Correspondence to: J. Kevin Foskett, Department of Physiology, B400 Richards Building, University of Pennsylvania, Philadelphia, PA 19104-6085. Fax:(215) 573-6808 E-mail:foskett{at}mail.med.upenn.edu.
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Abstract |
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A family of inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R) Ca2+ release channels plays a central role in Ca2+ signaling in most cells, but functional correlates of isoform diversity are unclear. Patch-clamp electrophysiology of endogenous type 1 (X-InsP3R-1) and recombinant rat type 3 InsP3R (r-InsP3R-3) channels in the outer membrane of isolated Xenopus oocyte nuclei indicated that enhanced affinity and reduced cooperativity of Ca2+ activation sites of the InsP3-liganded type 3 channel distinguished the two isoforms. Because Ca2+ activation of type 1 channel was the target of regulation by cytoplasmic ATP free acid concentration ([ATP]i), here we studied the effects of [ATP]i on the dependence of r-InsP3R-3 gating on cytoplasmic free Ca2+ concentration ([Ca2+]i). As [ATP]i was increased from 0 to 0.5 mM, maximum r-InsP3R-3 channel open probability (Po) remained unchanged, whereas the half-maximal activating [Ca2+]i and activation Hill coefficient both decreased continuously, from 800 to 77 nM and from 1.6 to 1, respectively, and the half-maximal inhibitory [Ca2+]i was reduced from 115 to 39 µM. These effects were largely due to effects of ATP on the mean closed channel duration. Whereas the r-InsP3R-3 had a substantially higher Po than X-InsP3R-1 in activating [Ca2+]i (<1 µM) and 0.5 mM ATP, the Ca2+ dependencies of channel gating of the two isoforms became remarkably similar in the absence of ATP. Our results suggest that ATP binding is responsible for conferring distinct gating properties on the two InsP3R channel isoforms. Possible molecular models to account for the distinct regulation by ATP of the Ca2+ activation properties of the two channel isoforms and the physiological implications of these results are discussed. Complex regulation by ATP of the types 1 and 3 InsP3R channel activities may enable cells to generate sophisticated patterns of Ca2+ signals with cytoplasmic ATP as one of the second messengers.
Key Words: allosteric regulation, calcium release channel, single-channel electrophysiology, patch clamp, Xenopus oocyte
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INTRODUCTION |
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Modulation of free cytoplasmic Ca2+ concentration ([Ca2+]i) is a ubiquitous cellular signaling system. In many cell types, binding of ligands to plasma membrane receptors activates the hydrolysis of phosphatidylinositol 4,5-bisphosphate by membrane-bound phospholipase C, generating inositol 1,4,5-trisphosphate (InsP3).1 InsP3 causes the release of Ca2+ from the endoplasmic reticulum (ER) by binding to its receptor (InsP3R), which itself is a Ca2+ channel (
The functional correlates of this impressive diversity of InsP3R expression are largely unknown (see INTRODUCTION of
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Because the properties of the Ca2+ activation sites represented the only significant distinction between the types 1 and 3 InsP3R channels that could be discerned in our previous studies, and Ca2+ activation of X-InsP3R-1 channel gating is modulated by ATP, here we have investigated the effects of ATP on the gating properties of the recombinant r-InsP3R-3 channel. Surprisingly, our results reveal that the presence of ATP is absolutely necessary to confer distinct Ca2+ activation properties to the types 1 and 3 channels because, in its absence, Ca2+ activation of the two channels is very similar. ATP activates type 3 channel gating in a dramatically different manner compared with its effects on the type 1 channel: whereas maximal Po of both isoforms is similarly unaffected by [ATP]i, ATP abolishes the cooperativity of Ca2+ activation of r-InsP3R-3 besides increasing the functional affinity of the activating Ca2+ binding sites. Thus, complex allosteric dependencies on [ATP]i of the gating of types 1 and 3 InsP3R channels, coupled with differential levels of expression and subcellular localization, may enable cells to generate sophisticated Ca2+ signals, with cytoplasmic ATP as one of the second messengers.
