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ATP-dependent adenophostin activation of inositol 1,4,5-trisphosphate receptor channel gating: kinetic implications for the durations of calcium puffs in cells.
Mak DO
,
McBride S
,
Foskett JK
.
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The inositol 1,4,5-trisphosphate (InsP(3)) receptor (InsP(3)R) is a ligand-gated intracellular Ca(2+) release channel that plays a central role in modulating cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)). The fungal metabolite adenophostin A (AdA) is a potent agonist of the InsP(3)R that is structurally different from InsP(3) and elicits distinct calcium signals in cells. We have investigated the effects of AdA and its analogues on single-channel activities of the InsP(3)R in the outer membrane of isolated Xenopus laevis oocyte nuclei. InsP(3)R activated by either AdA or InsP(3) have identical channel conductance properties. Furthermore, AdA, like InsP(3), activates the channel by tuning Ca(2+) inhibition of gating. However, gating of the AdA-liganded InsP(3)R has a critical dependence on cytoplasmic ATP free acid concentration not observed for InsP(3)-liganded channels. Channel gating activated by AdA is indistinguishable from that elicited by InsP(3) in the presence of 0.5 mM ATP, although the functional affinity of the channel is 60-fold higher for AdA. However, in the absence of ATP, gating kinetics of AdA-liganded InsP(3)R were very different. Channel open time was reduced by 50%, resulting in substantially lower maximum open probability than channels activated by AdA in the presence of ATP, or by InsP(3) in the presence or absence of ATP. Also, the higher functional affinity of InsP(3)R for AdA than for InsP(3) is nearly abolished in the absence of ATP. Low affinity AdA analogues furanophostin and ribophostin activated InsP(3)R channels with gating properties similar to those of AdA. These results provide novel insights for interpretations of observed effects of AdA on calcium signaling, including the mechanisms that determine the durations of elementary Ca(2+) release events in cells. Comparisons of single-channel gating kinetics of the InsP(3)R activated by InsP(3), AdA, and its analogues also identify molecular elements in InsP(3)R ligands that contribute to binding and activation of channel gating.
Figure 1. Molecular structures of various InsP3R-binding ligands.
Figure 2. Typical single-channel current traces of X-InsP3R-1 in various [Ca2+]i, activated by InsP3 or AdA as indicated. Arrows indicate the closed channel current levels. (A) In the presence of 0.5 mM ATP. (B) In the absence of ATP.
Figure 3. [Ca2+]i dependence of the Po of the X-InsP3R-1 channel in the presence of 0.5 mM ATP, activated by AdA or InsP3 (Mak and Foskett 1998). The solid and dashed curves are theoretical fits by the Hill equation () of the Po data from [AdA] = 100 nM and 0.5 nM, respectively.
Figure 4. [Ca2+]i dependence of the Po of the X-InsP3R-1 channel in the absence of ATP, activated by saturating (10 μM) or subsaturating (33 nM) concentrations of InsP3. The solid and dashed curves are theoretical fits by the Hill equation () of the Po data.
Figure 5. [Ca2+]i dependence of the Po of the X-InsP3R-1 channel activated by saturating concentrations of ligands in the presence or absence of ATP. (A) 10 μM InsP3; (B) 100 nM AdA. The solid and dashed curves are theoretical fits by the Hill equation () of the data in 0 or 0.5 mM of ATP, respectively.
Figure 6. [Ca2+]i dependence of the Po of the X-InsP3R-1 channel activated by AdA or InsP3 in the absence of ATP. The solid and dashed curves are theoretical fits by the Hill equation () of the Po data from [InsP3] = 10 μM and [AdA] = 100 nM, respectively.
Figure 7. [Ca2+]i dependence of the Po of the X-InsP3R-1 channel in the absence of ATP, activated by saturating (100 nM) or subsaturating (20 nM) concentrations of AdA. The solid and dashed curves are theoretical fits by the Hill equation () of the Po data. Note that the scale of the Po axis is different from that in the previous Po versus [Ca2+]i graphs.
Figure 8. Typical single-channel current traces of the X-InsP3R-1 activated by 10 μM Fur or Rib. In 0.5 mM ATP (+ ATP), [Ca2+]i = 5.0 μM. In the absence of ATP (0 ATP), [Ca2+]i = 6.2 μM. The arrows indicate the closed channel current levels.
Figure 9. Po of the X-InsP3R-1 channel in optimal [Ca2+]i (4.4–6.2 μM) and saturating concentrations of various ligands in 0 (white bars) and 0.5 mM (shaded bars) ATP.
Figure 10. [Ca2+]i dependencies of the mean open (〈τo〉) and closed (〈τc〉) dwell times of the X-InsP3R-1 channel. In the 〈τc〉 graphs, data points from the same experimental conditions are connected with solid or dashed lines for clarity. (A) Channel activated by AdA or InsP3 (Mak and Foskett 1998), in 0.5 mM ATP. (B) Channel activated by saturating (10 μM) or subsaturating (33 nM) concentrations of InsP3 in the absence of ATP. (C) Channel activated by saturating (100 nM) or subsaturating (20 nM) concentrations of AdA in the absence of ATP.
Figure 11. Open and closed dwell time histograms of the X-InsP3R-1 channel in 0.5 mM ATP and various [Ca2+]i, activated by saturating concentrations of InsP3 (10 μM) or AdA (100 nM). The smooth curves are the pdf. The time constant and relative weight of each exponential component of the pdf are tabulated next to the corresponding peak in the curves. [Ca2+]i used in each of the analyzed experiments and its Po are tabulated next to the corresponding graphs.
Figure 12. Open and closed dwell time histograms of the X-InsP3R-1 channel in the absence of ATP and various [Ca2+]i, activated by saturating concentrations of InsP3 (10 μM) or AdA (100 nM). The smooth curves are the pdf. The time constant and relative weight of each exponential component of the pdf are tabulated next to the corresponding peak in the curves. [Ca2+]i used in each of the analyzed experiments and its Po are tabulated next to the corresponding graphs.
Figure 13. 〈τc〉 and 〈τo〉 of X-InsP3R-1 channels in optimal [Ca2+]i (4.4–6.2 μM) and saturating concentrations of various ligands in 0 (white bars) and 0.5 mM (shaded bars) ATP.
Figure 14. Schematic diagrams representing interactions between the X-InsP3R-1 molecule and various ligands. (A) Interaction between X-InsP3R-1 and InsP3 in the presence of ATP. (B) Interaction between X-InsP3R-1 and AdA in the presence of ATP. (C) Interaction of X-InsP3R-1 and InsP3 in the absence of ATP. (D) Interaction of X-InsP3R-1 and AdA in the absence of ATP.
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