81 A number of studies have identified TREK-1 mRNA expression in rat atria, as well as in left, right, and gamma secretase structure septal ventricular myocytes. 83–86 The protein appears to be arranged in longitudinal stripes at the surface of cardiomyocytes: a pattern that might support directional stretch sensing. 80 At the tissue level, TREK-1 expression is distinctly heterogeneous, with a gradient of mRNA expression that increases, transmurally, from epicardial to endocardial cells.

86 This heterogeneity appears to correlate with transmural changes in MEF sensitivity, where stretch causes the most pronounced action potential shortening in the sub-endocardium. 87 To our knowledge, mRNA analysis thus far has failed to identify TREK-1 expression in

the human heart. 88,89 It has been suggested that the TWIK-related arachidonic acid-activated potassium channel (TRAAK (http://www.ncbi.nlm.nih.gov/gene/50801)) or TWIK-related acid-sensitive potassium channel (TASK-1 (http://www.ncbi.nlm.nih.gov/gene/3777)) of the K2P family, which appear to be expressed in the human heart, 90 may act as TREK-1 homologues. Indeed, when TRAAK is expressed in heterologous model systems, it forms a channel with very similar properties to TREK-1. 91 Characterisation of both the presence and functional relevance of these ion channels in human requires further elucidation. BKCa BKCa channels have large conductances, and they respond to voltage changes and alterations in intracellular calcium ion concentration in a manner that allows them to contribute to repolarisation. 92 Functionally, BKCa channels have been suggested to control heart rate and to offer cardioprotection during ischaemia. 93 Kawakubo et al. 94 identified mechanosensitivity of BKCa channels in membrane patches excised from cultured embryonic chick ventricular myocytes. Attempts to measure single-channel activity in post-hatch chick cardiomyocytes have been unsuccessful, although Iribe et al. 95 characterised a whole-cell ISAC,K GSK-3 which was sensitive to iberiotoxin (a BKCa inhibitor). Interestingly,

this ISAC,K was also sensitive to extracellular sodium. The authors suggest that BKCa activation could occur secondary to mechanical modulation of sodium ion influx (e.g. via SACNS), and consequentially shift sodium-calcium exchanger activity towards preservation of intracellular calcium. If this is the case, BKCa might not be directly stretch sensitive. Whether or not BKCa channels are responsible for ISAC,K in embryonic chick cardiomyocytes, there is little evidence to suggest that BKCa channels form cardiac SACK in other species. In the human heart, BKCa channels are sparsely expressed, 92 and they may be confined to cardiac fibroblasts (where BKCa was detected using Western blot 96 ).