69 Intuitively, this massive

structure, and the associated large surface ATM kinase assay area, could be well-adapted for sensing changes in bilayer curvature and/or stretch. In line with this hypothesis, it has been shown that Piezo1 gating is associated with dimensional changes. 70 Currently, no data has been published directly addressing Piezo1 mechanosensitivity in the heart. However, Piezo1 channel electrophysiological properties are similar to that of endogenous cardiac SACNS, including weak voltage dependency, comparable single channel conductance, inactivation, and sensitivity to GsMTx-4. 71–73 Furthermore, Piezo1 mRNA is expressed in the murine heart 46,74 albeit at low levels (see comment on whole-tissue expression levels, above). Piezo1 is involved in erythrocyte volume homeostasis. Morpholino-mediated knockdown

of Piezo1 results in swelling and lysis of red blood cells and consequent anemia. 75 Interestingly, this function is close to that of bacterial mechanosensitive channels of large and small conductance (MscL and MscS). 76 Undoubtedly this is an exciting and dynamic area of development. Basic science questions concerning structure, protein partners, and regulation of Piezo1 need to be addressed, 77 as does the question of whether Piezo1 is present in, and relevant for, the human heart. SACK Whole-cell SACK currents (ISAC,K) were first described by Kim et al. 35 in rat atrial myocytes. In contrast to SACNS, SACK, are outwardly rectifying, and as such, allow potassium ions to move more easily out of the cell than into it. Compared to SACNS, SACK tend to have larger single channel conductances. They also inactivate in a time-dependent manner and are generally insensitive to GsMTx-4. 78 Being potassium-selective, their reversal potential lies negative to the resting membrane potential of cardiac cells, so activation of SACK will generally cause membrane repolarisation or hyperpolarisation. 27 To date, single-channel recordings of ISAC,K in adult mammalian cardiac myocytes have been obtained from atrial 35 and ventricular myocytes, 36,79,80

suggesting that their subcellular compartmentalization differs from SACNS. Primary molecular candidates for cardiac SACK are TREK-1, BKCa and KATP. TREK-1 TREK-1 is a member of the two-pore domain potassium channel family, which is associated with a ‘leak’ potassium ion conductance in cardiomyocytes. 81 TREK-1, however, displays more complex permeation and gating properties than a simple ‘leak’ channel, Batimastat and is regulated by a number of factors including pH, temperature, second messenger systems, and membrane deformation/stretch. 82 Mechanosensitivity was attributed to TREK-1 by Patel et al. 39 based on single-channel patch clamp recordings from transfected COS cells. Subsequently, Terrenoire et al. 83 demonstrated that ISAC,K (endogenous to rat atrial myocytes) displays a number of properties that bear striking similarities to recombinant TREK-1 channels.