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MATERIALS AND METHODS |
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Xenopus oocytes were obtained and selected for a low functional expression level of the endogenous X-InsP3R-1 as described previously (
Nuclear patch-clamp experiments were performed on isolated nuclei from cRNA-injected oocytes as described in the companion paper (see
Data acquisition and analysis were performed as described in the companion paper (see
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RESULTS |
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ATP Activation of Recombinant Type 3 InsP3R
To study the effects of [ATP]i on gating of single recombinant r-InsP3R-3 channels in their native ER membrane environment, we performed patch-clamp experiments on nuclei isolated from oocytes injected with cRNA of r-InsP3R-3. Although the oocyte expresses endogenously a type 1 InsP3R, under the conditions of our experiments, >90% of the channels recorded were contributed by type 3 homotetramers (
r-InsP3R-3 channel activities with a high Po of 0.6 (Fig 2 A) and gating kinetics similar to those of the r-InsP3R-3 reported previously (see 250 nM free Ca2+. In the absence of ATP, in contrast, the r-InsP3R-3 channel had significantly lower Po of 0.2, either in the presence or absence of 3 mM Mg2+ (Fig 2B and Fig C). ATP did not affect the conductance of the r-InsP3R-3 channel (Fig 2A and Fig B). The time course of channel inactivation of the r-InsP3R-3 channel was not substantially different in the presence and absence of ATP.
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To examine in more detail if the presence of the MgATP complex affects the Po of the r-InsP3R-3, similar experiments were performed using pipet solutions containing 3 mM total Mg2+ and 0.5 mM total ATP, so that the calculated [MgATP], free Mg2+ concentration ([Mg2+]i), and [ATP]i were 0.5 mM, 2.5 mM, and 12 µM, respectively. The Po of the r-InsP3R-3 channel remained low under these conditions (Fig 2 D). Thus, the r-InsP3R-3 is activated by ATP free acid (ATP3- or ATP4-), but not by the MgATP complex (Fig 2 E), suggesting that ATP hydrolysis or phosphorylation is not involved in ATP activation of the type 3 InsP3R. Therefore, this behavior is similar to that of the type 1 InsP3R channel (
This activation of r-InsP3R-3 by ATP was prominently observed only at low [Ca2+]i (<1 µM). At optimal [Ca2+]i (>2 µM), the channel Po achieved the maximum value of 0.8 in both 0 or 0.5 mM free [ATP]i (Fig 3). Thus, as in the case for X-InsP3R-1 (
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Effects of ATP on the Ca2+ Dependence of Types 1 and 3 InsP3R Gating
To determine the mechanisms by which ATP activates r-InsP3R-3 channel gating, we investigated systematically the effects of cytoplasmic ATP on the channel kinetics over a wide range of [Ca2+]i. In the absence of ATP, Ca2+ dependence of channel Po of the InsP3R-3 was biphasic (Fig 4 A) and well fitted with the biphasic Hill equation (
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(1) |
with a maximum open probability (Pmax) of 0.84 ± 0.02, a half-maximal activating [Ca2+]i (Kact) of 800 ± 50 nM, an activation Hill coefficient (Hact) of 1.6 ± 0.3, a half-maximal inhibitory [Ca2+]i (Kinh) of 115 ± 15 µM, and an inhibition Hill coefficient (Hinh) of 2 ± 0.5 (Table 1).
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This behavior is dramatically different from the Ca2+ dependence of gating of the r-InsP3R-3 in the presence of 0.5 mM cytoplasmic free ATP (Fig 4 A). At high, inhibitory [Ca2+]i, the presence of 0.5 mM ATP decreased the value of Kinh from 115 to 39 µM such that, in [Ca2+]i > 50 µM, the r-InsP3R-3 channel activity was lower in the presence of 0.5 mM free ATP than in the absence of ATP (Fig 4B and Fig C). The value of Hinh was somewhat higher in the presence of ATP. Of likely greater physiological significance, ATP induced a much lower Kact of 77 ± 10 nM and reduced the value of Hact to 1.0 ± 0.1 (Fig 1 and Table 1). Thus, cytoplasmic ATP decreased both the half-maximal activating [Ca2+]i as well as the activation Hill coefficient, with the result that the Po of the r-InsP3R-3 at [Ca2+]i < 500 nM is substantially higher in the presence of ATP than in its absence (Fig 4 A). It is this dramatic increase of the Ca2+ affinity of the r-InsP3R-3 activating site(s) and loss of cooperativity between these sites in the tetrameric channel that give rise to the observed difference in channel activities of the r-InsP3R-3 and X-InsP3R-1 in activating [Ca2+]i (<1 µM) in the presence of ATP (Fig 1).
