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Assembly and Dynamics of Proteins of the Longitudinal and Junctional Sarcoplasmic Reticulum in Skeletal Muscle Cells

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Assembly and Dynamics of Proteins of the Longitudinal and Junctional Sarcoplasmic Reticulum in Skeletal Muscle Cells Assembly and dynamics of proteins of the longitudinal and junctional sarcoplasmic reticulum in skeletal muscle cells Vincenza Cusimano, Francesca Pampinella, Emiliana Giacomello, and Vincenzo Sorrentino1 Molecular Medicine Section, Department of Neuroscience, and Interuniversity Institute of Myology, University of Siena, 53100 Siena, Italy Edited by Clara Franzini-Armstrong, University of Pennsylvania Medical Center, Philadelphia, PA, and approved January 12, 2009 (received for review October 11, 2008) The sarcoplasmic reticulum (SR) of skeletal muscle cells is a complex tially localized near the M band and, to a lesser extent, to the network of tubules and cisternae that share a common lumen Z disk (11–16). delimited by a single continuous membrane. The SR contains The longitudinal SR tubules regularly merge into large structures longitudinal and junctional domains characterized by distinctive named terminal cisternae. The region of the terminal membrane patterns of protein localization, but how SR proteins reach and/or cisternae that faces the T tubule/plasma membrane represents the are retained at these sites is not known. Here, we report that the junctional SR domain, where the Ca2ϩ-release channels of skeletal organization of longitudinal SR proteins is a slow process charac- muscle cells (ryanodine receptor type 1; RyR1) and other junctional terized by temporally distinct patterns of protein localization. In SR proteins localize (17–19). The voltage-activated Ca2ϩ channels, contrast, junctional SR proteins rapidly and synchronously assem- dihydropyridine receptors (DHPRs), are organized in tetrads on bled into clusters which, however, merged into mature triadic the plasma membrane/T tubule system that faces the junctional SR junctions only after completion of longitudinal SR protein organi- (2, 20, 21). The juxtaposition of junctional SR and T tubule/plasma zation. Fluorescence recovery after photobleaching experiments membranes is essential for a functional coupling between the RyR1 indicated that SR organization was accompanied by significant and the ␣1S subunit of the DHPR (22, 23). In contrast to longitu- changes in the dynamic properties of longitudinal and junctional dinal SR proteins, junctional proteins are initially imaged as clusters proteins. The decrease in mobility that accompanied organization with no apparent relationship to the contractile apparatus. At a of the longitudinal SR proteins ank1.5-GFP and GFP-InsP3R1 was later stage, these clusters converge into triadic structures at the I-A abrogated by deletion of specific binding sites for myofibrillar or band borders (2, 20). cytoskeletal proteins, respectively. Assembly of junctional SR do- It appears, therefore, that although the SR is a unique mains was accompanied by a strong decrease in mobility of organelle delimited by a single continuous membrane, the junctional proteins that in triadin appeared to be mediated by its longitudinal and junctional SR domains are characterized by intraluminal region. Together, the data suggest that the organi- specific patterns of protein localization (2). However, little is zation of specific SR domains results from a process of membrane known about the mechanisms that mediate sorting or retention reorganization accompanied by the establishment of multiple of SR proteins at these specific sites (5). To address these points, protein–protein interactions with intrinsic and extrinsic cues. the temporal and spatial organization of longitudinal and junc- tional SR membrane proteins was followed in differentiating calcium store ͉ excitation–contraction coupling ͉ muscle differentiation ͉ primary myotubes. Additionally, dynamics of GFP-tagged SR protein dynamics proteins was analyzed by using fluorescence recovery after photobleaching (FRAP) and inverse FRAP (iFRAP) techniques. he sarcoplasmic reticulum (SR) of muscle cells is a special- Tized form of the endoplasmic reticulum (ER) dedicated to Results ϩ storage and release of Ca2 . Assembly of the SR starts in Localization Kinetics of Longitudinal and Junctional SR Proteins in embryonic muscle cells, where an apparently disorganized ac- Differentiating Myotubes. Labeling of 2-day differentiated myo- cumulation of membranes is observed (1, 2). Following a series tubes with a polyclonal antibody against ank1.5 revealed, in most of modifications occurring throughout embryonic life and the cells, a diffused signal throughout the entire SR (Fig. 1A). first postnatal weeks, the SR develops in a highly structured 3D However, in a small fraction of cells, ank1.5 immunostaining was network of tubules and cisternae arranged in close association