Department of Pharmacology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
Submitted 16 September 2003 ; accepted in final form 10 February 2004
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ABSTRACT |
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excitation-contraction coupling; ryanodine binding; ryanodine receptor
Ca2+ release through the RyR channel in skeletal muscle can be activated by two distinct modes: depolarization-induced Ca2+ release (DICR) and Ca2+-induced Ca2+ release (CICR). DICR is triggered by conformational change of the voltage sensor, the dihydropyridine receptor (DHPR), upon depolarization of the T tubule (43, 45). On this occasion, extracellular Ca2+ entry is not necessarily required. CICR is a ligand-gated mode in which Ca2+ itself activates the channel in a dose-dependent manner (12). Recent studies with transgenic mice lacking either RyR1 or RyR3 and a heterologous expression system with RyR-deficient "dyspedic" myotubes revealed that RyR1 can act as both DICR and CICR channels, whereas RyR3 can mediate only CICR but not DICR in mammalian skeletal muscle (14, 51, 52).
We (35) have recently determined the properties of Ca2+-dependent [3H]ryanodine binding, a biochemical measure of CICR activity, of the two isoforms coexisting in the native SR vesicles of frog skeletal muscle. The results demonstrated that [3H]ryanodine binding activity of -RyR was as low as
4% that of
-RyR without alteration of sensitivity to CICR ligands such as Ca2+, adenine nucleotide, and caffeine. These results led to the conclusion that CICR of
-RyR was selectively "stabilized" in the native SR of frog skeletal muscle. This, in turn, means that CICR activity should be attributed largely to
-RyR in the skeletal muscle (35). This could also be the case with mammalian skeletal muscle where the contribution of RyR3 to CICR activity could be assumed to be greater than that expected from its amount (3, 44, 53). The disproportionately greater contribution of RyR3 would be particularly remarkable in the skeletal muscle during development, because there were temporary changes in its content during growth (3, 54). The stabilized CICR activity of RyR1, the major isoform, also should be consistent with the finding that Ca2+ sparks are seldom observed in mammalian skeletal muscle, whereas they are frequently observed in frog skeletal muscle (47). To prove these possibilities, in this study we determined [3H]ryanodine binding of each of RyR1 and RyR3 in bovine diaphragm SR vesicles. Our results clearly demonstrated RyR1 with a lowered gain of CICR activity in mammalian skeletal muscle compared with RyR3, i.e., RyR1 selectively stabilized in the native SR vesicles. It was also shown that the stabilization of RyR1 was explained by isoform-specific inhibition both byFKBP12 and by some protein-protein or protein-lipid interactions that are sensitive to 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). The latter turned out to be common between frog and mammals.
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MATERIALS AND METHODS |
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Isolation of SR vesicles. SR vesicles were prepared from bovine diaphragm (32). The isolated vesicles were quickly frozen in liquid N2 and stored at 80°C until used. Membrane protein was measured by the biuret method using bovine serum albumin as a standard. In some experiments, SR vesicles were further treated with myosin light chain kinase-derived calmodulin binding peptide (Calbiochem) according to Balshaw et al. (1) to make them free from calmodulin. Western blot analysis with anti-calmodulin antibody IM7 (22) confirmed that treatment with 10 µM (but not 1 µM) of the peptide effectively removed calmodulin from the SR to <10% of its original content.
Western blot analysis. SR proteins were separated by SDS-polyacrylamide gel electrophoresis with 212% linear gradient gels. Gels were electrophoretically transferred onto polyvinylidene difluoride membranes. Western blotting was carried out with an enhanced chemiluminescence system (ECL; Amersham Biosciences) using peroxidase-conjugated secondary antibodies. Primary antibodies for RyR1, RyR3, DHPR, and FKBP12 were used at 1:20,000, 1:1,000, 1:5,000 and 1:1,000 dilutions, respectively.
