1Department of Pharmacology, Juntendo University School of Medicine, Tokyo; 2Department of Regulatory Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; 3Boston Biomedical Research Institute, Watertown; and 4Department of Neurology, Harvard Medical School, Boston, Massachusetts
Submitted 24 August 2004 ; accepted in final form 25 January 2005
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ABSTRACT |
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malignant hyperthermia; 3-[(3-cholamidopropyl)dimethylammonio]propane sulfonic acid; domain peptide 4
In addition to such modulations, Ikemoto and Yamamoto (6) recently proposed that interdomain interactions within the RyR modulate Ca2+ release channel activity. They found that [3H]ryanodine binding and Ca2+ release from the SR vesicles were enhanced by short synthetic peptides that corresponded to the NH2 terminus and the central domains of RyR1 (36), where most of the reported mutations of malignant hyperthermia (MH) are located (13). One of these peptides, designated as domain peptide 4 (DP4, corresponding to the Leu2442-Pro2477 region), was found to be a potent activator of [3H]ryanodine binding (36), Ca2+ release from the SR (36), contraction of skinned skeletal muscle fibers (10), and Ca2+ sparks in saponin-permeabilized fibers (32). Importantly, replacement of arginine with cysteine in DP4 (DP4-mut, mimicking the Arg2458Cys mutation in MH) totally abolished these effects. Furthermore, cross-linking studies have shown that DP4 binds to the NH2-terminal region of RyR1 (37). It was hypothesized that the two domains (NH2 terminus and central domains) of RyR interact with each other to stabilize the closed state of the channel. In this hypothesis, a mutation in either domain would weaken the domain-domain interaction, resulting in channel destabilization and enhanced channel activity. Similarly, exogenous domain peptides (e.g., DP4) interfere with the domain-domain interaction by competing with the corresponding domain for the mating domain, leading to destabilization of the RyR channel.
We have recently shown that the specific activity of Ca2+-dependent [3H]ryanodine binding to RyR1 is significantly lower than that to RyR3, suggesting that the gain of CICR activity of RyR1 is reduced because of selective stabilization in the native SR vesicles of mammalian skeletal muscle (19). This selective stabilization also occurs in frog skeletal muscle, where the CICR gain of -RyR, the homolog to RyR1, is much lower than that of
-RyR, the homolog to RyR3 (20). Interestingly, the stabilization is more pronounced in
-RyR in the frog (<4% of
-RyR) than in RyR1 in mammals (<15% of RyR3). The selective stabilization of RyR1 was attributed to two independent mechanisms: FKBP12 and 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS)-sensitive mechanisms (19). The latter mechanism seemed to play a major role (>70%), but the precise mechanism is not known.
In this study, we hypothesized that the interdomain interaction may account for the selective stabilization of the RyR1 channel, especially for the CHAPS-sensitive process. To test this hypothesis, we examined the effect of DP4 on the activity of RyR1. The results suggest that DP4 and CHAPS share a common mechanism in enhancing the CICR activity of RyR1, supporting our hypothesis. This conclusion is further supported by the finding of the present study that dantrolene (or its analog, azumolene) inhibits both DP4- and CHAPS-induced channel activation in the identical manner (e.g., by showing essentially identical concentration dependence of inhibition). We also found that DP4 markedly enhanced caffeine sensitivity in releasing Ca2+ from the SR vesicles. These results indicate that the state at a reduced gain of the CICR activity of RyR1 is important in normal Ca2+ handling in skeletal muscle, and perturbation of this state may cause the channel dysfunction observed in some muscle diseases such as MH.
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MATERIALS AND METHODS |
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[3H]Ryanodine binding.
