CaMKII Autophosphorylation and PP1 Saturation Lead to Bistability in the Phosphorylation States of CaMKII at Resting Ca²⁺

<div><p>(A) Phosphorylation of the first subunit is slow at resting Ca²⁺ because of the requirement for two Ca²⁺/calmodulin molecules (see text). Subsequent phosphorylation is faster because only one Ca²⁺/calmodulin is required.</p> <p>(B) Schematic figure indicating how bistability arises from the dependence of phosphorylation and dephosphorylation rates on the number of subunits phosphorylated. Stable states are at the left (DOWN) and right (UP) intersections of the two curves. The middle crossing is unstable. The greater the area of the shaded region between a stable steady state and the unstable steady state, the harder it is for fluctuations to destabilize that stable steady state (the larger their basins of attraction).</p> <p>(C) A 2-s pulse of high Ca²⁺ switches the system (with 16 holoenzymes) from a low state of phosphorylation to a higher state within the basin of attraction of the UP state (see [D]). Phosphorylation fraction is <i>Sp_tot</i>/12<i>N_CaMK</i>.</p> <p>(D) After the end of the Ca²⁺ pulse, it can take tens of minutes for the system to reach the dynamic equilibrium in the UP state.</p> <p>(E) The UP state is stable for many years in a system with 16 holoenzymes.</p>