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Abstract

  1. Top of page
  2. Abstract
  3. Calcium homeostasis in striated muscles
  4. Major and minor protein components of the sarcoplasmic reticulum
  5. Conclusions
  6. References
  7. Appendix

In striated muscle, activation of contraction is initiated by membrane depolarisation caused by an action potential, which triggers the release of Ca2+ stored in the sarcoplasmic reticulum by a process called excitation–contraction coupling. Excitation–contraction coupling occurs via a highly sophisticated supramolecular signalling complex at the junction between the sarcoplasmic reticulum and the transverse tubules. It is generally accepted that the core components of the excitation–contraction coupling machinery are the dihydropyridine receptors, ryanodine receptors and calsequestrin, which serve as voltage sensor, Ca2+ release channel, and Ca2+ storage protein, respectively. Nevertheless, a number of additional proteins have been shown to be essential both for the structural formation of the machinery involved in excitation–contraction coupling and for its fine tuning. In this review we discuss the functional role of minor sarcoplasmic reticulum protein components. The definition of their roles in excitation–contraction coupling is important in order to understand how mutations in genes involved in Ca2+ signalling cause neuromuscular disorders.

Abbreviations 
DHPR

dihydropyridine receptor

EC coupling

excitation–contraction coupling

JFM

junctional face membrane

KO

knock out

LSR

light sarcoplasmic reticulum

RyR

ryanodine receptor

SR

sarcoplasmic reticulum

SERCA

sarcoplasmic reticulum Ca2+-ATPase

Calcium homeostasis in striated muscles

  1. Top of page
  2. Abstract
  3. Calcium homeostasis in striated muscles
  4. Major and minor protein components of the sarcoplasmic reticulum
  5. Conclusions
  6. References
  7. Appendix

Over the decades, the role(s) played by Ca2+ in skeletal muscle have been unveiled and it is now clearly established that it is the key element underlying muscle contraction. Its importance is given by the fact that movement of the contractile proteins is dependent on the Ca2+ released from the sarcoplasmic reticulum (SR), an organelle constituting approximately 10% of the cell's volume and fully dedicated to uptake and release of Ca2+ (Peachey, 1965; Volpe & Simon, 1991). The SR can be structurally divided into two distinct portions: the terminal cisternae, which face the transverse tubules (invaginations of the plasma membrane) and the longitudinal sarcoplasmic reticulum, connecting two terminal cisternae. The terminal cisternae can be further divided into junctional face membrane (JFM) (the domain facing the transverse tubules) and non-junctional membrane (Saito et al. 1984; Costello et al. 1986).

Depolarization of the plasma membrane of skeletal muscle leads to release of Ca2+ from the SR resulting in muscle contraction, by a process known as excitation–contraction coupling (Schneider & Chandler, 1972; Melzer et al. 1995; Berchtold et al. 2000). Excitation–contraction coupling (EC coupling) occurs at the triad, a structure composed of the two membrane compartments, transverse tubules containing the voltage sensing dihydropyridine receptor (DHPR, an L-type Ca2+ channel) and terminal cisternae on which ryanodine receptor (RyR) Ca2+ release channels are localized (Mitchell et al. 1983; Rios & Pizarro, 1991). The disposition of DHPRs and RyRs on their respective membranes is highly ordered and each DHPR faces alternate rows of RyR tetramers (Fig. 1) (Block et al. 1988; Franzini-Armstrong & Jorgensen, 1994; Paolini et al. 2004). These two Ca2+ channels are the basic unit underlying excitation–contraction coupling, but they do not function alone – there are a number of accessory proteins involved in their fine regulation.

image

Figure 1. Schematic representation of the protein components of skeletal muscle sarcoplasmic reticulum

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Major and minor protein components of the sarcoplasmic reticulum

  1. Top of page
  2. Abstract
  3. Calcium homeostasis in striated muscles
  4. Major and minor protein components of the sarcoplasmic reticulum
  5. Conclusions
  6. References
  7. Appendix