[3H]Ryanodine binding was performed with SR vesicles from bovine diaphragm which expresses both RyR1 and RyR3 or bovine epicranial muscle that expresses a single isoform of RyR1 (19). Briefly, the SR vesicles (100 µg of protein) were incubated with 8.5 nM [3H]ryanodine for 5 h at 25°C (or for 2 h at 37°C in the experiments with dantrolene and azumolene) (see Fig. 4) in a 100-µl solution containing 0.17 M NaCl, 20 mM 3-(N-morpholino)-2-hydroxypropanesulfonic acid (MOPSO), pH 6.8, 2 mM dithiothreitol, various concentrations of Ca2+ buffered with 10 mM EGTA (calculated using the value of 8.79 x 105 M1 as the apparent binding constant for Ca2+ of EGTA; see Ref. 4), and 1 mM ,
-methyleneadenosine triphosphate (AMPPCP) unless otherwise indicated. For diaphragm SR vesicles, the amount of [3H]ryanodine bound to RyR1 and RyR3 were determined on the basis of the protein-bound radioactivity in the supernatant and the precipitated beads, respectively, after immunoprecipitating RyR3 with the anti-RyR3 antibody agarose beads (18). For epicranial muscle SR vesicles, the protein-bound [3H]ryanodine was separated by filtration through polyethyleneimine-treated Whatman GF/B filters (Whatman, Brentford, UK). In some experiments, CHAPS was added after mixing with half amounts of soybean lecithin (19). Dantrolene and azumolene were dissolved in dimethyl sulfoxide (10 mM as a stock solution). Nonspecific radioactivity was determined in the presence of 20 µM unlabeled ryanodine. The [3H]ryanodine binding data (indicated hereinafter by the variable B), which were obtained under various assay conditions in the presence of a fixed concentration of [3H]ryanodine (8.5 nM throughout these experiments), are expressed relative to the maximal binding sites for the ligand (Bmax); thus B/Bmax reflects apparent averaged activity of individual Ca2+ release channels. The Bmax value was calculated from the Scatchard plot of the amounts of bound [3H]ryanodine at various (1.836 nM) concentrations of [3H]ryanodine in the similar solution containing 1 M NaCl instead of 0.17 M. The Bmax values for RyR1 and RyR3 were 7.68.5 and 0.230.37 pmol/mg of protein, respectively.
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Ca2+ release measurements.
Ca2+ release from the isolated SR vesicles was fluorometrically measured by monitoring free Ca2+ concentration in the solution. Bovine epicranial SR vesicles (80 µg) were incubated at 25°C in a fluorometer cuvette containing 400 µl of 0.17 M KCl, 20 mM MOPSO, pH 6.8, 5 mM potassium phosphate, 10 mM phosphocreatine, 2 U/ml creatine kinase, and 2 µM fura-2. Fluorescence was measured using a Hitachi F-4500 fluorescence spectrophotometer with wavelength settings of 340 and 380 nm for excitation (alternating) and 510 nm for emission. The contaminating Ca2+ in the solution provided a sufficient extent of Ca2+ loading for Ca2+ release, and therefore no Ca2+ was added. Active loading of the SR vesicles with Ca2+ was started by addition of 1 mM Mg-ATP, which would give rise to 0.3 mM free Mg2+. Free Ca2+ concentration in the cuvette declined with time and reached the steady state within 5 min. At this point, test reagents (DP4 or caffeine) were added and the changes in fura-2 fluorescence were recorded.
Statistics. The data are expressed as means ± SE of n repeated experiments. Student's unpaired t-test was used to determine the significance of the differences between mean values.
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RESULTS |
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We next examined whether the combined effects of these reagents were additive or nonadditive (Fig. 3). In the presence of 2% CHAPS in experiments in which the activation reached the maximum (see Fig. 2B), the addition of DP4 did not cause a further increase in the activity up to 500 µM. With 1% CHAPS in experiments in which the activation was about half the maximum, DP4 showed a concentration-dependent activation but the maximal level attained was almost the same as the maximum attained in the presence of 2% CHAPS. Notably, the apparent EC50 value of DP4-induced activation was greater in the presence of 1% CHAPS than it was in its absence (from 50 µM in the control to
100 µM with 1% CHAPS), but again the maximum level remained the same. Thus the effects of DP4 and CHAPS are nonadditive. The highest attainable activation level was not due to the limitation of the assay system (e.g., saturation of [3H]ryanodine binding), because even much larger values were obtained with FK-506 (see Fig. 5) or at higher ionic strength (data not shown). These findings support the notion that DP4 and CHAPS act on RyR1 through a common activation mechanism.
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Dissociation of FKBP12 further increased [3H]ryanodine binding independently of DP4- and CHAPS-induced activation. FKBP12 is known to bind to RyR1 and RyR2 and to stabilize the channel in the closed state (11). A recent site-directed mutagenesis study demonstrated that Val2461 is the critical residue required for FKBP12 binding to RyR1 (3). Because Val2461 is located within the DP4 sequence, added DP4 might have competed with the corresponding domain of RyR1 to dissociate FKBP12 from RyR1, resulting in activation of the channel. To test this possibility, we examined the effect of DP4 on the amount of the RyR1-bound FKBP12. Incubation of the SR vesicles with 100 µM DP4 did not affect the amount of FKBP12 bound to the SR vesicles, whereas 10 µM FK-506 completely dissociated FKBP12 from the vesicles (Fig. 5A). No effect was observed with 100 µM DP4-mut either. [3H]Ryanodine binding to RyR1 in the presence of the maximally activating concentration of DP4 (300 µM) was further increased by 10 µM FK-506, the extent of which was similar to that of the control (Fig. 5B). This was also true with RyR1 treated with 2% CHAPS (Fig. 5B), the effect of which was independent of FKBP12 (19). Taken together, these results suggest that DP4 as well as CHAPS activates RyR1 through the mechanism independent of FKBP12-RyR1 interaction.
