REVIEW ARTICLE Organization of junctional sarcoplasmic reticulum proteins in skeletal muscle fibers Virginia Barone 1 • Davide Randazzo 1 • Valeria Del Re 1 • Vincenzo Sorrentino 1 • Daniela Rossi 1 Received: 15 July 2015 / Accepted: 8 September 2015 / Published online: 15 September 2015 Ó Springer International Publishing Switzerland 2015 Abstract The sarcoplasmic reticulum (SR) of striated muscles is specialized for releasing Ca 2? following sar- colemma depolarization in order to activate muscle con- traction. 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 machin- ery, suggesting that they may contribute to hold excitation– contraction coupling proteins to the sites where the j-SR is being organized. Keywords Excitation–contraction coupling Á Membrane contact site Á Calcium signalling Á Sarcoplasmic reticulum Á Muscle biology Introduction The SR is a specialized form of endoplasmic reticulum, which develops in the embryonic life starting from an apparently disorganized accumulation of membranes. In the post-natal life, it evolves in the formation of two dis- tinct but functionally linked domains: the longitudinal SR (l-SR) and the junctional SR (j-SR) that together wrap the contractile apparatus (Baumann and Walz 2001). In mammalian skeletal muscle, the l-SR corresponds to the largest part of the entire SR and it appears as a system of tubules distributed around the myofibrils (Takekura et al. 1994, 2001; Kaisto and Metsikko ¨ 2003; Rossi et al. 2008). The l-SR represents the main site for Ca 2? storage and uptake from the cytosol, a process operated by the SR/ER & Vincenzo Sorrentino vincenzo.sorrentino@unisi.it 1 Molecular Medicine Section, Department of Molecular and Developmental Medicine, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy 123 J Muscle Res Cell Motil (2015) 36:501–515 DOI 10.1007/s10974-015-9421-5