Piskorowski RA, Aldrich RW.

	Figure 1. BK channel currents recorded with four different permeant ions. (A) Currents recorded with 100 mM symmetrical potassium, rubidium, cesium, and thallium. (B) The conductance versus voltage curve from currents recorded in symmetrical potassium (squares), symmetrical cesium (triangles), symmetrical rubidium (diamonds), and symmetrical thallium (circles). Thallium produced a significant shift in the GV curve to higher potentials as analyzed by a shift in the V1/2 of the Boltzmann fit (by ANOVA, P = 6.87 × 10−8), unlike cesium and rubidium (P = 0.845 for cesium and P = 0.954 for rubidium). Thallium, rubidium, and cesium all changed the slope of the GV curve. Thallium alters the gating of BK channels: (C) Currents in response to a 200-mV voltage step traces recorded from the same patch. Currents were normalized to the maximal steady-state current for both symmetrical potassium (black) and symmetrical thallium (gray). (D) Inward tail currents in response to a −80-mV pulse. These currents were preceded by a +200-mV pulse. Currents are normalized to the peak of the tail current. Solutions are either symmetrical potassium (black) or symmetrical thallium (gray). All currents were recorded with 300 μM internal calcium.
	Figure 2. Deactivation rates shift at the reversal potential under biionic conditions. (A) Deactivation rates from data collected in symmetrical potassium (solid black squares) or internal potassium with external thallium (open gray squares). (B) Deactivation rates from data collected in symmetrical thallium (solid gray circles) or internal thallium with external potassium (open black circles). Each data point is the mean ± SEM. For symmetrical potassium, n = 19, symmetrical thallium, n = 17, internal thallium with external potassium, n = 15, internal potassium with external thallium, n = 13. Zero internal calcium.
	Figure 3. The gating of BK channels is influenced differently by internal and external thallium solutions. (A) The GV curve of BK channels recorded in four conditions: symmetrical potassium (solid black squares), internal potassium with external thallium (open black squares), internal thallium with external potassium (open gray circles), and symmetrical thallium (closed gray circles). The solid lines are fits with Boltzmann curve. (B) Box plots of the half activation, V1/2, from the Boltzmann fits for the four conditions. (C) Box plots of the z values from the Boltzmann fits. Box plots display the median and the 10th, 25th, 75th, and 90th percentiles. All data was recorded in 300 μM internal calcium.
	Figure 4. Gating effect from internal permeant ions. (A) Currents from an inside-out patch with external NMG and internal potassium. (B) Currents from an inside-out patch with external NMG and internal thallium. (C) The GV curves from multiple experiments. (D) Box plots of the V1/2 from Boltzmann fits of all the data with external NMG. (E) Box plots of the z values from Boltzmann fits (n = 6 for potassium and n = 5 for thallium). (F) Currents from an inside-out patch with internal NMG and external potassium. (G) Currents from an inside-out patch with internal NMG and external thallium. (H) The GV from multiple experiments. (I) Box plots of the V1/2 from Boltzmann fits of all the data with external NMG. (J) Box plots of the z values from Boltzmann fits. (n = 11 for potassium and n = 13 for thallium).
	Figure 5. The shift in the GV curve as internal potassium is replaced by thallium. (A) V1/2 from Boltzmann curve fits plotted as a function of the concentration of internal thallium. (B) The single channel current at 70 mV as a function of the concentration of internal thallium. The different symbols represent data recorded from different patches. All patches were recorded in external potassium and 50 μM internal calcium. The osmolarity is balanced by potassium.
	Figure 6. Calcium activation of BK channels in symmetrical potassium and thallium solutions. (A) Two patches with either symmetrical potassium (black) or symmetrical thallium (gray) at three different calcium concentrations. (B) Averages of GV curves from multiple voltage families from the patch shown in A. (C) Plot of V1/2 from Boltzmann fits at multiple calcium concentrations for symmetrical potassium solutions (black squares) and symmetrical thallium solutions (gray circles). (D) The difference in the V1/2 at each calcium concentration for symmetrical thallium and potassium. (E) The z values from Boltzmann fits of GV curves from patches with external potassium (black squares) or external thallium (gray circles).
