Proper cardiac function requires the synchronous mechanical and electrical coupling of individual cardiomyocytes. The intercalated disc (ID) mediates coupling of neighboring myocytes through intercellular signaling. Intercellular communication is highly regulated via intracellular signaling, and signaling pathways originating from the ID control cardiomyocyte remodeling and function. Herein, we present an overview of the inter- and intracellular signaling that occurs at and originates from the intercalated disc in normal physiology and pathophysiology. This review highlights the importance of the intercalated disc as an integrator of signaling events regulating homeostasis and stress responses in the heart and the center of several pathophysiological processes mediating the development of cardiomyopathies.

Obscurin, a giant modular cytoskeletal protein, is comprised mostly of tandem immunoglobulinlike (Ig-like) domains. This architecture allows obscurin to connect distal targets within the cell. The linkers connecting the Ig domains are usually short (3-4 residues). The physical effect arising from these short linkers is not known; such linkers may lead to a stiff elongated molecule or, conversely, may lead to a more compact and dynamic structure. In an effort to better understand how linkers affect obscurin flexibility, and to better understand the physical underpinnings of this flexibility, here we study the structure and dynamics of four representative sets of dual obscurin Ig domains using experimental and computational techniques.We find in all cases tested that tandem obscurin Ig domains interact at the poles of each domain and tend to stay relatively extended in solution. NMR, SAXS, and MD simulations reveal that while tandem domains are elongated, they also bend and flex significantly. By applying this behavior to a simplified model, it becomes apparent obscurin can link targets more than 200 nm away. However, as targets get further apart, obscurin begins acting as a spring and requires progressively more energy to further elongate.

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contraction and for increased cardiac contractility in response to inotropic stimuli. Mutations in MYBPC3, the gene encoding cMyBP-C, are the single most common genetic cause of hypertrophic cardiomyopathy (HCM). It has been proposed that the interaction of the N-terminal domains (NTDs) of cMyBP-C (e.g. C0, C1, M and C2) with myosin heads may stabilize the super-relaxed state (SRX-state) of the thick filament, while NMR experiments directly confirmed the binding of the C0 Ig-domain of cMyBP-C to the isolated regulatory light chain (RLC) of myosin. We recently demonstrated that C1 can activate the thin filament to the same extent as rigor myosin-S1, while C0 significantly enhances the activating effect of C1. Our data also show that C0 competes with myosin-S1 for binding to the thin filament. In order to understand how C0 interacts with the thick and thin filaments upon active cross-bridge formation we used cryo electron microscopy and image analysis of native cardiac thin filaments decorated with rigor myosin-S1 and the C0-domain of cMyBP-C. We show that C0 readily binds to the RLC of myosin-S1 bound to the thin filament in rigor state. Taking into account that the C0-domain is specific to the cardiac muscle and is absent in the skeletal MyBP-C we suggest a model of how the C0-domain of cMyBP-C participates in the regulation of cardiac contraction. 577-Pos Obscurin in Heart Failure