One of the major advances in the field of excitation–contraction coupling was the development of reproducible procedures enabling the fractionation of SR membranes enriched in proteins involved in calcium handling (Meissner et al. 1973; Campbell et al. 1980; Saito et al. 1984). This revealed that protein components of the longitudinal SR (LSR) and terminal cisternae are different, reflecting the functional subspecialization of these membrane fractions, which are, respectively, Ca2+ uptake and Ca2+ release. Figure 2 shows a 5–15% SDS–polyacrylamide gel stained with Coomassie Brilliant Blue of the protein components of LSR, terminal cisternae and junctional face membrane. The major component of the LSR, constituting approximately 80% of the total proteins present, is the 110 kDa Ca2+-ATPase (SERCA), i.e. the pump responsible for pumping the Ca2+ released by the RyR1s back into the SR. The 22 kDa protein band present in the longitudinal SR fraction is phospholamban, a protein involved in regulating the activity of the SERCA pump in heart and slow twitch muscle fibres. When phospholamban is dephosphorylated it inhibits the activity of SERCA, whereas in its phosphorylated state, inhibition is relieved (Slack et al. 1997; Liu et al. 1997; MacLennan et al. 2003). Ablation of phospholamban causes a significant (25%) decrease in the time to half-relaxation of isolated solei with no change in the contraction time (Jay et al. 1997), supporting its important role in regulation of SERCA activity.

image

Figure 2. Coomassie Brilliant Blue stained gradient (5–15%) SDS-PAGE of protein components present in the longitudinal sarcoplasmic reticulum (LSR), in terminal cisternae (TC) and in the junctional face membrane (JFM) fractions obtained from rabbit SR Reproduced from Fig. 2 of Zorzato et al. (1986).

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Two glycoproteins of 160 kDa (sarcalumenin) and 53 kDa (53 kDa glycoprotein) represent minor protein constituents of the LSR membrane fraction and are generated by alternative splicing of the same transcript, which is expressed both in heart and skeletal muscle. The large transcript (sarcalumenin) is a low affinity (KD= 0.6 mm), high capacity (35 mol mol−1 protein) Ca2+ binding protein, while the shorter product of 53 kDa lacks the NH2 terminus and thus the Ca2+ binding domain. Sarcalumenin is involved in the maintenance of the SERCA protein as illustrated by the fact that sarcalumenin knock-out (KO) animals exhibit significantly decreased SERCA activity and SERCA protein content (Leberer et al. 1990; Yoshida et al. 2005).

As shown in Fig. 2, the protein composition of the JFM is far more complex than that of the LSR (Costello et al. 1986); aside from the most abundant components, including the ryanodine receptor (RyR), calsequestrin (CsQ), histidine rich Ca2+ binding protein and triadin(s) (TRISK), which will not be discussed in this review, there are a number of other minor protein components whose function has recently been unravelled or that still await functional characterization. Much work has focused on the identification of the full set of protein constituents of the junctional face membrane and on understanding their functional role in excitation–contraction coupling. Two main approaches have been used to characterize the minor membrane protein components at the molecular, cellular and functional level: (i) the immuno-proteomic approach utilized by the group of Takeshima, which combines production of monoclonal antibodies directed against membrane proteins selected on the basis of specific triadic immunostaining of muscle sections, cDNA cloning, expression and biochemical analysis of identified proteins and gene knock-out techniques (Weisleder et al. 2008); and (ii) junctional face membrane purification or heparin agarose chromatography and identification of proteins co-eluting with the RyR, combined with Western blotting, mass spectrometry analysis and peptide sequencing (Divet et al. 2005). These approaches have been relatively successful and at least five minor membrane protein components, which will be described in the next section, have been identified and characterized.

Mitsugumin-29 This is a 29 kDa membrane protein related to the synaptophysin-family, originally identified in the SR of skeletal muscle and in the endoplasmic reticulum of kidney renal tubules (Shimuta et al. 1998). Analysis of its primary sequence, as well as biochemical and ultrastructural evidence, suggests that mitsugumin-29 contains four transmembrane domains and that it is localized in the transverse tubules of mature skeletal muscles where it self-associates as hexamers (Shimuta et al. 1998; Brandt et al. 2001). Though mitsugumin-29 does not tightly associate with other proteins, experimental evidence suggests that it can functionally interact with the RyR1, whereby it increases RyR1 open probability without affecting channel current amplitude (Pan et al. 2004). Muscles isolated from mitsugumin-29 KO mice exhibit swollen transverse tubules, vacuolated SR and misaligned triadic structures. These ultrastructural changes are accompanied by dysfunctional Ca2+ handling; specifically, the intracellular Ca2+ stores of myotubes from mitsugumin-29 KO mice deplete more rapidly and refill more slowly after depolarization than myotubes from control mice (Pan et al. 2002). Such alterations lead to ‘global’ functional changes, so that muscles from mitsugumin-29 KO mice fatigue more rapidly than their wild-type counterpart (Nagaraj et al. 2000). Taken together these results suggest that mitsugumin-29 functions as a tethering structure, forcing the transverse tubules into a conformation, which favours the formation of triadic structures. Lack of integral triads then leads to altered Ca2+ handling and defective SOC-dependent Ca2+ influx.

