The intercalated disc: a mechanosensing signalling node in cardiomyopathy

Fig. 1. Simplified schematic representation of the two main cytoskeletal multiprotein complexes in cardiomyocytes a sarcomeres and b the intercalated disc. The sarcomere or the region between two Z-discs is the basic contractile unit of myofibrils, consisting of thin (actin and associated proteins, horizontal blue lines), thick (myosin and associated proteins, horizontal yellow block) and elastic (titin, horizontal pink line) filaments. Intercalated disc was originally described to consist of adherens junctions (blue and yellow symbols), desmosomes (pink symbols) and gap junctions (green symbols). The adherens junctions and desmosomes ensure transmission of force between neighbouring cardiomyocytes, allowing the heart to function in synchrony

Fig. 2. Simplified schematic representation of the protein complexes involved in force sensing and transduction at the intercalated disc. Molecules suggested to act as molecular switches in response to mechanical force are shown in yellow. Vinculin, in pink, is a key protein binding several factors involved in actin filament regulation. Vinculin phosphorylation on Tyr822 at adherens junctions was shown to be increased in epithelial MCF10a cells, but whether a similar modification is found in the heart remains to be elucidated. The TRPV2 channel is responsive to force and ensures the integrity of the intercalated disc. Proteins marked with * are affected in cardiomyopathies

Fig. 3. Simplified schematic representation of the signalling molecules modulating the response to mechanical force at the intercalated disc. In the early stages of heart disease, these signalling pathways promote adaptive cell growth and contribute to stronger cell-cell contacts. Aberrant signalling can result in weaker contacts (e.g. in the hearts of TRPV2 knockout mice) and a failure to trigger adaptive hypertrophy (for instance, in the hearts of mice lacking either FAK, melusin or IQGAP1), leading to impaired contractile function. In some cases, impaired cell-cell contacts can result in a complete change in cardiomyocyte identity