A particularly surprising result is that, for a normally Selleck Autophagy Compound Library attractive factor at high levels of baseline calcium, reducing cAMP levels promotes attraction, exactly the opposite response to that previously observed at normal baseline calcium when cAMP levels are reduced. Together, these results generate a unifying quantitative explanation for a large number of previous experimental results, and the model provides a method for quantitatively predicting attraction versus repulsion of growth cone turning in a wide variety of biological situations. Previous work has shown that a calcium-calmodulin-dependent pathway

is responsible for the directional growth of axons during development (Han et al., 2007). This is mediated by CaMKII and CaN, where CaMKII promotes attraction

and CaN promotes repulsion (Wen et al., 2004, Henley and Poo, 2004 and Gomez and Zheng, 2006). These are both stimulated selleck screening library through the actions of calcium/calmodulin, while the activity of CaMKII is also inhibited by PP1. The activity of PP1 is directly inhibited by I1, which in turn is phosphorylated by cAMP-dependent PKA and dephosphorylated by CaN (Henley and Poo, 2004; Figure 1A). So far, the behavior of this complex network has been studied only qualitatively. We therefore developed a mathematical model of this process to understand quantitatively how calcium and cAMP determine attraction versus repulsion of growth cone responses. The model allows for analysis of the change in the CaMKII:CaN ratio in the up-gradient and down-gradient sides of the growth cone as the calcium concentration changes (see Figure S1 available online for an example of the activation of the different signaling components of the model as a function of calcium concentration). We assume that a higher CaMKII:CaN ratio in the up-gradient compartment only compared with the down-gradient compartment leads to attraction, whereas a lower CaMKII:CaN ratio in the up-gradient compartment compared to the down-gradient compartment

leads to repulsion. This means that an increase in calcium in the up-gradient compartment can result in attraction or repulsion, dependent on the resting level of calcium and the magnitude of the increase in calcium. In the model, the numerical value of the CaMKII:CaN ratio is not important, but rather it is the relative values of the CaMKII:CaN ratio between the two compartments that determines attraction or repulsion. The model addresses three separate problems of growth cone guidance: (1) the role of calcium influx into the growth cone during attraction and repulsion, (2) the role of baseline calcium in determining the response to a guidance cue, and (3) the role of cAMP in determining the response to a guidance cue.