Junctophilin-1 Junctophilins are membrane spanning proteins with a large cytoplasmic region containing a 14-amino-acid repeat motif (MORN motif) with selective binding affinity for the plasma membrane and a carboxy-terminal transmembrane segment spanning the ER/SR (Takeshima et al. 2000). At least three isoforms encoded by distinct genes, exist: junctophilin-1 is specifically expressed in skeletal muscle, junctophilin-2 is expressed in the heart, in skeletal muscles and in smooth muscles, and junctophilin-3 is expressed in the brain (Nishi et al. 2000). In skeletal muscle junctophilin-1 (72 kDa protein) is involved in physically linking the transverse tubules to the SR membrane. Protein overlay and surface plasmon assays suggest that it achieves this by interacting with phospholipids, especially with sphingomyelin and phosphatidylchloine, rather than through protein–protein interactions (Weisleder et al. 2008). Ablation of junctophilin-1 severely affects muscle function leading homozygous KO mice to premature death within 20 h after birth. Ultrastructural examination of the skeletal muscles of junctophilin-1 KO mice shows morphological abnormalities, including incomplete formation of the junctional complexes between transverse tubules and the SR, swollen terminal cisternae and reduced numbers of triads. As a consequence muscles develop less contractile force after electrical stimulation and show abnormal sensitivity to extracellular Ca2+ (Ito et al. 2001; Komazaki et al. 2002).

SRP-27/TRIC-A Mitsugumin-33 or TRIC-A (trimeric intracellular cation-selective channel) (Yazawa et al. 2007) also known as SRP-27 (sarcoplasmic reticulum protein of 27 kDa) (Bleunven et al. 2008) is expressed in excitable tissues and is particularly enriched in fast twitch skeletal muscles, where its expression level peaks after 2 months of post-natal development. Mice lacking TRIC/SRP-27 are viable and display no overt phenotype. Double-labelling immunocytochemistry experiments of mouse muscle fibres indicate that SRP-27 is localized in the perinuclear endoplasmic reticulum as well as in a SR subcompartment, which is adjacent to, but distinct from, that containing the RyR1 and SERCA (Bleunven et al. 2008). Interestingly, SRP-27/TRIC-A could be pulled-down by beads coated with maurocalcine and RyR1, but not with maurocalcine alone, raising the possibility that SRP-27/TRIC-A is part of the RyR1 macromolecular complex (Bleunven et al. 2008). Hydrophobicity plots and biochemical analysis also revealed that TRIC-A/SRP-27 is an integral ER/SR protein containing up to three membrane spanning domains, whose amino terminus is located in the lumen of the ER/SR and whose carboxy terminus is exposed to the cytoplasm. Sequence comparison also predicts the presence of an ion-conducting pore between the first and second transmembrane domains and cross-linking experiments demonstrate that TRIC-A/SRP-27 tends to form homo-oligomers (dimers and trimers). Three-dimensional reconstruction studies of the native protein suggest that it acquires a pyramidal elongated structure, similar to that of bacterial porin channels (Yazawa et al. 2007). Interestingly, reconstitution in lipid bilayers suggest that TRIC-A/SRP-27 is a cation channel, with a selectivity of K+ over Na+ (permeability ratio PK/PNa= 1.5) (Yazawa et al. 2007). To gain more insight into the function of this channel, Yazawa et al. (2007) followed changes in the membrane potential of isolated muscle fibres from control and TRIC-A/SRP-27 KO mice. The lack of TRIC-A/SRP-27 reduced the K+ permeability accompanying thapsigargin-induced Ca2+ efflux, without affecting Ca2+ permeability, suggesting that this protein may act as a monovalent-cation channel. Such a channel could be activated physiologically during RyR1-mediated Ca2+ release to counter-balance the charge movement due to efflux of Ca2+ (Somlyo et al. 1981), which would otherwise leave the SR lumen with a negative charge. However, the role of TRIC-A/SRP-27 as a monovalent-cation contercurrent channel during Ca2+ release has been challenged by data of Gillespie & Fill (2008), which indicates that the RyR1 channel mediates its own potassium countercurrent during SR Ca2+ release. This would obviate the need of an additional countercurrent carrier during SR Ca2+ release, leaving the exact functional role of TRIC-A/SRP-27 controversial.

