Ca2+ release from intracellular stores and influx from extracellular reservoir regulate a wide range of physiological functions including muscle contraction and rhythmic heartbeat. and physiologic and pathophysiologic roles in muscles. The specific property and the Taxol enzyme inhibitor dysfunction of this pathway in muscle diseases, and new directions for future research in this rapidly growing field are discussed. [BMB Reports 2014; 47(2): 69-79] mice, we demonstrated that SOCE was significantly impaired in myotubes lacking Taxol enzyme inhibitor RyR1 and RyR3, which provided direct evidence to support a model of RyR-coupled SOCE in muscle cells. This RyR-dependent SOCE can be activated by combination of caffeine and ryanodine in both myotubes and adult skeletal muscle fibers and is sensitive to azumolene (32), a water-soluble equipotent analog of dantrolene (the only available treatment for malignant hyperthermia [MH]). While thapsigargin-induced depletion of SR Ca2+ stores leads to maximal activation of SOCE, this TG-induced SOCE is insensitive to azumolene in muscle cells. These findings highlight that there are two distinct portions of SOCE in skeletal muscles, i.e. RyR1-dependent and RyR1-independent, which can be distinguished by azumolene. Another different property of SOCE in skeletal muscle is the fast kinetics. In non-excitable cells, the development of SOCE requires tens of seconds for full activation; whereas in skeletal muscle, SOCE is activated within a second (14,41). The possible mechanisms underlying the fast kinetics of skeletal muscle SOCE are discussed in next section. SOCE SIGNALING COMPLEX IN TRIAD JUNCTION The discoveries of ER Ca2+ sensor STIM1 and PM channel pore unit Orai1 have provided molecular tools to understand the mechanism of SOCE regulation in both non-excitable cells and skeletal muscles. We now know that the interaction between STIM1 and Orai1 is essential for transduction of the retrograde signal from ER/SR lumen to activation of SOCE at the PM in lymphocytes and other non-excitable cells. Recent crystal structure of Orai determined at 3.35A resolution further revealed that the channel gating requires Orai1-STIM1 coupling (42). In muscle cells, a large body of evidence convincingly demonstrated that Orai1 and STIM1 are the major players in SOCE signaling complex even though other PM Ca2+ permeable channels, e.g. TRPC may participate (43,44). Both Taxol enzyme inhibitor Orai1 and STIM1 are abundantly expressed in neonatal myotubes and adult skeletal muscle fibers as consistently shown by RT-PCR, Western blot and immunostaining (14,35,45,46). Orai1 apparently is required for the activation of SOCE in myotubes since expression of human dominant-negative Orai1 (dnOrai1, E106Q) resulted in abolished SOCE (47). In the same study, the authors also used transgenic mice with muscle-specific expression of dnOrai1 and characterized Orai1-dependent SOCE in adult skeletal muscle. STIM1 Taxol enzyme inhibitor is expressed at such a high level in skeletal muscle that Taxol enzyme inhibitor only T cells and the cerebellum have comparable expression levels (14). During myogenesis, STIM1 not only increases in expression but also aggregates and redistributes to the cellular periphery. Myotubes lacking STIM1 fail to exhibit SOCE and mice lacking STIM1 die perinatally from a skeletal Rabbit Polyclonal to AhR myopathy. These findings and other reports highlight both Orai1 and STIM1 as essential components of the SOCE machinery in skeletal muscle. E-C coupling occurs in the junction between the T-tubule, an invagination of sarcolemma, and the terminal cisternae of SR in a structure known as the triad (48,49) (see Fig. 1). The triad junction provides a unique architecture for the direct interaction between DHPRs and RyRs, which mediates signal transduction of voltage-induced Ca2+ release to initiate consequent myofilament contraction (22). The triad junction also seems to provide a specialized frame structure for rapid activation of SOCE, which is supported by several lines of evidence. Endogenous Orai1 co-localizes with STIM1 at triad junction to form STIM1COrai1 complexes upon store depletion in muscle fibers isolated from adult mice (47). Rosenberg and colleagues showed that STIM1 locates in both the terminal cisternae and the para-junctional SRs in electron micrograph, which is consistent with immunostaining study on partial co-localization of STIM1 and RYR1 (14). Based on these findings, they proposed that there are two pools of STIM1 proteins: a fast pool, in which STIM1s are ready to couple with Orai1s for a quick response; a.