Determination of [3H]ryanodine binding to RyR isoforms in native SR vesicles. Assays were essentially the same as the method described previously (35). Briefly, bovine diaphragm SR vesicles (200 µg of protein) were incubated with 8.5 nM [3H]ryanodine for 5 h at 25°C in 200 µl of a medium containing 0.17 M NaCl, 20 mM 3-(N-morpholino)-2-hydroxypropanesulfonic acid (MOPSO)-NaOH, pH 6.8, 2 mM dithiothreitol, various Ca2+ concentrations buffered with 10 mM EGTA, and 1 mM AMPPCP, unless otherwise indicated. The vesicles were then supplemented with 20 µM nonradioactive ryanodine to terminate incorporation of the radioactive ligand, cooled to 4°C, and solubilized with 1% CHAPS and 0.5% lecithin. All subsequent steps were carried out at 4°C; this is critically important to prevent the bound [3H]ryanodine from dissociating from RyRs (see Ref. 35). RyR3 was specifically immunoprecipitated by overnight incubation with the anti-RyR3 antibody-agarose beads (33). The radioactivity responsible for RyR1 was determined from the supernatant by filtration through polyethyleneimine-treated Whatman GF/B filters. The precipitated agarose beads were washed three times with the ice-cold medium containing 0.5 M NaCl, 20 mM MOPSO/NaOH, pH 6.8, 1% CHAPS, 0.5% lecithin, and 2 mM dithiothreitol. The radioactivity responsible for RyR3 was recovered by incubating the beads with 0.1 M glycine-HCl (pH 1.5). Nonspecific radioactivity was determined in the presence of 20 µM unlabeled ryanodine at the onset of the binding reaction.
French press and sucrose density gradient ultracentrifugation. The SR vesicles were diluted with 0.15 M KCl and 20 mM MOPSO/NaOH, pH 6.8, at a concentration of 10 mg/ml. They were then passed through a French press (2 cycles at 6,000 lb./in.2) (7). The sample was placed on top of four layers of sucrose [0.8 M (12 ml), 1.1 M (10 ml), 1.3 M (10 ml), and 1.6 M (5 ml)], buffered at pH 6.8 with 20 mM MOPSO/NaOH, and centrifuged at 25,000 rpm in a Hitachi SRP28SA rotor overnight at 4°C. The 1.3 M-1.6 M sucrose interface that contains the terminal cisterna (TC) fraction was collected, diluted with the above medium, sedimented by ultracentrifugation, and resuspended in the medium containing 0.3 M sucrose.
Statistics. Quantitative data are given as means ± SE of the number of repeated experiments (n). For determination of the significance of the difference between mean values, Student's unpaired t-test was applied.
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RESULTS |
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Separation of the isoforms was achieved by immunoprecipitation with an anti-RyR3 antibody that specifically reacts with RyR3 among three mammalian RyR isoforms (34). As shown in Fig. 1A, immunoprecipitation with the antibody specifically and completely precipitated RyR3 into the beads from CHAPS-solubilized SR vesicles, with RyR1 remaining in the supernatant. This precipitation was prevented by addition of an epitope peptide (RyR3-peptide). With the use of vesicles that had been incubated with [3H]ryanodine, significant radioactivity was detected in the beads immunoprecipitated with the anti-RyR3 antibody, with the complementing radioactivity in the supernatant (Fig. 1B). In contrast, no radioactivity was detected in the beads with control IgG or in the presence of the RyR3-peptide, where RyR3 did not precipitate. These findings indicate that radioactivities of the supernatant and of the beads represent the [3H]ryanodine bound to RyR1 and RyR3, respectively. The antibody did not affect the [3H]ryanodine binding activity of the purified RyR3 (32), indicating no artificial modification of the RyR3 activity in the procedure. Thus this procedure determined the [3H]ryanodine binding activity of each of RyR1 and RyR3 in bovine diaphragm SR.
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The stabilized activity of RyR1 means that the functional contribution of RyR1 in CICR activity should be less than the magnitude expected from its abundance in the muscle. In other words, the contribution of RyR3 would be much higher. In fact, about one-fifth of the total binding was attributed to RyR3, although its amount was as small as 4% of the total RyR channels (Fig. 3A). These situations reasonably explain the previous unexpected results of the much greater contribution of RyR3 to Ca2+ release in skeletal muscles of RyR1- or RyR3-knockout mice (3, 53).