Effect of DP4 on single Ca2+ release channel activity in native SR and purified RyR1. Single-channel currents through the RyR1 channel were recorded in symmetrical solutions containing 250 mM KCl (or Cs-methanesulfonate) at a holding potential of 40 mV (see MATERIALS AND METHODS). We used both the native SR vesicles and purified RyR1. Although RyR1 has bound calmodulin and FKBP12 in the native SR (15, 24), the purified RyR1 is free of such associated proteins (17). With the native SR vesicles, 10 µM DP4 increased mean Po of the channel (Fig. 6A, left). A further increase in Po was observed with 30 µM DP4. With the purified RyR1, DP4 also activated the channel in a concentration-dependent manner (Fig. 6A, right). No significant change in the current amplitude was observed in either specimen. There was no difference between the purified RyR1 and the native SR vesicles with regard to the magnitude of activation by DP4 (Fig. 6B). Although the purified RyR1 contained 1% CHAPS, the detergent concentration had to be reduced to a negligible level when RyR1 was incorporated into the lipid bilayer. On the basis of the results shown in Fig. 2B, the effect of CHAPS is expected to be reversible. These findings suggest that DP4 directly activates RyR1 without any requirement of accessory modulators.
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DP4 (100 µM) increased [3H]ryanodine binding sixfold without substantial changes in Ca2+ dependence (Fig. 7A). The EC50 value for Ca2+ activation was slightly but significantly (P < 0.05) smaller in the presence of 100 µM DP4 (3.2 ± 0.5 µM) than that in control (5.1 ± 0.9 µM), whereas the IC50 value for Ca2+ inactivation was unchanged (0.32 ± 0.02 mM in control and 0.36 ± 0.03 mM with 100 µM DP4). The concentration dependence of Mg2+ inhibition is shown in Fig. 7B. Mg2+ decreased the [3H]ryanodine binding with or without 100 µM DP4, showing similar concentration dependence: the IC50 values for Mg2+ were 0.21 ± 0.06 mM (without DP4) and 0.13 ± 0.02 mM (with 100 µM DP4) (Fig. 7B).
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DISCUSSION |
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The main aim of the present study was to test whether the hypothesized interdomain interaction is involved in the CHAPS-induced activation and/or destabilization of the RyR1 channel. We examined the effects of CHAPS and DP4 on RyR1 of bovine skeletal muscle SR vesicles using a [3H]ryanodine binding assay. We have demonstrated that 1) DP4 and CHAPS activated RyR1 but not RyR3 (Fig. 1); 2) the two reagents showed the identical level of maximal activation (Fig. 2), and these activation effects were nonadditive (Fig. 3); 3) RyR1 activated by DP4 or CHAPS was inhibited by dantrolene and azumolene, showing an identical pattern of inhibition (Fig. 4); and 4) activation by DP4 or CHAPS was independent of FKBP12-dependent stabilization (Fig. 5). All of these findings suggest that DP4 and CHAPS share a common mechanism for the activation of RyR1.
An increasing body of evidence supports the hypothesis that the interactions between the two key domains harboring many of the reported MH mutations (NH2-terminal and central domains) play an important role in the regulation of RyR1 Ca2+ channels. Thus domain peptides and antibodies that bind specifically to either of these domains produced MH-like hyperactivation and hypersensitization of RyR1 channels (8, 10, 32, 36). The channel activation by these agents is well correlated with increased accessibility of the fluorescent probe, attached to either of these domains, to a macromolecular fluorescence quencher, indicative of an increased gap between the interacting domains, namely, domain unzipping (8, 37). Furthermore, dantrolene that binds to the Leu590-Cys609 region of the NH2-terminal domain of RyR1 (28) inhibited DP4- and anti-DP4 antibody-induced channel activation, accompanied by a decrease in the probe accessibility to the quencher (i.e., a decrease in the gap of the interacting domains, or domain zipping) (7). As described above, CHAPS- and DP4-induced channel activation share various common features in the process of not only channel activation but also channel inhibition by dantrolene. Thus it seems that the actual mechanism of CHAPS-induced activation and/or destabilization of the RyR1 channel is mediated by destabilization of the interacting domain pair consisting of the NH2-terminal and central domains. It is likely, then, that the hypothesized interdomain interaction is affected by CHAPS, resulting in enhanced activity of RyR1, the effect that is indistinguishable from the one caused by DP4. However, little is known about how the conformational signal elicited in the interacting domains can be transmitted to the channel, although there must be some mechanisms by which the channel is functionally coupled with the operation of these domains. There remains a strong possibility that DP4 and CHAPS change allosteric domain-domain and domain-channel interactions, reducing the free energy barrier to facilitate the change from the closed to the open state of the channel.