JP-45 JP-45 is a 45 kDa polypeptide containing a single transmembrane segment, which is highly enriched in skeletal muscle junctional face membrane where its expression is developmentally regulated, reaching maximal levels during the second month of post-natal development (Anderson et al. 2003). Originally JP-45 was identified as a protein weakly phosphorylated by cAMP-dependent protein kinase and co-eluting with the RyR1 and DHPR from a heparin-agarose column (Zorzato et al. 2000). Surprisingly, however, co-immunoprecipitation experiments revealed that JP-45 is not part of the RyR1 macromolecular complex, but rather it interacts with calsequestrin via its luminal carboxy-terminal domain and with Cav1.1, through its cytoplasmic amino terminus (Anderson et al. 2003). Extensive pulldown and co-immunoprecipitation experiments revealed that JP-45 binds to different regions on the Cav1.1, namely to its carboxy terminus and to a region within the I–II loop referred to as AID, where the β1a subunit also binds (Anderson et al. 2006). The interaction between Cav1.1 and β1a is thought to be essential for targeting or stabilizing Cav1.1 on the plasma membrane (Flucher et al. 2002).

Several approaches have been exploited to unravel the function of JP-45 in skeletal muscle: (i) acute over-expression and depletion of JP-45 in differentiated C2C12 myotubes (Anderson et al. 2006; Gouadon et al. 2006), and (ii) chronic depletion in JP-45 knock out mice (Delbono et al. 2007). Interestingly both over-expression and ablation of JP-45 result in a decrease of voltage-dependent Ca2+ release. This effect could be due to a decrease of functional expression of the Cav1.1 on the transverse tubules (Anderson et al. 2006; Delbono et al. 2007). Alternatively, the effect on Ca2+ release may be linked to alterations of the interaction of JP-45 with calsequestrin. Gouadon et al. (2006) showed that low levels of JP-45 over-expression affect the permeability of the Ca2+ release unit by altering excitation–contraction coupling transfer function (Gouadon et al. 2006). Given that the lumenal carboxy terminus of JP-45 binds to calsequestrin, it is possible that JP-45 constitutes a key protein for a signalling pathway between calsequestrin and Cav1.1. Over-expression of JP-45 may result in the accumulation of JP-45 molecules which are not associated with calsequestrin, and this in turn may send an inhibitory signal to the Cav1.1.

Interestingly the skeletal muscle phenotype of young JP-45 KO mice is reminiscent of that of aged mice. During mouse ageing, the membrane density of the voltage sensor (Cav1.1), the SR membrane content of JP-45 and the Ca2+ currents of muscle membranes are significantly lower compared to those of young animals (Delbono et al. 1995; Renganathan et al. 1997; Gonzales et al. 2003; Anderson et al. 2006). These data suggest that both Cav1.1 and JP-45 may be important for the maintenance of muscle strength, and indicate that JP-45 KO mice may be a useful experimental model to investigate alterations of excitation–contraction coupling linked to ageing.

Junctate/humbug Junctate is a 33 kDa protein with a single ER/SR membrane spanning domain, expressed in a variety of excitable and non-excitable tissues (Treves et al. 2000; Dinchuk et al. 2000; Hong et al. 2001). Figure 3A shows how transcripts deriving from the same gene (BAH or AβH-J-J locus) located on human chromosome 8q12.1 can give rise to four distinct classes of proteins via a complex pattern of alternative splicing. Though the complexity of AβH-J-J locus is more the exception than the rule, it illustrates how important it is to precisely establish the number and type of gene products when deciding to create knock out animal models of protein(s) encoded by the BAH gene.