Similar responses of RyR1 and RyR3 to adenine nucleotides, Mg2+, and caffeine. Figure 4 demonstrates the dose-dependent enhancing effect of AMPPCP, a nonhydrolyzable ATP analog, on RyR1 and RyR3 in the presence of 100 µM Ca2+, a concentration at which Ca2+ activation is near the optimum. The [3H]ryanodine binding of the two isoforms similarly increased with increases in AMPPCP and reached a plateau around 1 mM. The apparent EC50 values of AMPPCP were estimated to be 0.3 mM for both isoforms. Thus the sensitivity of RyR3 to activation by adenine nucleotides is similar to that of RyR1.
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Effect of high salt on stabilization of RyR1. High salt clearly stimulates the channel activity of RyRs (28, 36). To examine whether high salt destabilizes RyR1, we examined its effect on the [3H]ryanodine binding to RyR1 and RyR3 (Fig. 9). An increase in NaCl concentration from 0.17 to 1 M greatly enhanced the binding to RyR1 (from 0.14 ± 0.02 to 2.0 ± 0.2 pmol/mg, n = 3) and to RyR3 (from 0.051 ± 0.004 to 0.31 ± 0.03 pmol/mg, n = 3) (Fig. 9A). The extent of increase was greater in RyR1 (14-fold) than in RyR3 (6-fold). In 1 M NaCl medium, the binding of RyR1 was further increased by FK506 (3.6 ± 0.1 pmol/mg, n = 3) or CHAPS/phospholipids (4.7 ± 0.2 pmol/mg, n = 3), indicating that high salt and FK506 or CHAPS/phospholipids are additive to each other in activating RyR1 (Fig. 9B). By combining FK506 and CHAPS/phospholipids, the binding was further increased to 5.1 ± 0.3 pmol/mg (n = 3), which corresponds to Bmax. The combined effect of the two treatments was probably saturated in magnitude. In contrast, no further increase by these treatments was observed with RyR3, as was true in 0.17 M NaCl medium (see Figs. 7 and 8). It should be pointed out that [3H]ryanodine binding sites of RyR3 were almost saturated with the ligand in the 1 M NaCl medium. Taken together, these results suggest that stimulation by high salt may be different in the underlying mechanisms from that by FK506 or CHAPS/phospholipids.
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We also examined whether calmodulin coexisting in SR vesicle preparation is involved in the stabilization. SR vesicles were treated with myosin light chain kinase-derived calmodulin-binding peptide, which is reported to bind to calmodulin with a high affinity and thus remove it from the vesicles (1). Western blot analysis with anti-calmodulin monoclonal antibody IM7 (22) revealed that this treatment with an excess amount of the calmodulin binding peptide (10 µM) effectively removed calmodulin from SR (<10% of original content), but the [3H]ryanodine binding of RyR1 was not significantly changed (0.20 ± 0.02 pmol/mg in control vs. 0.24 ± 0.02 pmol/mg in treated SR, n = 3). This excludes the possible involvement of calmodulin in the stabilization of RyR1.
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DISCUSSION |
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We (35) previously showed that -RyR is selectively stabilized in the CICR activity in frog skeletal muscle. The common characteristics of the stabilization between mammalian and frog muscles are as follows: 1) stabilized isoforms (RyR1 and
-RyR) show greatly lowered affinity for ryanodine; 2) modulation by Ca2+, Mg2+, adenine nucleotides, or caffeine remains unaffected even in the stabilized state; and 3) stabilization is reversed by CHAPS/phospholipids. Thus the stabilized CICR activity of RyR1 homologues may be well conserved among vertebrate skeletal muscles. Some interesting differences also were obvious between them. First, the extent of stabilization was greater in frog than in bovine muscle; B/Bmax values of
-RyR and RyR1 were 0.009 and 0.037, respectively. In other words, the magnitude of the stabilization with
-RyR (
4%) was greater than that with RyR1 (
15%), because
-RyR and RyR3 showed similar B/Bmax values of 0.200.25. Second, whereas the stabilization of RyR1 was caused by both FKBP12 and the CHAPS/phospholipids-sensitive mechanism, the latter is likely to be fully responsible for the stabilization of
-RyR because of lack of the effect of FK506 (35). Thus
-RyR might not be regulated by FKBP12 in frog skeletal muscle. It seems interesting that the partial amino acid sequence of FKBP12 coprecipitated with
-RyR was more similar to that of mammalian FKBP12.6 than to FKBP12.0 (35).
