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* Department of Physiology, Texas Tech University Health Sciences Center, Lubbock, Texas; and Department of Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana
Correspondence: Address reprint requests to Dr. Sandor Györke, Dept. of Physiology, Texas Tech University Health Sciences Center, 3601 4th St., STOP 6551, Lubbock, TX 79430-6551. Fax: 806-743-1512; E-mail: sandor.gyorke{at}ttuhsc.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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; Li and Chen, 2001). When RyR channels open, a much larger amount of Ca is released to the myoplasm, leading to activation of contractile proteins. This mechanism is known as Ca-induced Ca release (CICR) (Fabiato, 1985; Bers, 2002). Besides the high-affinity cytosolic activation sites, the RyR channel is positively controlled by low-affinity Ca sensing sites accessible from the luminal side of the channel (Lukyanenko et al., 1996; Györke and Györke, 1998; Ching et al., 2000). Dissociation of Ca from these sites on decline of intra-SR [Ca] ([Ca]SR) leads to RyR deactivation and robust termination of CICR, permitting cardiac relaxation (Terentyev et al., 2002). RyRs, sensitive to levels of Ca in the SR, also render a luminal Ca-dependent leak pathway that plays an important role in setting the SR Ca content and in shaping the response of cardiac cells to various inotropic influences that affect the Ca release or uptake mechanisms (Lukyanenko et al., 2001; Shannon, et al., 2002). Abnormal regulation of RyRs by luminal Ca has been implicated in certain pathological states, including Ca overload, arrhythmia, and heart failure (Györke et al., 2002; Terentyev et al., 2003).
Although significant progress has been made in elucidating the molecular basis of RyR activation by cytosolic Ca (Meissner et al., 1997; Li and Chen, 2001), the molecular mechanisms of luminal Ca sensing remain unknown. One possibility is that the luminal calcium sensor is a part of the RyR protein itself. Alternatively, auxiliary proteins in the heart with luminal localization, such as calsequestrin (CSQ), triadin 1, and junctin, could mediate the effects of luminal Ca on RyR (Ikemoto et al., 1989; Donoso et al., 1995; Zhang et al., 1997; Shin et al., 2000). Cardiac CSQ is a major Ca binding protein in the SR lumen (Scott et al., 1988; Jones et al., 1998) that undergoes conformational changes upon Ca binding (Mitchell et al., 1988) and interacts with RyR either directly (Herzog et al., 2000) or via triadin 1 and junctin (Zhang et al., 1997). Functional studies of RyR modulation by CSQ, mostly conducted with the skeletal muscle isoform, have yielded controversial results. In lipid bilayer studies, adding skeletal muscle CSQ to the luminal side of RyR has been reported to either increase (Kawasaki and Kasai, 1994; Ohkura et al., 1998; Szegedi et al., 1999) or decrease skeletal muscle RyR activity (Beard et al., 2002). Understanding of the role of CSQ as the potential luminal Ca sensor for RyR is further complicated by the fact that high luminal Ca concentrations that lead to maximal RyR potentiation are also known to dissociate CSQ from the RyR complex (Zhang et al., 1997).
Triadin 1 (Kobayashi and Jones, 1999) and junctin (Jones et al., 1995) are transmembrane proteins that form quaternary complexes between themselves, RyR, and CSQ (Zhang et al., 1997; Kobayashi and Jones, 1999; Jones et al., 1995; Kobayashi et al., 2000). The structures of both triadin 1 and junctin have luminal domains with areas of highly dense, charged amino acid residues that could form the putative luminal Ca receptor (Kobayashi and Jones, 1999; Jones et al., 1995; Kobayashi et al., 2000). Alternatively, these proteins could be involved in luminal Ca sensing by mediating interactions between RyR and CSQ (Zhang et al., 1997). In this study, we examined the impact of purification of canine cardiac RyR and the effects of subsequent reassociation of the purified channel with canine cardiac CSQ, triadin 1, and junctin on the functional activity of the RyR channel and its ability to sense luminal Ca. The results show that a complex of CSQ, triadin 1, and/or junctin confers luminal Ca sensitivity to RyR. CSQ apparently serves as a luminal Ca sensor that inhibits RyR channel activity at low luminal [Ca]; furthermore, triadin 1 and/or junctin are stimulatory by themselves and are required to mediate the inhibitory interactions between CSQ and the RyR channel.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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). Bilayers were composed of 80% phosphatidylethanolamine and 20% phosphatidylcholine dissolved in decane at a final concentration of 50 mg/ml. Channel incorporation was performed in solutions containing (in mM) 350 CsCH3SO3, 0.02 CaCl2, and 20 Hepes (pH 7.4), on the cis (cytosolic) side of the bilayer, and 20 CsCH3SO3, 0.02 CaCl2, and 20 Hepes (pH 7.4) on the trans (luminal) side of the bilayer. The experimental solutions contained (in mM) 350 CsCH3SO3, 3 MgATP, 0.6 MgCl2 (free [Mg2+] 
