SACK candidates are TREK-1, the large-conductance calcium-activated K+ channel (BKCa; a member of the ‘Big K+’ channel family), and the ATP-sensitive potassium channel (KATP); see Table 1. Table 1 Summary of the currently known main molecular candidates chemical library price for stretch-activated ion channels in cardiac myocytes. TT: T-tubules, S: sarcolemma;

N/S: not specified. In the following, we evaluate the available evidence for presence and contributions of these main cardiac SAC candidates, including their sensitivity to pharmacological interventions, highlight some of the present experimental challenges, and conclude with a consideration of anticipated further developments in this exciting and dynamic field of translational heart research. We will not discuss alternative mechano-sensors, detailed signalling

pathways, or protein-protein interactions, all of which form deserving topics for separate reviews. Sacns Whole-cell currents with a linear current-voltage relationship attributed to SACNS (ISAC,NS), were first identified in cardiac cells by Craelius et al., 34 using whole-cell patch clamp recordings from neonatal rat ventricular myocytes. By applying a voltage clamp, Zeng et al. 40 later described the properties of this current further, including a lack of inactivation and a pronounced sensitivity to block by gadolinium ions (Gd3+). The channel’s reversal potential is positive to the resting potential of working cardiomyocytes, so that activation of SACNS will depolarise resting cells. 27 In contrast to SACK, SACNS are distinctly sensitive to a peptide, isolated by Sachs et al. from Chilean tarantula venom: GsMTx-4 (Grammostola spatulata Mechano-Toxin 4 41 ). The use of GsMTx-4 has allowed researchers to extend the evidence on whole-cell ISAC,NS towards identification of SACNS effects at the

tissue and whole organ levels. At the same time, no SACNS single-channel recordings from freshly-isolated adult ventricular cardiomyocytes have been reported. This has led to the suggestion that SACNS may be localised in membrane regions that are difficult to access in patch clamp studies, such as transverse tubules (T-tubules 42 ), caveolae (which, themselves, form a mechanosensitive GSK-3 structural domain that may be integrated into the surface sarcolemma by excess stretch 43 ), or at intercalated discs. 44 The main molecular candidates for cardiac SACNS, TRP channels 45 and the recently discovered Piezo1 protein, 46 will be discussed in more detail. TRP channels TRP proteins form a family of widely expressed cation channels, responsible for a variety of cellular functions. Polymodal regulation is a distinct feature of TRP (http://www.ncbi.nlm.nih.gov/gene/724608). Known activators of TRP channels include chemical stimuli, temperature elevation, and mechanical interventions ranging from local patch deformation to membrane stretch and shear strain. 47 In particular, the so-called ‘canonical’ TRP channels TRPC1 (http://www.ncbi.nlm.nih.