For these reasons, VAC are unlikely to be main contributors to acute and/or beat-by-beat responses of the heart to mechanical stimuli, and they will not be considered in detail here (for a review on VAC, see 30 ). SAC were discovered in 1984 in embryonic chick skeletal myocytes by Guharay and Sachs. 31 In subsequent years, SAC have been identified in many other cell types 32,33 including order TAK-875 cardiomyocytes. 34 Cardiac SAC can be either cation non-selective (SACNS) 34 or potassium-selective (SACK) 35 (Figure 3). The development of the patch clamp technique was vital for the study of cardiac SAC, and it revealed, in addition

to stretch-activated whole-cell currents, evidence of single-channel activity in atrial myocytes, 35 foetal 34 and (for SACK at least) adult ventricular myocytes, 36 as well as cardiac non-myocytes. 19 That said, formation of membrane patches is associated with significant alterations

in local mechanical and structural properties, especially in complex and densely ‘crowded’ cells such as cardiac myocytes. This leaves the potential for false-positive (e.g. channels that would normally be protected from opening, such as by cytoskeletal interaction) and false-negative observations (channels that are constitutively activated by patch formation may not be identified as mechano-sensitive upon additional patch deformation). This highlights the importance of multi-level investigations, combining a range of electrophysiological recording techniques, from lipid bilayers to sub-cellular and cellular studies in expression systems and native cells, to cultures, tissue slices, native tissue and organs, right through to whole animal or patient research. As pointed out elsewhere, much of this hinges on the availability of improved pharmacological agents, and it requires quantitative structure-based integration, such as by computational modelling. Figure 3. Overview of cation

non-selective (SACNS) and potassium-selective (SACK) channel function, effects, and pharmacological modulators. A. SACNS opening leads to sodium and possibly calcium Carfilzomib entry (in addition to also present potassium fluxes); this depolarises … First insights into the structure and possible mechanisms of operation of these channels were provided by the cloning and crystallization of two bacterial SAC. 37,38 However, even after an exhaustive search, no sequence homologues of these particular ion channels were found in mammals. The first cloned mammalian SAC was the TREK channel (a ‘tandem of two-pore K+ domains in a weak inwardly rectifying K+ channel’ = TWIK-related potassium channel). 39 Despite these significant steps, the molecular identities of mammalian cardiac SAC have yet to be determined. In spite of a lack of firm molecular identification, there are several prominent candidates for mammalian cardiac SAC, and these will be reviewed here.