In sharp contrast, the biphasic Ca2+ dependence of the r-InsP3R-3 in the absence of cytoplasmic free ATP is remarkably similar to the biphasic Ca2+ dependence of the X-InsP3R-1 in the absence of ATP (Fig 5), with Pmax = 0.80 ± 0.02, Kact = 550 ± 50 nM, Hact = 1.9 ± 0.6, Kinh = 110 ± 15 µM, and Hinh = 4.0 ± 0.7 (Table 1). Thus, in the absence of cytoplasmic ATP, there are no significant differences between the responses to Ca2+ of the types 1 and 3 InsP3R channels.
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Examination of the gating kinetics of the r-InsP3R-3 channel revealed that the mean open channel duration (o) in the absence of cytoplasmic ATP lay within a narrow range between 3 and 12 ms over the range of [Ca2+]i studied (0.2120 µM; Fig 6). Within this range,
o varied with [Ca2+]i in a biphasic fashion, increasing as [Ca2+]i increased from 0.2 to 2 µM, and decreasing as [Ca2+]i further increase from 6 to 120 µM. This partly mirrored the variation of r-InsP3R-3 channel Po with [Ca2+]i (Fig 4 A). In contrast, the mean closed channel duration (
c) decreased nearly an order of magnitude, from 18 to 2 ms, as [Ca2+]i was increased from 0.2 to 6 µM, and then remained low (
2 ms) in high [Ca2+]i (6120 µM). The changes in
c accounted for the major part of the Ca2+ activation of channel activity. These Ca2+ dependencies of
c and
o of the type 3 channel in the absence of ATP are reminiscent of those of X-InsP3R-1 in 0 mM ATP (
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The presence of ATP enhanced r-InsP3R-3 channel activity at low [Ca2+]i (<2 µM) (Fig 2 and Fig 3) by both stabilizing the open channel kinetic state(s) and destabilizing the closed kinetic state(s) (Fig 6). As [Ca2+]i increased from 10 to 83 µM, ATP reduced r-InsP3R-3 channel activity by stabilizing closed kinetic state(s) so that c increased dramatically (Fig 4 and Fig 6).
Effects of ATP Concentration on Ca2+ Activation of r-InsP3R-3
The effects of cytoplasmic ATP concentration on the Ca2+ activation of the r-InsP3R-3 were studied in more detail in a series of patch-clamp experiments using various [ATP]i between 0 and 9.5 mM, over a wide range of [Ca2+]i between 20 nM and 6 µM. The pipet solutions again contained 10 µM InsP3, sufficient to saturate the InsP3R (
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(2) |
with Pmax 0.8 for all [ATP]i used (09.5 mM). Between [ATP]i of 0 and 500 µM, both Kact and Hact changed continuously (Fig 4 A and Table 1). At concentrations of ATP >500 µM, the activation of r-InsP3R-3 by Ca2+ exhibited no further systematic change (Fig 4 A).
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DISCUSSION |
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Inositol trisphosphatemediated intracellular Ca2+ signaling is under complex regulation because the gating of the InsP3R Ca2+ release channel is sensitive to [Ca2+]i as well as to [InsP3]i (0.8 over a wide range of [Ca2+]i (
50 nM for both channels, and both channel isoforms exhibit Kinh of
4050 µM with Hill coefficient of 34 in the presence of 0.5 mM free ATP and saturating concentrations (
10 µM) of InsP3.
In contrast, the properties of the Ca2+ activation sites differ between the two isoforms. In nuclear patch-clamp studies, the type 3 channel is uniquely distinguished from the type 1 channel by enhanced sensitivity of (Kact of 77 nM instead of 190 nM) and lack of cooperativity between the Ca2+ activation sites (Hact of 1 instead of 2) in the presence of 0.5 mM free ATP and saturating concentrations (10 µM) of InsP3 (
Our previous study of the regulation by ATP of the X-InsP3R-1 channel (
Because the Ca2+ activation properties of channel gating was the major feature distinguishing the types 1 and 3 channels, and these properties of the type 1 channel were regulated by [ATP]i, we therefore investigated the effects of ATP on the gating of the type 3 channel.