It was reported that RyR3 is sensitive to ligands for CICR, e.g., Ca2+, Mg2+, adenine nucleotide, and caffeine (8, 21, 32, 33). The present results demonstrated that the responses of RyR3 to Mg2+, adenine nucleotide, and caffeine are similar to those of RyR1 (Figs. 46). RyR3 was slightly lower than RyR1 in Ca2+ sensitivity to not only activating but also inactivating Ca2+ (Fig. 3A), consistent with the previous findings with the purified isoforms (32, 33) and with skinned muscle fibers from dyspedic mice (53). The most notable difference is that RyR3 was not stabilized at all in the SR vesicles, in marked contrast to RyR1. The B/Bmax value for RyR3 was sevenfold greater than that for RyR1 (Fig. 3B). Thus RyR3 may form Ca2+ release channels characteristic of the unstabilized activity compared with the RyR1 channels. This means that RyR3 could contribute to the CICR activity much more than that expected from its amount in the muscle. This can reasonably explain the previous results of an unexpectedly much greater contribution of RyR3 to Ca2+ release in skeletal muscles of RyR-knockout mice (3, 53). It is also possible that the unstabilized activity of RyR3 might appear to enhance the sensitivity of CICR to Ca2+ or ligands such as caffeine. In fact, the B/Bmax values of single RyR3 were higher than those of the single RyR1 at all Ca2+ concentrations (Fig. 3B). These situations might explain the previous reports of greater sensitivity of RyR3 to caffeine in Ca2+ sparks with myotubes from RyR-knock out mice (10) or Ca2+ transients in 1B5 cells expressing RyR (14).
The selective stabilization of RyR1 is entirely due to the state of RyR1 at which the isoform shows a reduced affinity for [3H]ryanodine. It is important to note that the stabilization cannot be brought about by changes in the sensitivity to CICR ligands such as Ca2+, Mg2+, adenine nucleotide, or caffeine (Figs. 36). Thus stabilization may be independent of the responses to CICR ligands. These findings suggest that the activity of RyR1 channels would always be stabilized in muscle, irrespective of the changes in the environment or state of muscle (resting or contracting). This, in turn, implies that abnormality in the stabilization of RyR1 would cause substantial changes in Ca2+ homeostasis that might lead to critical disorder in the muscle as discussed below.
We found that the stabilization of RyR1 is attributed partly to FKBP12 (Fig. 7) and partly to some mechanism sensitive to CHAPS/phospholipids (Fig. 8). The fact that the effects of FK506 and CHAPS/phospholipids are additive suggests that the mechanisms are independent of each other. We found that FKBP12 interacts with RyR1 but weakly with RyR3 in skeletal muscle. The lack of FKBP12 interaction of RyR3 is consistent with recent reports (6, 14). Interestingly, stabilization still occurred under high salt conditions where the RyR activity is known to be greatly enhanced (28, 36) (Fig. 9). Thus destabilization is different in a mechanism than stimulation by high salt. The fact that high salt enhanced the binding not only to RyR1 but also to RyR3 may support this idea.