0.9 mM), 0.02 CaCl2, and 20 Hepes, pH 7.4 (cis), and 350 CsCH3SO3, 0.02 CaCl2, and 20 Hepes, pH 7.4 (trans). The holding potential in all experiments was +40 mV. Single channel currents were recorded with an Axopatch 200A (Axon Instruments, Foster City, CA) patch-clamp amplifier. Acquisition and analysis of data were performed using pClamp 6.01 software (Axon Instruments). Data are presented as mean ± SE. Paired or unpaired data sets were statistically evaluated using a Student's t-test or a Mann-Whitney U test (P < 0.05), as appropriate. Canine cardiac RyRs were purified from SR vesicles using methods of Lai et al. (1988) and Zhang et al. (1997). These methods yield samples of purified RyRs that do not contain junctin, triadin, and calsequestrin (Zhang et al., 1997; Beard et al., 2002). Recombinant purified canine cardiac calsequestrin (Kobayashi et al., 2000), junctin (Zhang et al., 1997), and triadin 1 (Kobayashi and Jones, 1999) were obtained as described. To test the effects of calsequestrin, junctin, and triadin 1 on the RyR channel activity, the purified proteins were added to the trans chamber at concentrations of 5–20 µg/ml. CSQ was stored and added from a buffer solution containing 20 mM Mops, 150 mM NaCl (pH 7.0), and 3 mg/ml of the protein; the solutions containing triadin 1 and junctin (-1.0 mg/ml) included 1% CHAPS, 0.8 M NaCl, and 20 mM Mops (pH 7.2). |
RESULTS |
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), the native RyRs responded with a dramatic increase in Po; however, the purified RyRs showed negligible difference in channel activity upon increasing luminal Ca concentration. Traces of native and purified controls (Fig. 1, A I and B III, respectively) as well as the activity upon luminal [Ca] increase can be seen in Fig. 1 (native and purified luminal traces in Fig. 1, A II and B IV, respectively). Pooled data for these conditions show that the native RyR channel activity increased from a Po of 0.08 to a Po of 0.40, whereas the purified channels remained virtually unaffected from a Po of 0.12 to 0.15 (Fig. 1 C). These results suggested that the luminal Ca sensor is not located on the RyR protein itself, but may be part of a complex of luminal proteins that were lost during the purification process.
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; Zhang et al., 1997). To explore the potential role of these proteins in mediating RyR luminal Ca sensitivity, we examined the regulatory effects of different combinations of purified cardiac triadin 1, junctin, and CSQ on purified RyRs. We began our examination with the trans addition of triadin 1 and junctin (5 µg/ml of each) to purified RyR. Both triadin 1 and junctin have well-defined hydrophobic domains (Kobayashi and Jones, 1999; Jones et al., 1995), which should facilitate incorporation of these proteins into bilayer after their addition to the solution in the trans chamber. Cis [Ca] was 6 µM and trans [Ca] was 20 µM for the control and the initial addition of triadin 1 and junctin (Fig. 2 A, I and II). Then, cis [Ca] was reduced to 2 µM due to excessive channel activity and the necessity to observe any changes in channel activity once the luminal [Ca] was increased (Fig. 2 A III). Next, luminal [Ca] was increased to 5 mM (Fig. 2 A IV). Initial addition of triadin 1 and junctin showed a significant increase in channel activity from Po of 0.11 to 0.54, but addition of 5 mM luminal Ca did not affect channel activity (Fig. 2 B). Similar potentiatory effects on channel Po were observed when either triadin 1 or junctin alone was added to the trans side of purified RyRs in several additional experiments (not shown). The increase in RyR open probability observed with these proteins provided a "functional control" for their association with the RyR. Addition of the proteins to the cis side of the bilayer had no effect on channel activity (not shown). Additional experiments in which CSQ alone (5 µg/ml) was added to the trans side yielded no significant change in Po, nor did it recover luminal Ca sensitivity (Fig. 2 C). We interpret these results to suggest that neither triadin 1, junctin, nor CSQ alone mediate RyR responsiveness to luminal Ca, although triadin 1 and junctin have a dramatic, positive regulatory effect on RyR activity.