We previously proposed that the stabilization of RyR1 might cause reduction in the gain of CICR activity because the ligand sensitivity remains unchanged in the SR vesicles (19). In this study, 100 µM DP4 consistently increased the B/Bmax value of [3H]ryanodine binding (6- to 7-fold), regardless of the presence and absence of the CICR modulators, including Ca2+, Mg2+, AMPPCP, and caffeine (Figs. 7 and 8). No obvious alteration by DP4 was observed in the sensitivity to inactivating Ca2+ (Fig. 7A), Mg2+ (Fig. 7B), or activating AMPPCP (Fig. 8A), whereas slight sensitization was observed with activating Ca2+ (1.5-fold) (Fig. 7A) or caffeine (
2-fold) (Fig. 8B). The enhancing effect of DP4 with slight sensitization was also reported with rabbit skeletal muscle SR (36). These results suggest that the primary effect of DP4 is to increase the gain of CICR activity. This supports our hypothesis that the stabilization of RyR1 primarily causes the reduction in gain of CICR.
The importance of the CICR gain seems to have been overlooked often in previous investigations. It is difficult to compare CICR activity directly between different samples (e.g., SR vesicles from different tissues or cells expressing different RyR mutants) because of different RyR contents. Therefore, comparisons generally have been made after normalization of the activity with its peak activity (e.g., [3H]ryanodine binding at the optimum Ca2+) (see Fig. 7, A and B) to correct for the RyR contents. Such normalization is useful for determining the sensitivity to ligands (e.g., Ca2+, Mg2+, or caffeine) but may lead to misinterpretation of the CICR gain. We could overcome this problem by using the B/Bmax expression, which reflects apparent average activity of individual channels and holds the information about CICR gain (19). Thus the B/Bmax expression connoting the CICR gain is useful for the evaluation of CICR activity.
The concept of CICR gain may also explain some species differences with regard to caffeine sensitivity. For instance, it was found that caffeine easily causes contracture of frog skeletal muscle, but that it often is abortive in mammalian skeletal muscle (25, 35). In frog skeletal muscle, -RyR may account for most of the CICR activity because it shows a B/Bmax value (0.20.25) greater than that for
-RyR (as low as 0.009) (20). RyR1 demonstrated higher Ca2+ sensitivity for activation (EC50 of
5 µM in this study) than
-RyR (EC50 of
16 µM; see Ref. 20) but much lower B/Bmax (
0.02) than
-RyR. Thus the lower sensitivity to caffeine in mammalian skeletal muscle could reasonably be explained by lower CICR gain of RyR1.
Lamb et al. (10) recently reported that DP4 potentiated caffeine-induced Ca2+ release from the SR of rat skinned skeletal muscle fibers. They also found that DP4 by itself induced Ca2+ release when the cytoplasmic Mg2+ concentration ([Mg2+]i) was set at 0.2 mM, but not when it was set at 1 mM, suggesting that the Ca2+-releasing effect of DP4 by itself does not occur at physiological [Mg2+]i level, which was assumed to be 1 mM. In the present study, DP4 induced small, transient Ca2+ release from the SR vesicles (Fig. 9A), in which the free [Mg2+] was calculated to be
0.3 mM. At 1 mM [Mg2+]i, no significant Ca2+ release by DP4 (up to 100 µM) was observed (data not shown). Thus activation by DP4 alone is not sufficient for Ca2+ release in the presence of 1 mM Mg2+, but it may greatly potentiate caffeine-induced Ca2+ release (10) (Fig. 9). These features correlate well with the characteristics of MH, in which muscle contracture or Ca2+ release may occur only when it is exposed to specific drugs such as halothane or caffeine (16, 21). Thus the enhanced CICR activity induced by DP4 is likely to mimic the altered Ca2+ handling observed in the MH phenotype. The findings to date also imply that the low CICR gain of the RyR1 channel is critically important in normal Ca2+ handling in skeletal muscle.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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