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Neurogranin Controls the Spatiotemporal Pattern of Postsynaptic Ca²⁺/CaM Signaling

Yoshihisa Kubota ^*, John A. Putkey  and M. Neal Waxham ^*

^* Department of Neurobiology and Anatomy, and Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, Texas

Correspondence: Address reprint requests to Y. Kubota, E-mail: Yoshihisa.Kubota{at}uth.tmc.edu.

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.