Calmodulin (CaM) is most recognized for its role in activating Ca²⁺-CaM dependent enzymes following increased intracellular Ca²⁺. However, high intracellular concentration of CaM indicates CaM has the potential to play a significant role as a Ca²⁺-buffer. Neurogranin (Ng) is a small neuronal IQ-motif containing protein that accelerates Ca²⁺ dissociation from CaM. In cells that contain high concentrations of both Ng and CaM, like CA1 pyramidal neurons, we hypothesize that the accelerated Ca²⁺ dissociation from CaM by Ng decreases the buffering capacity of CaM and thereby shapes the transient dynamics of intracellular free Ca²⁺. We examined this hypothesis using a mathematical model constructed on the known biochemistry of Ng and confirmed the simulation results with Ca²⁺ imaging data in the literature. In a single compartment model that contains no Ca²⁺ extrusion mechanism, Ng increased the steady-state free Ca²⁺. However, in the presence of a Ca²⁺ extrusion mechanism, Ng accelerated the decay rate of free Ca²⁺ through its ability to increase the Ca²⁺ dissociation from CaM, which in turn becomes subject to Ca²⁺ extrusion. Interestingly, PEP-19, another neuronal IQ-motif protein that accelerates both Ca²⁺ association and dissociation from CaM, appears to have the opposite impact on free Ca²⁺ than Ng. As such, Ng may regulate, in addition to Ca²⁺/CaM dependent process, Ca²⁺ sensitive enzymes by influencing the buffering capacity of CaM and subsequently free Ca²⁺ levels. We examined the relative impact of these Ng-induced effects in the induction of synaptic plasticity.