The relationship between form and function throughout the history of excitation–contraction coupling

Franzini‐Armstrong, Clara

doi:10.1085/jgp.201711889

Cited by 72 publications

(58 citation statements)

References 234 publications

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“…To perform many of these functions, the ER contains a number of tethering proteins that mediate the establishment of specific membrane contact sites (MCSs) with other organelles (1,2). In muscle cells, the complex organization of the sarcoplasmic reticulum (SR), together with the occurrence of peculiar MCSs between the SR and the plasma membrane (PM) of muscle fibers, from here on referred to as sarcolemma, represent key elements for regulating Ca 2+ homeostasis and muscle contraction (3). In skeletal muscle, the SR is organized in longitudinal tubules (l-SR) that surround, like a sleeve, each myofibril.…”

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“…At regular intervals, l-SR tubules converge into the so-called terminal cisternae, which represent the junctional SR (j-SR), since they participate in the formation of specialized muscle-specific MCSs with the surface sarcolemma or with the transverse tubules (T-tubules). T-tubules are infoldings of the sarcolemma that radially penetrate muscle cells (3).…”

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“…MCSs between the j-SR and the surface sarcolemma are called peripheral couplings, while MCSs with T-tubules are called dyads or triads depending on whether the T-tubule makes contact with 1 or 2 regions of the j-SR. In skeletal muscle, peripheral couplings and dyads are present in the early stages of differentiating myotubes, while both structures are gradually replaced by triads positioned at the borders between the A and I bands of the sarcomere in mature skeletal muscle fibers (3,8,9). The function of these muscle-specific MCSs is to support the structural organization of components of the excitation-contraction (e-c) coupling machinery that transduces depolarization of the sarcolemma into activation of Ca 2+ release from the SR (10,11).…”

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Molecular determinants of homo- and heteromeric interactions of Junctophilin-1 at triads in adult skeletal muscle fibers

Rossi

Scarcella

Liguori

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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In adult skeletal muscles, 2 junctophilin isoforms (JPH1 and JPH2) tether the sarcoplasmic reticulum (SR) to transverse tubule (T-tubule) membranes, generating stable membrane contact sites known as triads. JPHs are anchored to the membrane of the SR by a C-terminal transmembrane domain (TMD) and bind the T-tubule membrane through their cytosolic N-terminal region, which contains 8 lipid-binding (MORN) motifs. By combining expression of GFP-JPH1 deletion mutants in skeletal muscle fibers with in vitro biochemical experiments, we investigated the molecular determinants of JPH1 recruitment at triads in adult skeletal muscle fibers. We found that MORN motifs bind PI(4,5)P2 in the sarcolemma, but do not mediate the selective localization of JPH1 at the T-tubule compartment of triads. On the contrary, fusion proteins containing only the TMD of JPH1 were able to localize at the junctional SR compartment of the triad. Bimolecular fluorescence complementation experiments indicated that the TMD of JPH1 can form dimers, suggesting that the observed localization at triads may result from dimerization with the TMDs of resident JPH1. A second domain, capable of mediating homo- and heterodimeric interactions between JPH1 and JPH2 was identified in the cytosolic region. FRAP experiments revealed that removal of either one of these 2 domains in JPH1 decreases the association of the resulting mutant proteins with triads. Altogether, these results suggest that the ability to establish homo- and heterodimeric interactions with resident JPHs may support the recruitment and stability of newly synthesized JPHs at triads in adult skeletal muscle fibers.

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Molecular determinants of homo- and heteromeric interactions of Junctophilin-1 at triads in adult skeletal muscle fibers

Rossi

Scarcella

Liguori

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Gene expression values from rabbit muscle were mined from RNA-seq data deposited with SRA accession number SAMN00013649. 3 This article contains Table S1 and Figures S1-S12 as Supporting Information. 4 Research Collaboratory for Structural Bioinformatics Protein Databank.…”

Section: Experimental Design Statistical Analysis and Data Presentamentioning

confidence: 99%

Horse gluteus is a null-sarcolipin muscle with enhanced sarcoplasmic reticulum calcium transport