The stabilization of RyR1 was partially reversed by CHAPS/phospholipids (Fig. 8A). It was also demonstrated that CHAPS/phospholipids alter Ca2+ sensitivity of RyR1 (41). These results suggest that some protein-protein or protein-lipid interactions sensitive to CHAPS are critically involved in the stabilization and function of RyR1. It is also possible that lecithin added with CHAPS might directly increase the activity of RyR1, because a recent report (5) demonstrated that the RyR channel activity was affected by the composition of phospholipids. Lecithin used here, however, cannot be the cause of destabilization of RyR1 because destabilization by CHAPS was also found in the absence of lecithin. The stabilization was still observed with the TC-rich fraction, indicating that it occurs in the SR vesicle itself but not through interaction with T tubules (Fig. 10B). Thus proteins or lipids of TC membranes are plausible candidates for the stabilization. Neither coexisting RyR3 (Fig. 10A) nor calmodulin was the cause. Several molecules have been reported to inhibit the RyR channel activity, such as triadin (17), calsequestrin (2), and sphingolipids (46). It is also likely that the stabilization of RyR1 may be caused by interactions within or between four monomers of RyR1 tetramers. This is supported by findings that the "purified" RyR1 channels display lower open probability than RyR3 channels in planar lipid bilayer experiments (8, 32). Thus stabilization may be the inherent nature of the RyR1 channels in vertebrate skeletal muscles. Recently, Yamamoto et al. (55) demonstrated that a peptide corresponding to amino acid sequence 24422477 of rabbit RyR1 (DP4) increased the Ca2+ release activity of RyR1. They suggested that the peptide probably acts by competing for the NH2-terminal domain that normally interacts with the central domain of RyR1 to stabilize the channel activity (19). It is quite possible that such intermolecular interactions are sensitive to CHAPS. Further characterizations are necessary to clarify the mechanisms of stabilization.
In physiological Ca2+ release, RyR1 channels are activated by conformational changes of DHPR upon depolarization of the T tubule (45). In the triad junction, tetrad (four assembled DHPRs) in the T tubule is tightly apposed alternately to every other foot (RyR tetramer) in the SR (16). This indicates that half of the RyR1 channels are coupled to DHPR and the other half are not. It is therefore postulated that the "uncoupled" RyR1 channels might act as the CICR channels amplifying Ca2+ that was released by DICR via the "coupled" channels (45). Our results indicate that the CICR activity of RyR1 may be greatly stabilized in the native SR vesicles. In addition, Mg2+ in the cytoplasm also strongly inhibits RyR in skeletal muscle (28, 36) (see Fig. 5). Thus the CICR activity of RyR1 may be very low in mammalian skeletal muscle. This seems unfavorable for the suggestion that RyR1 could amplify Ca2+ by the CICR mechanism. The contribution of CICR via the RyR1 channels to the physiological Ca2+ release might be minor, if any; rather, RyR3 would be favorable as an amplifier of Ca2+ because it is not stabilized at all in skeletal muscle. In this sense, it seems reasonable that Ca2+ sparks are easily observed in frog skeletal muscle, where an almost equal amount of -RyR is expressed, whereas no or very few sparks are detected in adult mammalian muscles, which primarily express RyR1 (47).
Our present results also provide an interesting idea about etiology for malignant hyperthermia (MH) (26). MH is linked with a missense mutation of a single amino acid residue of RyR1 that should enhance the CICR activity. The mutated sites are largely classified into three regions, but the mutations are broadly distributed within these regions (19, 26). Hypotheses proposed to date are that these mutations should alter the sensitivity of mutated RyR1 to Ca2+/Mg2+ or to the Ca2+-releasing agents (19, 26). It would be quite interesting if the MH mutations cause destabilization of RyR1, resulting in an enhanced CICR activity as seen with CHAPS. This is consistent with the idea proposed by Yamamoto et al. (55). In pigs, it was reported that solubilization with CHAPS/phospholipids or the presence of high salt eliminated the differences in the [3H]ryanodine binding between MH and normal SR vesicles (49). Further investigations are required to clarify the mechanism and the physiological and/or pathological significance of this selective stabilization of CICR in RyR1.
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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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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Beard NA, Sakowska MM, Dulhunty AF, and Laver DR. Calsequestrin is an inhibitor of skeletal muscle ryanodine receptor calcium release channels. Biophys J 82: 310320, 2002.
3. Bertocchini F, Ovitt CE, Conti A, Barone V, Scholer HR, Bottinelli R, Reggiani C, and Sorrentino V. Requirement for the ryanodine receptor type 3 for efficient contraction in neonatal skeletal muscles. EMBO J 16: 69566963, 1997.
