In addition to SAC in the outer cell membrane, there may be non-sarcolemmal SAC in the sarcoplasmic reticulum 12 or mitochondria. 139,140 Sunitinib supplier Cardiac non-myocytes are also mechanosensitive and exhibit electrophysiological properties modulated by mechanical

stimuli. 18,141–143 Channels, such as Nav1.5 and TRPM7, that were initially identified as stretch-modulated in non-cardiac cell types, 144,145 have now been found in cardiac fibroblasts. 146,147 Finally, there is a growing body of evidence to suggest that many cardiac ion channels, even those that are not classically considered as SAC (e.g. voltage- or ligand-gated channels), are sensitive to mechanical modulation of their gating behaviour. 148 Future research should therefore focus on characterising the mechanical stimuli experienced by cardiomyocytes in vivo, so that they can be more closely replicated in vitro. This can be aided greatly by high-resolution imaging of the beating heart, 149 followed by whole heart histological reconstruction 150,151 and subsequent computational re-integration of tissue deformation

152,153 with a granularity that allows identification of local stress-strain dynamics 154 and prediction of microstructural effects on electrophysiology. 155 Direct measurement, and validation of modelling predictions, currently suffers from a number of technical limitations, in particular the inability to measure locally acting forces in situ. The recent development of Förster Resonance Energy Transfer (FRET)-based force sensors that can be genetically inserted into intracellular proteins, 156 may open up a treasure chest of novel insight if they can be applied to heart research. These force sensors are based on the energy transfer between two compatible fluorophores. The efficacy of the energy transfer is inversely proportional to the distance between the donor and the acceptor, multiplied by 106, making the FRET signal very sensitive to small distance changes. Meng and Sachs 157 have calibrated their probe using DNA to be

able to quantify forces from fluorescent signal changes. These sensors constitute a very powerful tool for the assessment of the mechanical state in components of single cells or tissues. Until now little is known about forces within the cell/cytoskeleton, both when cells are at rest, or while mechanically stimulated. In addition, intracellular force reporters would be very Cilengitide useful to improve our understanding of the interplay of SAC with other mechanosensors, like integrins and the cytoskeleton. Armed with a more thorough understanding of physiological mechanical stimuli, and novel techniques, we expect to improve our understanding of the molecular substrate of cardiac SAC, and to better predict their pathophysiological roles for the regulation of heart rate and rhythm in the mechanosensitive heart (Figure 4). Figure 4. Timing-, amplitude-, and target-dependent stretch effects on heart rhythm. AP: action potential, Δ: change in.