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0.05 to 0.22 (Fig. 3 B). These results suggested that a combination of CSQ and triadin 1 and/or junctin is required to endow the RyR with an ability to respond to changes in luminal Ca.
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0.15). The increase of trans [Ca] to 5 mM once again resulted in a significant increase in channel Po to 0.45 (Fig. 4 B), indicating that the channels were responsive to luminal Ca. In two additional experiments triadin 1 and junctin were added separately and both found to have effects similar to those observed with the combination of these proteins. Thus triadin 1 and junctin might play interchangeable roles in mediating RyR responsiveness to luminal Ca, consistent with the similarities between the molecular structures of these proteins (Kobayashi and Jones, 1999; Jones et al., 1995; Kobayashi et al., 2000). Further studies are now on the way to provide a detailed characterization of the effects of triadin 1 and junctin on RyR. The restoration of RyR luminal Ca sensitivity is summarized in Fig. 5, which depicts the percentage of change compared to the control Po for each combination of proteins used in these experiments.
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; Beard et al., 2002). To assess the impact of elevated Ca on RyR/triadin/junctin-CSQ interactions under the conditions of our experiments, we tested the reversibility of the effects of luminal Ca on purified RyRs reassociated with triadin 1, junctin, and CSQ and on native RyR channels in SR vesicles. Luminal Ca was reduced by chelating the excess Ca with EGTA. Only in two out of six native RyR channels that responded to increases in luminal Ca were the effects of luminal Ca found to be reversible; in the four other channels reverting to low trans [Ca] did not restore the initial low activity (Fig. 6 B). These results suggest that 5 mM luminal Ca results in the loss of CSQ from most but not all of the native RyR channels in the bilayer. Interestingly, in channels that maintained their high activity on returning to low luminal Ca, addition of CSQ (5 µg/ml) to the trans chamber reduced Po to original low levels (Fig. 5 B). In purified RyRs reassociated with triadin 1, junctin, and CSQ, the effects of increased luminal Ca were reversible in all experiments performed (n = 3) (Fig. 6 C). These results could be ascribed to CSQ molecules present in the trans compartment reassociating with the RyR/triadin/junctin complex. Taken together, the results of our experiments point toward CSQ as a luminal Ca sensor that negatively affects RyR channel activity at low luminal [Ca] when RyR is complexed with triadin 1 and/or junctin. This inhibitory effect is overcome at increased luminal [Ca] as a result of Ca binding to, and dissociation of CSQ from, the RyR.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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, for review). However, the molecular basis of RyR regulation by luminal Ca remains to be determined. In the present study, we have investigated the molecular identity of the cardiac luminal Ca sensor by reconstituting purified RyR together with the luminally located auxiliary proteins triadin 1, junctin, and CSQ. Our results indicate that the luminal Ca sensitivity of RyR is conferred by a complex of CSQ, triadin 1 and/or junctin. The hypothesized functional interactions between these proteins in the SR membrane are illustrated in Fig. 7. Based on our results, we conclude that CSQ serves as the actual luminal Ca sensor for RyR. Triadin 1 and/or junctin are required to physically link RyR and CSQ. At the same time, they stabilize the RyR in an increased activity mode and by this fashion, prime the RyR channel for Ca-dependent regulation by CSQ. When CSQ binds to triadin 1 and/or junctin, it inhibits the activity of the RyR channel complex at low luminal Ca concentrations. On raising luminal Ca, this inhibition is gradually relieved as the Ca binding sites on CSQ become increasingly occupied with Ca, leading to weakened interactions between CSQ and triadin 1 (junctin) and increased channel open probability; the channel becomes maximally active when CSQ dissociates completely from the RyR complex at >5 mM Ca. Which of these two possible forms of control by CSQ (i.e., changes in tightness of binding interactions or dynamic dissociation/reassociation from/to the RyR complex) operates inside cardiac myocytes remains to be determined.