4. Bultynck G, De Smet P, Rossi D, Callewaert G, Missiaen L, Sorrentino V, De Smedt H, and Parys JB. Characterization and mapping of the 12 kDa FK506-binding protein (FKBP12)-binding site on different isoforms of the ryanodine receptor and of the inositol 1,4,5-trisphosphate receptor. Biochem J 354: 413422, 2001.[CrossRef][ISI][Medline]
5. Cannon B, Hermansson M, Gyorke S, Somerharju P, Virtanen JA, and Cheng KH. Regulation of calcium channel activity by lipid domain formation in planar lipid bilayers. Biophys J 85: 933942, 2003.
6. Carmody M, Mackrill JJ, Sorrentino V, and O'Neill C. FKBP12 associates tightly with the skeletal muscle type 1 ryanodine receptor, but not with other intracellular calcium release channels. FEBS Lett 505: 97102, 2001.[CrossRef][ISI][Medline]
7. Caswell AH, Lau YH, Garcia M, and Brunschwig JP. Recognition and junction formation by isolated transverse tubules and terminal cisternae of skeletal muscle. J Biol Chem 254: 202208, 1979.[ISI][Medline]
8. Chen SRW, Li X, Ebisawa K, and Zhang L. Functional characterization of the recombinant type 3 Ca2+ release channel (ryanodine receptor) expressed in HEK293 cells. J Biol Chem 272: 2423424246, 1997.
9. Chugun A, Taniguchi K, Murayama T, Uchide T, Hara Y, Temma K, Ogawa Y, and Akera T. Subcellular distribution of ryanodine receptors in the cardiac muscle of carp (Cyprinus carpio). Am J Physiol Regul Integr Comp Physiol 285: R601R619, 2003.
10. Conklin MW, Ahern CA, Vallejo P, Sorrentino V, Takeshima H, and Coronado R. Comparison of Ca2+ sparks produced independently by two ryanodine receptor isoforms (type 1 or type 3). Biophys J 78: 17771785, 2000.
11. Conti A, Gorza L, and Sorrentino V. Differential distribution of ryanodine receptor type 3 (RyR3) gene product in mammalian skeletal muscles. Biochem J 316: 1923, 1996.[ISI][Medline]
12. Endo M. Calcium release from the sarcoplasmic reticulum. Physiol Rev 57: 71108, 1977.
13. Felder E and Franzini-Armstrong C. Type 3 ryanodine receptors of skeletal muscle are segregated in a parajunctional position. Proc Natl Acad Sci USA 99: 16951700, 2002.
14. Fessenden JD, Wang Y, Moore RA, Chen SR, Allen PD, and Pessah IN. Divergent functional properties of ryanodine receptor types 1 and 3 expressed in a myogenic cell line. Biophys J 79: 25092525, 2000.
15. Flucher BE, Conti A, Takeshima H, and Sorrentino V. Type 3 and type 1 ryanodine receptors are localized in triads of the same mammalian skeletal muscle fibers. J Cell Biol 146: 621630, 1999.
16. Franzini-Armstrong C and Protasi F. Ryanodine receptors of striated muscles: a complex channel capable of multiple interactions. Physiol Rev 77: 699729, 1997.
17. Groh S, Marty I, Ottolia M, Prestipino G, Chapel A, Villaz M, and Ronjat M. Functional interaction of the cytoplasmic domain of triadin with the skeletal ryanodine receptor. J Biol Chem 274: 1227812283, 1999.
18. Harafuji H and Ogawa Y. Re-examination of the apparent binding constant of ethylene glycol bis (-aminoethyl ether)-N,N,N',N'-tetraacetic acid with calcium around neutral pH. J Biochem (Tokyo) 87: 13051312, 1980.[ISI][Medline]
19. Ikemoto N and Yamamoto T. Regulation of calcium release by interdomain interaction within ryanodine receptors. Front Biosci 7: d671d683, 2002.[ISI][Medline]
20. Jeyakumar LH, Ballester L, Cheng DS, McIntyre JO, Chang P, Olivey HE, Rollins-Smith L, Barnett JV, Murray K, Xin HB, and Fleischer S. FKBP binding characteristics of cardiac microsomes from diverse vertebrates. Biochem Biophys Res Commun 281: 979986, 2001.[CrossRef][ISI][Medline]
21. Jeyakumar LH, Copello JA, O'Malley AM, Wu GM, Grassucci R, Wagenknecht T, and Fleischer S. Purification and characterization of ryanodine receptor 3 from mammalian tissue. J Biol Chem 273: 1601116020, 1998.
