Neurogranin controls the spatiotemporal pattern of postsynaptic Ca2+/CaM signaling

Neurogranin ( Ng) is a postsynaptic IQ- motif containing protein that accelerates Ca2+ dissociation from calmodulin ( CaM), a key regulator of long- term potentiation and long- term depression in CA1 pyramidal neurons. The exact physiological role of Ng, however, remains controversial. Two genetic knockout studies of Ng showed opposite outcomes in terms of the induction of synaptic plasticity. To understand its function, we test the hypothesis that Ng could regulate the spatial range of action of Ca2+/ CaM based on its ability to accelerate the dissociation of Ca2+ from CaM. Using a mathematical model constructed on the known biochemistry of Ng, we calculate the cycle time that CaM molecules alternate between the fully Ca2+ saturated state and the Ca2+ unbound state. We then use these results and include diffusion of CaM to illustrate the impact that Ng has on modulating the spatial profile of Ca2+-saturated CaM within a model spine compartment. Finally, the first-passage time of CaM to transition from the Ca2+-free state to the Ca2+-saturated state was calculated with or without Ng present. These analyses suggest that Ng regulates the encounter rate between Ca2+ saturated CaM and its downstream targets during postsynaptic Ca2+ transients.