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; Shin et al., 2000; Kobayashi et al., 2000). Biochemical studies have shown that triadin 1 and junctin directly bind to RyR and CSQ, thus anchoring CSQ to the junctional membrane in proximity to the RyR channel (Zhang et al., 1997). It has been reported that the interaction of triadin 1 and junctin with CSQ occurs at highly charged homologous luminal domains within the structure of these proteins (Shin et al., 2000; Kobayashi et al., 2000). These domains are characterized by the presence of alternating positively and negatively charged amino acids referred to as the KEKE motif (Zhang et al., 1997; Jones et al., 1995; Kobayashi et al., 2000). The same luminal domains appear to be involved in interactions of junctin and triadin 1 with RyR (Zhang et al., 1997). The triadin-binding domain of skeletal muscle CSQ was localized to an Asp-rich region at the carboxyl-terminus of CSQ, a region which is also implicated in Ca binding (Shin et al., 2000). Binding of Ca to cardiac (Scott et al., 1988) and skeletal (Shin et al., 2000) CSQ is expected to weaken the electrostatic interactions between CSQ and triadin (junctin) by screening the negatively charged interaction sites, thereby accounting for the relief in inhibition of the Ca release channel activity by CSQ at increased luminal Ca. At still higher concentrations, Ca results in dissociation of CSQ from triadin 1 and junctin (Zhang et al., 1997; Shin et al., 2000). On the other hand, junctin and triadin 1 remain tightly bound to the RyR, independent of intraluminal Ca concentration (Zhang et al., 1997).
Previous lipid bilayer studies on native and purified RyRs have demonstrated that luminal Ca can affect RyR by at least two different mechanisms. In native cardiac RyRs, it has been found that luminal Ca acts at Ca sensing sites localized at the luminal side of the RyR complex (Györke and Györke, 1998; Ching et al., 2000). Experiments on purified cardiac and skeletal RyRs have convincingly shown that in some cases, luminal Ca, after passing the pore, can induce RyR openings by acting at the cytosolic activation sites instead of influencing channel activity at luminal Ca sensing sites (Xu and Meissner, 1998). Apparently, purification can result in loss of some regulatory proteins that are involved in luminal Ca sensing. At the same time, purification may lead to alterations of the cytosolic Ca regulatory sites, making the sites more accessible for activation for Ca passing through the channel. In this study, the observed failure of purified RyRs to respond to changes in [Ca] at the luminal side of the protein is consistent with the notion that purification causes disruption of the luminal Ca regulatory sites. As to why the channels did not exhibit changes in activity that could be attributed to the "feed-through" activation from the cis side reported in other purified RyR studies is not clear. One possibility is that the changes to RyR activation sites depend on the degree of purification of RyR. It is conceivable that harsher dissociation procedures make the channel more prone to feed-through Ca activation since native RyR channels in SR vesicles lack this mechanism (Lukyanenko et al., 1996; Györke and Györke, 1998; Ching et al., 2000). The difference could also be due to the fact that all our measurements were performed in the presence of millimolar [Mg] that may antagonize the effects of Ca passing through the pore at the activation sites.
Several previous studies have addressed the effects of CSQ on RyR activity using RyRs isolated from skeletal muscle. Although in some of these studies adding skeletal muscle CSQ to the luminal side of the channel was found to activate RyR (Kawasaki and Kasai, 1994; Ohkura et al., 1998; Szegedi et al., 1999), in other studies CSQ reduced RyR activity (Beard et al., 2002). In the latter report, skeletal muscle CSQ had no significant effects on the purified skeletal RyR, but reduced the activity of the native RyR in SR membranes depleted of CSQ. Similarly, in a preliminary study, cardiac CSQ was reported to inhibit the activity of cardiac RyRs stripped of their CSQ by treatment with 10 mM luminal Ca (Wang et al., 2001). Our findings are in line with these results. Although the reasons behind the discrepancies between different studies are not known, they could involve differences in experimental conditions. For example, our measurements with purified cardiac RyRs, as well as those by Beard et al. (2002) with CSQ-extracted skeletal muscle membranes, were performed in the presence of physiological concentrations of ATP, whereas the other studies were carried out with cytosolic Ca as the sole RyR activating ligand. The effects of luminal Ca seem to require the presence of allosteric modulators of RyR, such as ATP, caffeine, or sulmazole (Györke and Györke, 1998; Ching et al., 2000). Thus, the conditions of some studies might not have been optimal for defining the role of CSQ as a luminal Ca sensor. Variation in the degree of purification of RyR could also contribute to the differences in results. Since inhibition of RyR by CSQ occurs only in the presence of triadin and/or junctin (Beard et al., 2002; this study), it is possible that the RyR preparations from some of the studies lacked these proteins. In a previous work, addition of triadin to the cytosolic side of the skeletal RyR inhibited channel activity (Ohkura et al., 1998). Although in our experiments cytosolic triadin did not affect the cardiac RyR channel open probability, potentiation of the channel specifically on addition of luminal triadin suggests that this effect was due to interaction of the protein with the putative intraluminal triadin-binding domain of the RyR (Zhang et al., 1997).