22. Kobayashi K, Yoshida M, Shinoda Y, Yazawa M, and Yagi K. Monoclonal antibodies toward scallop (Patinopecten yessoensis) testis and wheat germ calmodulins. J Biochem (Tokyo) 109: 551558, 1991.[Abstract]
23. Kurebayashi N, Takeshima H, Nishi M, Murayama T, Suzuki E, and Ogawa Y. Changes in Ca2+ handling in adult MG29-deficient skeletal muscle. Biochem Biophys Res Commun 310: 12661272, 2003.[CrossRef][ISI][Medline]
24. Laver DR, Baynes TM, and Dulhunty AF. Magnesium inhibition of ryanodine-receptor calcium channels: evidence for two independent mechanisms. J Membr Biol 156: 213229, 1997.[CrossRef][ISI][Medline]
25. Lohn M, Jessner W, Furstenau M, Wellner M, Sorrentino V, Haller H, Luft FC, and Gollasch M. Regulation of calcium sparks and spontaneous transient outward currents by RyR3 in arterial vascular smooth muscle cells. Circ Res 89: 10511057, 2001.
26. Loke J and MacLennan DH. Malignant hyperthermia and central core disease: disorders of Ca2+ release channels. Am J Med 104: 470486, 1998.[CrossRef][ISI][Medline]
27. Marks AR. Cellular functions of immunophilins. Physiol Rev 76: 631649, 1996.
28. Meissner G. Ryanodine receptor/Ca2+ release channels and their regulation by endogenous effectors. Annu Rev Physiol 56: 485508, 1994.[CrossRef][ISI][Medline]
29. Meissner G and El-Hashem A. Ryanodine as a functional probe of the skeletal muscle sarcoplasmic reticulum Ca2+ release channel. Mol Cell Biochem 114: 119123, 1992.[ISI][Medline]
30. Meissner G, Rios E, Tripathy A, and Pasek DA. Regulation of skeletal muscle Ca2+ release channel (ryanodine receptor) by Ca2+ and monovalent cations and anions. J Biol Chem 272: 16281638, 1997.
31. Murayama T, Kurebayashi N, and Ogawa Y. Role of Mg2+ in Ca2+-induced Ca2+ release through ryanodine receptors of frog skeletal muscle: modulations by adenine nucleotides and caffeine. Biophys J 78: 18101824, 2000.
32. Murayama T, Oba T, Katayama E, Oyamada H, Oguchi K, Kobayashi M, Otsuka K, and Ogawa Y. Further characterization of the type 3 ryanodine receptor (RyR3) purified from rabbit diaphragm. J Biol Chem 274: 1729717308, 1999.
33. Murayama T and Ogawa Y. Characterization of type 3 ryanodine receptor (RyR3) of sarcoplasmic reticulum from rabbit skeletal muscles. J Biol Chem 272: 2403024037, 1997.
34. Murayama T and Ogawa Y. Properties of Ryr3 ryanodine receptor isoform in mammalian brain. J Biol Chem 271: 50795084, 1996.
35. Murayama T and Ogawa Y. Selectively suppressed Ca2+-induced Ca2+ release activity of -ryanodine receptor (
-RyR) in frog skeletal muscle sarcoplasmic reticulum: potential distinct modes in Ca2+ release between
- and
-RyR. J Biol Chem 276: 29532960, 2001.
