The delicate bistability of CaMKII.

Calcium/calmodulin-dependent protein kinase II (CaMKII) is a synaptic, autophosphorylating kinase that is essential for learning and memory. Previous models have suggested that CaMKII functions as a bistable switch that could be the molecular correlate of long-term memory, but experiments have failed to validate these predictions. These models involved significant approximations to overcome the combinatorial complexity inherent in a multisubunit, multistate system. Here, we develop a stochastic particle-based model of CaMKII activation and dynamics that overcomes combinatorial complexity without significant approximations. We report four major findings. First, the CaMKII model system is never bistable at resting calcium concentrations, which suggests that CaMKII activity does not function as the biochemical switch underlying long-term memory. Second, the steady-state activation curves are either laserlike or steplike. Both are characterized by a well-defined threshold for activation, which suggests that thresholding is a robust feature of this system. Third, transiently activated CaMKII can maintain its activity over the time course of many experiments, and such slow deactivation may account for the few reports of bistability in the literature. And fourth, under in vivo conditions, increases in phosphatase activity can increase CaMKII activity. This is a surprising and counterintuitive effect, as dephosphorylation is generally associated with CaMKII deactivation.