	Figure 7. Simultaneous fits of GV curves with the allosteric model of Scheme 1. The top graph has data from three different calcium concentrations in symmetrical potassium solutions. The solid lines are fits with the 70-state model. All the calcium concentrations were simultaneously fit. The lower graph has data from the same patch in the top panel, except with internal thallium and three concentrations of calcium. The solid curves are fit with the Scheme 1.
	Figure 8. NPO for external potassium and external thallium. NPO versus voltage plots from these two patches are being used as an example because their Ns are in the same range. (A) NPO at very low voltages for external potassium with internal potassium (solid black circles) or internal thallium (solid gray circles). (B) NPO at very low voltages for a patch with external thallium and with internal potassium (open black circles) or internal thallium (open gray squares). (C) Fit of logPO with the seventy state allosteric model. The opening probability over a very wide range of voltages for symmetrical potassium (black circles) and from −160 to 0 mV external thallium with internal potassium and from 0 to +300 mV internal thallium with external potassium (gray circles).
	Figure 9. Single channels currents from the same inside-out patch. (A and B) The external solution (pipette) contained 100 mM NMG and the internal solution (bath) contained either 100 mM potassium or 105 mM thallium. This data was recorded at +150 mV with 0 μM internal calcium. (C and D) Open and closed dwell time histograms from the same patch shown in A and B. Black bins are from currents measured with internal potassium and gray bins are from currents measured with internal thallium.
	Figure 10. Mole fraction effects on the mean open time and number of openings per burst. At point 0 on the x axis, the internal solutions is 100 mM potassium. The potassium in the internal solution was replaced by thallium until the internal thallium concentration was 100 mM. Potassium solutions were external for all experiments and the membrane potential was held at 70 mV. (A) The mean open time decreased as thallium replaced potassium. (B) The number of openings per burst increased as the fraction of thallium increased.
	Figure 11. Concentration dependence of the mean open time and number of openings per burst. Increasing concentrations of potassium (black squares) had little to no effect on the mean open time and number of openings per burst. However, increasing concentrations of thallium (gray circles) decreased the mean open time and increases the number of openings per burst. Membrane potential was held at 70 mV.
	Figure 12. (A) Mean open time (overestimate) from patches containing multiple channels. Symbols are the average ± SEM of mean open durations from patches with symmetrical potassium (black squares, n = 10) or internal potassium and external thallium (gray circles, n = 9). (B) Average number of openings per burst recorded at very low PO for currents recorded with potassium (black squares, n = 10) and symmetrical thallium (gray circles, n = 11).
	Figure 13. Duration histograms from one patch with either internal potassium (black bars) or internal thallium (gray bars) solutions. Potassium solutions were in the pipette.
	Figure 14. Results of further single channel analysis at high Po. (A) The mean open duration for currents with potassium as the permeating ion (black squares) or thallium as the permeating ion (gray circles). (B) The mean number of openings per burst for the two conditions. (C) The mean open time per burst for the two conditions. This value is the product of the mean open time and the number of openings per burst for each patch.
	Figure 15. Simulated data with Scheme 3. (A) GV curves calculated from currents simulated with Scheme 3 with parameters that can account for permeating potassium (black trace) and permeating thallium (gray trace). The kinetic effects of permeating thallium can be mimicked by enhancing the exit rates from the open state. All of the other rate constants are constrained by the model. (B) Simulated currents for permeating potassium (black trace) and thallium (gray traces) reveal that the activation rate is altered by an increase in the rate from going to the open state to the flicker state. (C) Similarly, deactivation rates are decreased by the increase in the open to flicker rate in simulated currents for permeating potassium (black trace) and thallium (gray trace).

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