In conclusion, our results determine, for the first time, the identities and modes of interactions of molecules involved in luminal Ca regulation of single cardiac RyR channels. The levels of luminal Ca are sensed by CSQ; then, this information is transmitted to RyR via the intermediate proteins, triadin 1 and/or junctin (Fig. 7). The regulation consists of a luminal Ca-dependent relief of inhibition that Ca-free CSQ exerts on the activity of the RyR channel complexed with triadin 1 and junctin. This dynamic, Ca-dependent modulation of RyR by CSQ has important ramifications for SR Ca handling in cardiac myocytes. Before the onset of Ca release when the [Ca]SR is high, a large fraction of RyRs would be in a CSQ-uninhibited mode. During Ca release when [Ca]SR declines, the increased level of Ca-free CSQ would result in inhibition of the RyR channels, thereby providing a molecular mechanism for the luminal Ca-dependent termination of Ca release in cardiac muscle (Terentyev et al., 2002, 2003). At the same time, the excessively large fraction of CSQ-uninhibited RyR channels at elevated basal [Ca]SR could contribute to the increased diastolic SR Ca leak (Lukyanenko et al., 2001; Shannon et al., 2002) and increased frequency of spontaneous Ca sparks and Ca waves (Cheng et al., 1996; Lukyanenko et al., 1996, 2001) under the conditions of Ca overload. Future studies will have to define the specific structural domains involved in the described intermolecular interactions and to verify the roles of these interactions in controlling SR Ca release inside living cells.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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This work was supported by American Heart Association grant 0245088N and National Institutes of Health grants HL-74045 HL-63043 (to S.G.) and HL-28556 (to L.R.J.).
Submitted on September 11, 2003; accepted for publication November 21, 2003.
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Y. Yan, J. Liu, C. Wei, K. Li, W. Xie, Y. Wang, and H. Cheng Bidirectional regulation of Ca2+ sparks by mitochondria-derived reactive oxygen species in cardiac myocytes Cardiovasc Res, January 15, 2008; 77(2): 432 - 441. [Abstract] [Full Text] [PDF]
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V. Bito, F. R. Heinzel, L. Biesmans, G. Antoons, and K. R. Sipido Crosstalk between L-type Ca2+ channels and the sarcoplasmic reticulum: alterations during cardiac remodelling Cardiovasc Res, January 15, 2008; 77(2): 315 - 324. [Abstract] [Full Text] [PDF]
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X. Shen, C. Franzini-Armstrong, J. R. Lopez, L. R. Jones, Y. M. Kobayashi, Y. Wang, W. G. L. Kerrick, A. H. Caswell, J. D. Potter, T. Miller, et al. Triadins Modulate Intracellular Ca2+ Homeostasis but Are Not Essential for Excitation-Contraction Coupling in Skeletal Muscle J. Biol. Chem., December 28, 2007; 282(52): 37864 - 37874. [Abstract] [Full Text] [PDF]
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A. Belevych, Z. Kubalova, D. Terentyev, R. L. Hamlin, C. A. Carnes, and S. Gyorke Enhanced Ryanodine Receptor-Mediated Calcium Leak Determines Reduced Sarcoplasmic Reticulum Calcium Content in Chronic Canine Heart Failure Biophys. J., December 1, 2007; 93(11): 4083 - 4092. [Abstract] [Full Text] [PDF]
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T. Guo, X. Ai, T. R. Shannon, S. M. Pogwizd, and D. M. Bers Intra Sarcoplasmic Reticulum Free [Ca2+] and Buffering in Arrhythmogenic Failing Rabbit Heart Circ. Res., October 12, 2007; 101(8): 802 - 810. [Abstract] [Full Text] [PDF]
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N. MacQuaide, J. Dempster, and G. L. Smith Measurement and Modeling of Ca2+ Waves in Isolated Rabbit Ventricular Cardiomyocytes Biophys. J., October 1, 2007; 93(7): 2581 - 2595. [Abstract] [Full Text] [PDF]
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S. A. Goonasekera, N. A. Beard, L. Groom, T. Kimura, A. D. Lyfenko, A. Rosenfeld, I. Marty, A. F. Dulhunty, and R. T. Dirksen Triadin Binding to the C-Terminal Luminal Loop of the Ryanodine Receptor is Important for Skeletal Muscle Excitation Contraction Coupling J. Gen. Physiol., September 24, 2007; 130(4): 365 - 378. [Abstract] [Full Text] [PDF]
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