Hypothetical mechanisms underlying the distinct impact of cardiotonic steroids (CTS) on survival of cells, expressing the CTS-sensitive (α1S) and the CTS-resistant (α1R) Na+,K+-ATPase subunits. In both cases, saturating levels of CTS strongly increase the [Na+]i/[K+]i ratio. In addition, CTS trigger distinct conformational changes in α1S and α1R isoforms that, in turn, affect their interactions with unknown protein partner(s) I and II. These subsequent signaling events lead to activation of p38 and ERK1/2 MAPK and result in cell death and survival, respectively. ? – steps showing possible additional effects of the transcriptomic changes, which can be directly induced by elevation of the [Na+]i/[K+]i ratio. For more details, see text.