Organization of junctional sarcoplasmic reticulum proteins in skeletal muscle fibers

Abstract

The sarcoplasmic reticulum (SR) of striated muscles is specialized for releasing Ca(2+) following sarcolemma depolarization in order to activate muscle contraction. To this end, the SR forms a network of longitudinal tubules and cisternae that surrounds the myofibrils and, at the same time, participates to the assembly of the triadic junctional membrane complexes formed by the close apposition of one t-tubule, originated from the sarcolemma, and two SR terminal cisternae. Advancements in understanding the molecular basis of the SR structural organization have identified an interaction between sAnk1, a transmembrane protein located on the longitudinal SR (l-SR) tubules, and obscurin, a myofibrillar protein. The direct interaction between these two proteins results in molecular contacts that have the overall effect to stabilize the l-SR tubules along myofibrils in skeletal muscle fibers. Less known is the structural organization of the sites in the SR that are specialized for Ca(2+) release and are positioned at the junctional SR (j-SR), i.e. the region of the terminal cisternae that faces the t-tubule at triads. At the j-SR, several trans-membrane proteins like triadin, junctin, or intra-luminal SR proteins like calsequestrin, are assembled together with the ryanodine receptor, the SR Ca(2+) release channel, into a macromolecular complex specialized in releasing Ca(2+). At triads, the 12 nm-wide gap between the t-tubule and the j-SR allows the ryanodine receptor on the j-SR to be functionally coupled with the voltage-gated L-type calcium channel on the t-tubule in order to allow the transduction of the voltage-induced signal into Ca(2+) release through the ryanodine receptor channels. The muscle-specific junctophilin isoforms (JPH1 and JPH2) are anchored to the j-SR with a trans-membrane segment present at the C-terminus and are capable to bind the sarcolemma with a series of phospholipid-binding motifs localized at the N-terminus. Accordingly, through this dual interaction, JPH1 and JPH2 are responsible for the assembly of the triadic junctional membrane complexes. Recent data indicate that junctophilins seem also to interact with other proteins of the excitation-contraction machinery, suggesting that they may contribute to hold excitation-contraction coupling proteins to the sites where the j-SR is being organized.

Ryanodine receptors are part of the myospryn complex in cardiac muscle

“…S6). In common with cardiac muscle, the SR of striated muscle can be divided into two sub-domains; the j-SR or triad couplon formed between the t-tubule and terminal cisternae of the SR and the l-SR 30, 31, 35, 40 .…”

Obscure functions: the location–function relationship of obscurins

“…The SR is a striated muscle-specific, specialized form of smooth endoplasmic reticulum which functions to maintain intracellular Ca 2+ homeostasis necessary for excitation-contraction coupling (Armani et al 2006;Barone et al 2015). The SR is organized into two main functional domains, namely, the junctional SR and the network SR, and surrounds the contractile apparatus at regular intervals throughout the sarcomere (Gyorke 2004).…”

“…sAnk1, expressed in both cardiac and skeletal muscle, is one of five small isoforms of the ANK1 gene, which also encodes a much larger ankyrin-R protein (Bagnato et al 2003;Borzok et al 2007). The NH 2− terminus of sAnk1 contains a transmembrane domain which inserts into the membranes of the SR while its COOH-terminus, located on the cytoplasmic side of the SR, interacts with the ankyrin binding domain of the COOH-terminus of obscurin-A (Barone et al 2015;. The tight interaction between obscurin and sAnk1 is mediated by electrophilic interactions of positively charged amino acids on sAnk1 and negatively charged residues within the ankyrin binding domain of obscurin (Borzok et al 2007;Busby et al 2011).…”

Identification and characterization of three novel mutations in theCASQ1gene in four patients with tubular aggregate myopathy

“…Further increases in Ca 2+ levels lead to the formation of polymers, mediated by back-to-back interactions, that result in an increased ability to bind Ca 2+ (Park, Wu, Dunker, & Kang, 2003;Sanchez et al, 2012). CASQ1 participates, together with other proteins as triadin, junctin, and the ryanodine receptor Ca 2+ release channel (RyR1) in the assembly of a large macromolecular machinery dedicated to Ca 2+ release from the SR (Barone, Randazzo, Del Re, Sorrentino, & Rossi, 2015). Previous studies have provided evidence that CASQ1 may have an inhibitory effect on the pathways that regulate Ca 2+ entry (Shin et al, 2003;Zhao et al, 2010).…”