IQ-Motif Proteins Influence Intracellular Free Ca2+in Hippocampal Neurons Through Their Interactions With Calmodulin

Abstract

Calmodulin (CaM) is most recognized for its role in activating Ca2+–CaM-dependent enzymes following increased intracellular Ca2+. However, CaM's high intracellular concentration 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 than that of Ng on free Ca2+. As such, Ng may regulate, in addition to the 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.