ATP Tuning of the Affinities of the InsP3R Inhibitory Ca2+ Binding Sites
Our patch-clamp experimental data indicate that ATP decreases Kinh of both types 1 and 3 InsP3R in very similar manner, whereas Pmax values remained unchanged (Table 1). Thus, ATP reduces the channel activities of both InsP3R channels at [Ca2+]i > 10 µM by decreasing Kinh, from 110 µM in the absence of ATP to
45 µM at 0.5 mM ATP (Fig 1, Fig 4, and Fig 5). This reduction of Kinh could not be reversed by the application of supersaturating [InsP3]i (10 µM) that was substantially higher than the half-maximal [InsP3]i
50 nM for X-InsP3R-1 (
Although binding assays have indicated that ATP can competitively inhibit binding of InsP3 to InsP3R-3 (55 nM;
ATP Enhancement of Ca2+ Activation of r-InsP3R-3 Channel
Our systematic single-channel patch-clamp experimental data demonstrated that, in the nuclear membrane system, cytoplasmic free ATP, but not MgATP, enhanced the activation by Ca2+ (<1 µM) of recombinant type 3 InsP3R channel through an increase of the Ca2+ affinity and decrease of the cooperativity of the activating sites of the channel.
The effects of cytoplasmic ATP on the activity of the InsP3R-3 have been studied previously primarily by Ca2+ release assays using cells that expressed endogenous type 3 InsP3R as the only (0.6 to
0.2 in r-InsP3R-3 (Fig 4 A), whereas Po changed from 0.8 to 0.2 in XInsP3R-1 (
Under our experimental conditions, only free ATP, not the MgATP complex, enhanced r-InsP3R-3 channel activity, as in the case for the X-InsP3R-1 (
Recently, the effects of ATP on InsP3R-3 channel properties were studied (0.05) for both the type 3 (
Molecular Models for ATP Regulation of Ca2+ Activation of the InsP3R
In a previous study of ATP regulation of the single-channel activity of the X-InsP3R-1 (
In contrast, the regulation by ATP of the r-InsP3R-3 observed in this study is dramatically different. Whereas Pmax of the r-InsP3R-3 was similarly unaffected by [ATP]i, both Hact and Kact of the type 3 channel were reduced by ATP. Furthermore, these effects of ATP on the Ca2+ activation of the r-InsP3R-3 were saturated by 0.5 mM ATP (Fig 4 A), whereas increasing [ATP]i up to several mM continued to further decrease Kact of the type 1 channel (
How can we account for the distinct regulation by ATP of the Ca2+ activation properties of the two channel isoforms? Analysis of the primary sequence of the type 1 InsP3R (0.27 mM to the functional ATP binding site in type 1 InsP3R and increases the sensitivity of the channel to Ca2+ activation without affecting the cooperativity of Ca2+ activation (
Alternately, the regulation of InsP3R by ATP and Ca2+ can be accounted for by the molecular Monad-Wyman-Changeux (MWC) model (
In the MWC model, InsP3R channel activity can exhibit a dependence on the concentration of one of its ligands (Ca2+) with a Hill coefficient >1 regardless of the number of Ca2+ required to bind to the channel to open it (our unpublished data). The MWC model also predicts that the apparent half-maximal activating concentration (Kact) of one ligand (Ca2+) can vary in the presence of different concentrations of the other ligand (ATP), even though the dissociation constants for the ligands of both conformations of the channel remains unchanged. Furthermore, heterotropic effects of Ca2+ and ATP on the InsP3R channel can change the Hill coefficient for Ca2+ activation (Hact) of the channel without changing the number of Ca2+ required to bind to the channel before it can adopt the active conformation. Thus, according to the MWC model, binding of ATP, a heterotropic ligand, to the r-InsP3R-3 channel can abolish the cooperativity of Ca2+ and simultaneously decrease its half-maximal activating concentration (
Differential Regulation by ATP of Ca2+ Activation of the Types 1 and 3 InsP3R Isoforms
We characterized previously the permeation properties, propensity to cluster, and regulation by Ca2+ and InsP3 of the type 3 InsP3R channel (
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Whereas the MgATP concentration in the cytoplasm is in the range of 38 mM (
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Footnotes |
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1 Abbreviations used in this paper: ER, endoplasmic reticulum; InsP3, inositol 1,4,5-trisphosphate; MWC, Monad-Wyman-Changeux; Po, open probability; r-InsP3R-3, rat type 3 InsP3R; X-InsP3R-1, Xenopus type 1 InsP3R.
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Acknowledgements |
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We thank Dr. Graeme Bell (University of Chicago, Chicago, IL) for providing r-InsP3R-3 cDNA.
This work was supported by grants to J.K. Foskett from the National Institutes of Health (MH59937 and GM56328) and to D.-O.D. Mak from the American Heart Association (9906220U).
Submitted: 19 January 2001
Revised: 15 March 2001
Accepted: 19 March 2001
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