36. Ogawa Y. Role of ryanodine receptors. Crit Rev Biochem Mol Biol 29: 229274, 1994.[Abstract]
37. Ogawa Y and Harafuji H. Effect of temperature on [3H]ryanodine binding to sarcoplasmic reticulum from bullfrog skeletal muscle. J Biochem (Tokyo) 107: 887893, 1990.[Abstract]
38. Ogawa Y and Harafuji H. Osmolarity-dependent characteristics of [3H]ryanodine binding to sarcoplasmic reticulum. J Biochem (Tokyo) 107: 894898, 1990.[Abstract]
39. Ogawa Y, Kurebayashi N, and Harafuji H. Cooperative interaction between Ca2+ and ,
-methylene adenosine triphosphate in their binding to fragmented sarcoplasmic reticulum from bullfrog skeletal muscle. J Biochem (Tokyo) 100: 13051318, 1986.[Abstract]
40. Ogawa Y, Kurebayashi N, and Murayama T. Ryanodine receptor isoforms in excitation-contraction coupling. Adv Biophys 36: 2764, 1999.[CrossRef][ISI][Medline]
41. Ogawa Y, Murayama T, and Kurebayashi N. Comparison of properties of Ca2+ release channels between rabbit and frog skeletal muscles. Mol Cell Biochem 190: 191201, 1999.[CrossRef][ISI][Medline]
42. Protasi F, Takekura H, Wang Y, Chen SR, Meissner G, Allen PD, and Franzini-Armstrong C. RYR1 and RYR3 have different roles in the assembly of calcium release units of skeletal muscle. Biophys J 79: 24942508, 2000.
43. Rios E and Pizarro G. Voltage sensor of excitation-contraction coupling in skeletal muscle. Physiol Rev 71: 849908, 1991.
44. Rossi R, Bottinelli R, Sorrentino V, and Reggiani C. Response to caffeine and ryanodine receptor isoforms in mouse skeletal muscles. Am J Physiol Cell Physiol 281: C585C594, 2001.
45. Schneider MF. Control of calcium release in functioning skeletal muscle fibers. Annu Rev Physiol 56: 463484, 1994.[CrossRef][ISI][Medline]
46. Sharma C, Smith T, Li S, Schroepfer GJ Jr, and Needleman DH. Inhibition of Ca2+ release channel (ryanodine receptor) activity by sphingolipid bases: mechanism of action. Chem Phys Lipids 104: 111, 2000.[CrossRef][ISI][Medline]
47. Shirokova N, Garcia J, and Rios E. Local calcium release in mammalian skeletal muscle. J Physiol 512: 377384, 1998.
48. Shirokova N, Shirokov R, Rossi D, Gonzalez A, Kirsch WG, Garcia J, Sorrentino V, and Rios E. Spatially segregated control of Ca2+ release in developing skeletal muscle of mice. J Physiol 521: 483495, 1999.
49. Shomer NH, Louis CF, Fill M, Litterer LA, and Mickelson JR. Reconstitution of abnormalities in the malignant hyperthermia-susceptible pig ryanodine receptor. Am J Physiol Cell Physiol 264: C125C135, 1993.
50. Sutko JL and Airey JA. Ryanodine receptor Ca2+ release channels: does diversity in form equal diversity in function? Physiol Rev 76: 10271071, 1996.
51. Takeshima H, Iino M, Takekura H, Nishi M, Kuno J, Minowa O, Takano H, and Noda T. Excitation-contraction uncoupling and muscular degeneration in mice lacking functional skeletal muscle ryanodine-receptor gene. Nature 369: 556559, 1994.[CrossRef][ISI][Medline]
52. Takeshima H, Ikemoto T, Nishi M, Nishiyama N, Shimuta M, Sugitani Y, Kuno J, Saito I, Saito H, Endo M, Iino M, and Noda T. Generation and characterization of mutant mice lacking ryanodine receptor type 3. J Biol Chem 271: 1964919652, 1996.
53. Takeshima H, Yamazawa T, Ikemoto T, Takekura H, Nishi M, Noda T, and Iino M. Ca2+-induced Ca2+ release in myocytes from dyspedic mice lacking the type-1 ryanodine receptor. EMBO J 14: 29993006, 1995.[Abstract]
54. Tarroni P, Rossi D, Conti A, and Sorrentino V. Expression of the ryanodine receptor type 3 calcium release channel during development and differentiation of mammalian skeletal muscle cells. J Biol Chem 272: 1980819813, 1997.
55. Yamamoto T, El-Hayek R, and Ikemoto N. Postulated role of interdomain interaction within the ryanodine receptor in Ca2+ channel regulation. J Biol Chem 275: 1161811625, 2000.