concentrated in a region of the SR near the M band (Fig. 1D). with the contractile apparatus (2–5). From a structural and All cells labeled with an antibody against SERCA presented a functional point of view, 2 regions are identified in the SR: the diffused staining (Fig. 1B). Staining with antibodies against RyR longitudinal and the junctional SR. The longitudinal SR is and triadin yielded a partially superimposable punctate pattern morphologically characterized by a series of parallel tubules and (Fig. 1 G and H), in agreement with previous data (4, 21). In is specialized in Ca2ϩ uptake, a process operated by the SR/ER ϩ 4-day differentiated myotubes, ank1.5 was organized in bands in Ca2 -ATPase (SERCA) pumps (6, 7). The longitudinal SR Ϸ55% of the myotubes. In approximately half of these cells, corresponds to the larger part of the SR and covers most of the ank1.5 was only found at the level of M bands (Fig. 1J), whereas sarcomere. However, a major density of membrane is observed in the remaining cells, a second band was detected at the level in correspondence with the Z disk, where some ER domains may of the Z disk (Fig. S1 A–C). In approximately 1/3 of 4-day also be localized (8) and, to a minor extent, near the M band (2, 9). Accordingly, immunofluorescence staining of adult skeletal muscle sections has shown that most longitudinal SR proteins, Author contributions: V.C., F.P., E.G., and V.S. designed research; V.C., F.P., and E.G. including SERCA pumps and the inositol-trisphosphate recep- performed research; V.C. and V.S. analyzed data; and V.C. and V.S. wrote the paper. tors (InsP3R), are detected predominantly in correspondence The authors declare no conflict of interest. with the Z disk and with a weaker signal over the M band (10). This article is a PNAS Direct Submission. In contrast, the small muscle-specific isoform of ankyrin 1 1To whom correspondence should be addressed. E-mail: [email protected]. CELL BIOLOGY (ank1.5), a transmembrane protein of the longitudinal SR known This article contains supporting information online at www.pnas.org/cgi/content/full/ to interact with the myofibrillar protein obscurin, is preferen- 0810243106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0810243106 PNAS ͉ March 24, 2009 ͉ vol. 106 ͉ no. 12 ͉ 4695–4700 Downloaded by guest on October 1, 2021 Table 2. Mobility of longitudinal SR and junctional GFP-protein ABC constructs expressed in NIH3T3 cells 2 D (␮m /s) Mf (%) n D EF GFP-SERCA2a 0.17 Ϯ 0.07 92.2 Ϯ 9.2 13 GFP-InsP3R1 0.12 Ϯ 0.10 72.2 Ϯ 16.0 18 ank1.5-GFP 0.37 Ϯ 0.16 87.1 Ϯ 9.7 20 G H I GFP-RyR1 0.20 Ϯ 0.18 75.3 Ϯ 11.5 17 GFP-␣1S 0.17 Ϯ 0.10 67.1 Ϯ 15.7 12 GFP-JP1 reticular 0.06 Ϯ 0.02 72.3 Ϯ 19.4 14 GFP-JP1 clusters 0.06 Ϯ 0.05 51.8 Ϯ 11.0 19 JKL Triadin-GFP 0.22 Ϯ 0.15 87.1 Ϯ 8.9 15 Junctin-GFP 0.39 Ϯ 0.29 92.8 Ϯ 7.1 18 Diffusion constants (D) and mobile fractions (Mf) of GFP fusion constructs M N O are shown; n indicates the number of experiments; all means are reported with SDs. myotubes where ank1.5 was organized at least at the M band. P Q R RyR staining was still found in distinct clusters in the majority of 6-day differentiated myotubes (Fig. 1T), although in Ϸ10% of these myotubes, it was detected at the border between A and I S T U bands (Fig. 1W). Interestingly, this triadic pattern of RyR1 was observed only in those myotubes were SERCA was organized at the Z disk (Fig. S1 G–I) and ank1.5 at both the M band and the VWX Z disk regions (Fig. 1 V–X). The relative percentages of myo- tubes based on the localization pattern of SR proteins at 2, 4, and 6 days of differentiation are reported in Table 1. Fig. 1. Sequential organization of longitudinal and junctional SR proteins Dynamics Studies of Longitudinal and Junctional SR Proteins in NIH during skeletal muscle cell differentiation. Immunolabeling of primary rat skeletal muscle cells at 2 (A–I),4(J–O), and 6 (P–X) days after induction of 3T3 Cells. The specific localization of SR proteins observed in differentiation. The majority of 2-day differentiated myotubes showed a mature myotubes may result from the reorganization of the SR diffused staining for ank1.5 (A) and SERCA (B). Only in a minority of myotubes membrane around the developing myofilaments (2, 8, 24) and ank1.5 was observed at the level of the M band (D), in an alternating pattern from the establishment of interactions with intracellular struc- with ␣-actinin. (E) In all 2-day differentiated myotubes, RyR (G) and triadin (H) tures, like the cytoskeleton, the myofilaments, and the plasma formed clusters. Improved organization of ank1.5 (J) and SERCA (K) was membrane (25). To address this question, a set of transmem- observed in 4-day differentiated myotubes, whereas RyR (M) and triadin (N) were still organized in clusters. In 6-day differentiated myotubes, a further brane proteins representative of longitudinal and junctional SRs improvement in ank1.5 (P, S, and V) and SERCA (Q) localization was observed.
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