Mak DO, McBride SM, Foskett JK.

GM565328 NIGMS NIH HHS , MH59937 NIMH NIH HHS, GM38626 NIGMS NIH HHS , GM48752 NIGMS NIH HHS , R37 GM056328 NIGMS NIH HHS , R01 MH059937 NIMH NIH HHS, R01 GM056328 NIGMS NIH HHS

	Figure 1. . Typical single-channel current traces of X-InsP3R-1 channels in various [Ca2+]i, [ATP] and [InsP3], as labeled. Arrows indicate closed channel current levels. 100 μg/ml heparin was used in +heparin experiments.
	Figure 2. . (A) Channel current versus applied transmembrane potential curve for InsP3R channels (n = 4) observed in symmetric 140 mM KCl in the presence of [Ca2+]i < 5 nM, 0.5 mM ATP and no InsP3. (B and C) Current traces with InsP3R channel observed under an applied potential ramp in 140 mM KCl bath and 14 mM KCl pipette solutions. For B, pipette solution contained [Ca2+]i < 5 nM, 0.5 mM ATP and no InsP3, whereas for C, pipette solution contained 1 μM [Ca2+]i, 0.5 mM ATP and 10 μM InsP3. The slope conductances of the channels were evaluated as the difference between the slopes of the open (dashed line) and closed (solid line) channel current levels. The positive reversal potentials (as tabulated in the graphs) indicate that the InsP3R channels observed are cation selective.
	Figure 3. . (A) Pd and (B) Po histograms of the X-InsP3R-1 channel in various experimental conditions. In the Pd graph, numbers above each bar represent the fraction of nuclear membrane patches obtained that exhibited X-InsP3R-1 channel activities. In the Po graph, the number above each bar is the number of single-channel current records used to evaluate Po. Given the variance of the channel Po in experiments performed under the same experimental conditions, the channel Po observed under the various set of experimental conditions are not statistically different (P > 0.05 from t test) from Po observed under control conditions (0 InsP3, 0.5 mM ATP, [Ca2+]i < 5 nM).
	Figure 4. . Typical single-channel current traces of r-InsP3R-3 channels in various [Ca2+]i, [ATP] and [InsP3], as labeled. Arrows indicate closed channel current levels. 100 μg/ml heparin was used in +heparin experiments.
	Figure 5. . (A) Pd and (B) Po histograms of the r-InsP3R-3 channel in various experimental conditions. Numbers tabulated in the graphs have the same meanings as in Fig. 3. Given the variance of the channel Po in experiments performed under the same experimental conditions, the channel Po observed under the various set of experimental conditions are not statistically different (P > 0.05 from t test) from Po observed under control conditions (0 InsP3, 0.5 mM ATP, [Ca2+]i < 5 nM).
	Figure 6. . Estimating Kinh0 and Pmax0 from channel activities at low [Ca2+]i for (A) X-InsP3R-1 and (B) r-InsP3R-3. Different colors correspond to different InsP3 and ATP concentrations as tabulated in the graphs. InsP3R channel Po observed in calculated [Ca2+]i of 0.9–1.5 nM are plotted as data points at [Ca2+]i = 1.5 nM (c.f. Figs. 3 B and 5 B). InsP3R channel Po at various [Ca2+]i can be calculated with Eq. 4 using the values of Pmax∞, Kact, Hact, and Hinh obtained in our previous studies for X-InsP3R-1 (Mak et al., 1998, 1999) and r-InsP3R-3 (Mak et al., 2001a,b). The values of parameters Kinh0 and Pmax0 in Eq. 4, which were not determined in previous experiments, must be constrained so that: (a) the calculated channel Po at various InsP3 and ATP concentrations agree with experimental observations (i.e., lie within the error limits of the data points at 1.5 nM [Ca2+]i), and (b) the calculated channel Po in the absence of InsP3 is <0.001 at 25 nM [Ca2+]i, so that no channel activity was detected at 25 nM [Ca2+]i. The continuous and dashed curves represent channel Po calculated using two extreme sets of values for Kinh0 and Pmax0 that satisfy those requirements. For X-InsP3R-1, the continuous curves are calculated with Pmax0 = 0.07 and Kinh0 = 1.2 nM; and the dashed curves are calculated with Pmax0 = 0.02 and Kinh0 = 5.5 nM. For r-InsP3R-3, the continuous curves are calculated with Pmax0 = 0.018 and Kinh0 = 1.2 nM; and the dashed curves are calculated with Pmax0 = 0.005 and Kinh0 = 3.8 nM. The observed channel Po data points in both graphs and the continuous curves in A are slightly offset along the [Ca2+]i axis for easier visualization.
	Figure 7. . The MWC-based four-plus-two-conformation model for InsP3R channel gating. Only conformation transitions are represented in the schemes. Reactions involving binding of InsP3 and Ca2+ to the InsP3R channel and the state of occupation of the various ligand-binding sites of the channel are omitted from the schemes for clarity. The green boxes represent the grouping of the open A* and closed A′ conformations into the active A conformation, and the grouping of the C* and C′ conformations into the active C conformation.
	Figure 8. . Fitting of the InsP3R channel Po in various [Ca2+]i and [InsP3] by the MWC-based four-plus-two-conformation model. (A) InsP3R-1 in regular bath (300 nM [Ca2+]), (B) InsP3R-3 in regular bath (300 nM [Ca2+]), and (C) InsP3R-1 in bath containing <5 nM Ca2+. The symbols represent the experimental Po in the tabulated [InsP3]. The continuous curves are the theoretical Po calculated from the model. The dashed curves indicate the range of calculated Po for ± 10% of the tabulated [InsP3]. Parameters used for the Po calculations are tabulated in Table I.

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