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Figure 3. Genomic organization, splicing pattern and main protein products deriving from of the A-β-J-J locus A, coloured boxes represent different exons. Products deriving from exon 1 (green box) give rise to β-aspartyl-hydroxylase/humbug; products deriving from exon 1b (light blue) give rise to junctin/junctate. Yellow box encodes the transmembrane domain. Reproduced from Fig. 4 of Dinchunk et al. 2000. B, schematic representation of the 4 main proteins (junctin, junctate, aspartyl-β-hydroxylase and humbug) derived by assembling the different exons (colours of the protein domains match those of the exons from which they are derived).

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Figure 3B illustrates schematically how the different polypeptides are assembled to yield: (i) junctin, a structural calsequestrin binding protein present in cardiac and skeletal muscle SR that forms a quaternary complex with triadin, RyR1 and calsequestrin (Jones et al. 1995; Kagari et al. 1996; Zhang et al. 1997); (ii) aspartyl-β-hydroxylase, an enzyme catalysing posttranslational hydroxylation of aspartate and asparagine residues within epidermal growth factor-like domains present in receptors and receptor ligands involved in cell growth and differentiation, and extracellular matrix molecules (Stenflo et al. 1989; Gronke et al. 1989; Monkovic et al. 1992); (iii) junctate, a moderate affinity (KD 217 μm), high capacity (21 mol Ca2+/mol protein) Ca2+ binding protein (Treves et al. 2000); and (iv) humbug, a truncated version of aspartyl-β-hydroxylase, lacking its catalytic domain, which shares with junctate the high capacity moderate affinity Ca2+ binding domain (Dinchuk et al. 2000; Treves et al. 2000; Hong et al. 2001). Analysis of the genomic organization of the AβH-J-J locus has revealed the presence of two distinct promoters, P1 and P2 (Feriotto et al. 2006), which are regulated by specific transcription factors, giving rise to polypeptides with distinct amino termini and tissue distribution. Transcripts starting from exon 1 (green box in Fig. 3A), which is under the control of the P1 promoter, are expressed in most tissues and share their NH2 terminus with aspartyl-β-hydroxylase (Treves et al. 2000; Dinchuk et al. 2000; Feriotto et al. 2007). Exon 1a (blue box in Fig. 3A) is approximately 8 kb downstream from exon 1 and is under the control of the P2 promoter, whose induction is controlled by the muscle specific transcription factor MEF-2 (Feriotto et al. 2005). Transcripts starting from this exon are expressed in striated muscles and share their NH2 termini with junctin/junctate (Treves et al. 2000; Dinchuk et al. 2000). Exon 2 encodes the transmembrane domain (yellow box in Fig. 3A) and together with exon 3 is shared by all family members deriving from the AβH-J-J locus. The carboxy-terminal portion of the proteins depends on which exons are transcribed: junctin results from transcription of exons 4a and 5a, while all other products are generated via transcription of exons 4–24 and result in a variety of products of different sizes. The longer transcripts give rise to the enzyme aspartyl-β-hydroxylase with an apparent molecular mass of approximately 120 kDa. The shorter transcripts generate proteins with molecular masses ranging from 40 to 53 kDa which share the acidic Ca2+ binding domain (Treves et al. 2000; Dinchuk et al. 2000; Hong et al. 2001). Heart expresses junctin and junctate, as well as humbug and aspartyl-β-hydroxylase (Treves et al. 2000; Dinchuk et al. 2000; Hong et al. 2001). Interestingly, humbug is also highly expressed in a variety of invasive human tumours and its level of expression has been suggested to be useful as a prognostic marker for cancer progression (Wang et al. 2007; Lee, 2008).