Karim

Svensson

et al. 2019

Preprint

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We have analyzed gene transcription, protein expression, and enzymatic activity of the Ca 2+ -transporting ATPase (SERCA) in horse gluteal muscle. Horses are bred for peak athletic performance but exhibit a high incidence of exertional rhabdomyolysis, with myosolic Ca 2+ suggested as a correlative linkage. To assess Ca 2+ regulation in horse gluteus, we developed an improved protocol for isolating horse sarcoplasmic reticulum (SR) vesicles. RNA-seq and immunoblotting determined that the ATP2A1 gene (protein product SERCA1) is the predominant Ca 2+ -ATPase expressed in horse gluteus, as in rabbit muscle. Gene expression was assessed for four regulatory peptides of SERCA, finding that sarcolipin (SLN) is the predominant regulatory peptide transcript expressed in horse gluteus, as in rabbit muscle. Surprisingly, the RNA transcription ratio of SLN-to-ATP2A1 in horse gluteus is an order of magnitude higher than in rabbit muscle, but conversely, the protein expression ratio of SLN-to-SERCA1 in horse gluteus is an order of magnitude lower than in rabbit. Thus, the SLN gene is not translated to a stable protein in horse gluteus, yet the suprahigh level of SLN RNA suggests a non-coding role. Gel-stain analysis revealed that horse SR expresses calsequestrin (CASQ) protein abundantly, with a CASQ-to-SERCA ratio ~3-fold greater than rabbit SR. The Ca 2+ transport rate of horse SR vesicles is ~2-fold greater than rabbit SR, suggesting horse myocytes have enhanced luminal Ca 2+ stores that increase intracellular Ca 2+ release and muscular performance. The absence of SLN inhibition of SERCA and the abundant expression of CASQ may potentiate horse muscle contractility and susceptibility to exertional rhabdomyolysis. The horse has been selectively bred for thousands of years to achieve remarkable athletic ability, in part conferred by a naturally-high proportion (75-95%) of fast-twitch myofibers in locomotor muscles that provide powerful contractions and high speed (1). Calcium (Ca 2+ ) 1 is the signaling molecule that controls muscle contraction by activating the actomyosin sliding-filament mechanism (2). In turn, myosolic Ca 2+ is controlled predominantly by the sarcoplasmic reticulum (SR), a membrane organelle that connects with transverse tubules as membrane junctions and also surrounds actomyosin myofibrils as longitudinal sheaths (3). Thus, SR is a dual structure/function membrane system comprising junctional SR with the ryanodine receptor Ca 2+ release channel (RYR) acting to initiate contraction, and longitudinal SR with the Ca 2+ transporting ATPase (SERCA) acting to induce relaxation (4,5). For muscle contraction, the bolus of released Ca 2+ originates almost solely from SR through the RYR channel, and this released Ca 2+ is subsequently re-sequestered in the SR lumen by SERCA (6). The strength of muscle contraction is controlled by the amount of Ca 2+ released from SR, which is in turn modulated by the Ca 2+ load in the SR lumen (7). Calsequestrin (CASQ), which binds up to 80 Ca 2+ ions (mol/mol), is the high-capacity ...

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“…Some areas of science underpin so much of modern physiology that it is important to be reminded of their development, and I note a few areas where articles in JGP have been drivers of the development of the fields with Milestones that summarize JGP ’s contributions: regulation of cell volume (Kay and Blaustein, 2019); the constant field equation and its link to the membrane potential (Alvarez and Latorre, 2017); the physiology of Na and K channels (Bezanilla, 2018a); calcium and muscle contraction (Ríos, 2018); and photoreception (Pugh, 2018). Another theme that runs through JGP is the link between structure and function (Franzini-Armstrong, 2018). Today, this is not only important at the level of the cell but also at the level of the molecule (Robertson, 2018).…”

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Eisner

2019

Journal of General Physiology

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The relationship between form and function throughout the history of excitation–contraction coupling

Abstract: Franzini-Armstrong reviews the development of the excitation–contraction coupling field over time.

Cited by 72 publications

References 234 publications

Molecular determinants of homo- and heteromeric interactions of Junctophilin-1 at triads in adult skeletal muscle fibers

Molecular determinants of homo- and heteromeric interactions of Junctophilin-1 at triads in adult skeletal muscle fibers

Horse gluteus is a null-sarcolipin muscle with enhanced sarcoplasmic reticulum calcium transport

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