Post–Abers Na/K pump cycle with suggested inactivation reactions. When three Na are bound to pumps with inwardly facing binding sites (E₁, state 1), pumps phosphorylate themselves and occlude Na (state 2), followed by opening to the outside (E₂, state 3), release of Na and binding of 2 K (state 4), deposphorylation with opening to the inside and release of K (state 5), and rebinding of cytoplasmic Na. Pumps appear to inactivate from E₁ states in which Na-binding sites are not fully occupied (states 5 to 6), and recovery from inactivation occurs primarily when binding sites are loaded with Na (states 7 to 1). It is speculated that a small molecule could mediate inactivation by interacting with the phosphorylation site of functionally associated sites (“X” in state 6). It is assumed in simulations that pump failures can occur in which pumps in E₂ configuration with three Na loaded dephosphorylate and return to the E₁ state, thereby returning three Na to the cytoplasm without completing a pump cycle. Alternatively, ADP may accumulate significantly in isolated myocytes and allow backward movement of three Na with synthesis of ATP. In either case, the slippage caused by such “failures” becomes negligible in the presence of extracellular K.