6 mV and slope factor of G-V: 24.0 ± 1.1 mV; V1/2 of ΔF-V: 106.0 ± 9.9 mV and slope factor of ΔF-V: 24.9 ± 7.7 mV (n = 12). D, left and middle, representative results showing S527Anap-TPC3 current and fluorescence traces before (black) and after (red) long depolarization. The long depolarization is expected to increase PI(3,4)P2 concentration in the oocyte. These traces were recorded from the same oocyte. Right, statistical comparison of the F changes of S527Anap-TPC3 before and after long depolarization. The averages of the detected F changes are as follows: before long depolarization: 0.16 ± 0.09%; after long depolarization: 0.29 ± 0.15% (n = 9) (p = 0.003 by paired t test. ∗∗ means a statistically significant difference of p < 0.01). ΔF-V relationship, F change-voltage relationship; Anap, 3-(6-acetylnaphthalen-2-ylamino)-2-aminopropanoic acid; F change, change of fluorescence intensity; G-V relationship, conductance-voltage relationship; S4, the fourth helix; TPC3, two-pore channel; V1/2, membrane voltage for half maximum activation; VCF, voltage clamp fluorometry.
	Figure 10. Coexpression of CiVSP with S527Anap-TPC3 evokes a rapid and biphasic F change.A, a schematic explanation of the enzymatic activity of CiVSP. B, a representative result of the coexpression experiment of S527Anap-TPC3 with CiVSP, in which CiVSP activated by the long depolarization transiently produced and then degraded PI(3,4)P2. Anap, 3-(6-acetylnaphthalen-2-ylamino)-2-aminopropanoic acid; CiVSP, Ciona intestinalis VSP; F change, change of fluorescence intensity; TPC, two-pore channel; VSP, voltage sensitive phosphatase.
	Figure 11. The effect of PI(3,4)P2binding on the second S4. A schematic explanation of the potentiation of the structural change of the second S4 by PI(3,4)P2 binding to the first repeat revealed by this study. This ‘global modulation’ in TPC3 is the molecular mechanism underlying the potentiation of the voltage dependence of TPC3 gating by PI(3,4)P2. S4, the fourth helix; TPC3, two-pore channel.

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