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. 2005 Jul 29;1(2):e20. doi: 10.1371/journal.pcbi.0010020

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Copyright: © 2005 Hayer and Bhalla.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.

PMC Copyright notice

CaMKII-thr286* indicates Thr286-phosphorylated CaMKII, and CaMKII-thr286*-thr305* indicates Thr286/Thr305-phosphorylated CaMKII.

(A) Schematic of CaMKII autophosphorylation in the PSD. Reactions (in bold) and PP1 concentrations are altered in the PSD from the basal model to achieve bistability. Block arrows indicate the CaMKII states that translocate. There are two shaded sets of molecules, indicating states that are summed to give rise to an enzyme activity. The Tot-CaM-CaMKII activity is the sum of concentrations of CaM-CaMKII and CaM–Thr286-phosphorylated CaMKII. The Aut-CaMKII activity is the sum of the calcium-autonomous states Thr286-phosphorylated and Thr286/Thr305-phosphorylated CaMKII.

(B) Bistability analysis. The Aut-CaMKII molecular species has been bifurcated into Aut-CaMKII enzyme, and Aut-CaMKII readout. The enzyme activity is buffered numerically (x-axis). The readout (y-axis) remains the sum of Thr286-phosphorylated and Thr286/Thr305-phosphorylated CaMKII. Fixed points are given by the intersection points of the amount of Aut-CaMKII with the 45° line. These fixed points indicate the number of Aut-CaMKII molecules that would exactly sustain their own activity through autophosphorylation. The upper and lower points are stable, and the middle point is the transition point.

(C) Time course of bistable response. The first arrow is a Ca²⁺ stimulus of 2.7 μM for 500 s that switches on the CaMKII bistable loop. The second arrow is a 5-fold increase in k _cat of PSD-localised PP1 for a period of 500 s, which switches CaMKII off.

(D) Parameter sensitivity analysis. Key parameters are scaled up and down and the model is tested for bistability. Most parameters can be varied 2-fold or more in either direction without the model losing bistability.

(E) Stochastic run showing stability in both high and low states, when PKA is buffered.

(F) Stochastic run showing spontaneous state flips in either direction, with the complete PKA model.

(G) Statistics of spontaneous state flips with the complete PKA model. Average turn on and turn off times are both over 15 h.