In the rest of this section, only the functional properties of junctate will be discussed, and the reader is referred to other articles describing the function of aspartyl-β-hydroxylase and junctin (Gronke et al. 1989; Jones et al. 1995; Kagari et al. 1996; Zhang et al. 1997; Wang et al. 2007). Because of its calcium binding properties, a number of approaches were undertaken to define the potential role of junctate in Ca2+ homeostasis: (i) acute over-expression and depletion of junctate from cultured cells (Treves et al. 2000, 2004), and (ii) chronic over-expression of junctate in skeletal muscles (Divet et al. 2007) and heart (Hong et al. 2008). Acute over-expression of junctate in COS-7 and HEK293 cells is accompanied by significant functional and structural changes of the ER membrane. Specifically, in HEK cells over-expressing TRPC3 channels (HEKT3), over-expression of junctate induces extensive proliferation of the ER resulting in significantly larger and more frequent couplings between the ER and the plasma membrane (Treves et al. 2004). The induction of ER plasma membrane couplings by junctate is in agreement with co-immunoprecipitation data showing that junctate forms a supramolecular complex with InsP3R and TRPC channels. These structural changes are paralleled by alterations of Ca2+ homeostasis, specifically by increased peak Ca2+ release and store depletion activated Ca2+ influx; on the other hand, knocking down junctate results in diminished agonist induced peak [Ca2+]i transients and store depletion activated Ca2+ influx (Treves et al. 2000, 2004). The increase of store depletion activated Ca2+ influx is mediated by the short cytoplasmic NH2-terminal domain of the protein, while the luminal carboxy-terminus Ca2+ binding domain of junctate (and thus also of humbug) increases the Ca2+ content of ER/SR stores and affects calcium transients evoked by SERCA inhibitors.

As to the effect of chronic over-expression of junctate, some discrepancies have arisen from the transgenic mouse models. Over-expression in skeletal muscles does not lead to an overt phenotype but is accompanied by a small increase in Ca2+ loading and Ca2+ storage of the SR resulting in a significant increase in RyR1 mediated Ca2+ release and an increased Ca2+ influx following depletion of intracellular Ca2+ stores (Divet et al. 2007). These changes were attributed to the over-expression of junctate's Ca2+ binding sites since the expression levels of other SR Ca2+ handling proteins such as SERCA, calsequestrin or sarcalumenin were not changed. Interestingly, the increased Ca2+ cycling across the SR membrane was accompanied by an adaptive increase in the number of mitochondria in fast fibres of Extensor Digiforum Longus (EDL) (but not soleus) muscles, which was not due to fast-to-slow fibre type transition (Divet et al. 2007). Junctate over-expression in the heart, on the other hand, leads to severe cardiac hypertrophy, bradycardia and arrythmias as well as alterations in the expression level of the SR proteins SERCA2, calsequestrin-2 and calreticulin. This decreased SR content of Ca2+ handling proteins is accompanied by an up-regulation of the Na+/Ca2+ exchanger and plasmalemma calcium pump, two component of the cardiac sarcolemma involved in extrusion of Ca2+ from the cytoplasm. The decrease of the major calcium binding proteins of cardiac SR is paralleled by a decrease in caffeine induced Ca2+ release indicating a lower cardiac Ca2+ SR loading. At the moment the reasons for these apparent opposite effects of junctate over-expression in the heart and in skeletal muscle have not yet been elucidated.

Conclusions

  1. Top of page
  2. Abstract
  3. Calcium homeostasis in striated muscles
  4. Major and minor protein components of the sarcoplasmic reticulum
  5. Conclusions
  6. References
  7. Appendix

The past three decades have seen major advancements in our understanding of the role of skeletal muscle SR proteins in excitation–contraction coupling. The use of genetically modified animal models has also taught us that few of these proteins, namely the ryanodine receptor, Cav1.1 and junctophilin, are essential for EC coupling. On the other hand, the minor protein components seem to be important for the regulation of the EC coupling machinery. Mouse and cellular models have also shown that acute and/or chronic over-expression/depletion of a variety of minor components do not result in lethal phenotypes and/or in severe damage of to the EC coupling machinery, suggesting that its fine regulation is provided by functionally redundant minor components. The comprehension of EC coupling and its involvement in the pathophysiology of neuromuscular disorders awaits the identification and functional characterisation of the complete array of proteins of the transverse tubule and junctional face membrane compartments.

References

  1. Top of page
  2. Abstract
  3. Calcium homeostasis in striated muscles
  4. Major and minor protein components of the sarcoplasmic reticulum
  5. Conclusions
  6. References
  7. Appendix
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Appendix

  1. Top of page
  2. Abstract
  3. Calcium homeostasis in striated muscles
  4. Major and minor protein components of the sarcoplasmic reticulum
  5. Conclusions
  6. References
  7. Appendix

Acknowledgements

This work was supported by the Swiss National Science Foundation (SNF grant number SNF 3200BO-114597), by the Fondation Suisse de Recherche sur les maladies musculaires, by the Association Française contre les Myopathies and by Telethon Italy.