Calmodulin (CaM) is most recognized for its role in activating Ca(2+)-CaM-dependent enzymes following increased intracellular Ca(2+). However, CaM's high intracellular concentration indicates CaM has the potential to play a significant role as a Ca(2+) buffer. Neurogranin (Ng) is a small neuronal IQ-motif-containing protein that accelerates Ca(2+) dissociation from CaM. In cells that contain high concentrations of both Ng and CaM, like CA1 pyramidal neurons, we hypothesize that the accelerated Ca(2+) dissociation from CaM by Ng decreases the buffering capacity of CaM and thereby shapes the transient dynamics of intracellular free Ca(2+). We examined this hypothesis using a mathematical model constructed on the known biochemistry of Ng and confirmed the simulation results with Ca(2+) imaging data in the literature. In a single-compartment model that contains no Ca(2+) extrusion mechanism, Ng increased the steady-state free Ca(2+). However, in the presence of a Ca(2+) extrusion mechanism, Ng accelerated the decay rate of free Ca(2+) through its ability to increase the Ca(2+) dissociation from CaM, which in turn becomes subject to Ca(2+) extrusion. Interestingly, PEP-19, another neuronal IQ-motif protein that accelerates both Ca(2+) association and dissociation from CaM, appears to have the opposite impact than that of Ng on free Ca(2+). As such, Ng may regulate, in addition to the Ca(2+)-CaM-dependent process, Ca(2+)-sensitive enzymes by influencing the buffering capacity of CaM and subsequently free Ca(2+) levels. We examined the relative impact of these Ng-induced effects in the induction of synaptic plasticity.