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

Kubota Y, Putkey JA, Shouval HZ, Waxham MN. IQ-motif proteins influence intracellular free Ca in hippocampal neurons through their interactions with calmodulin. J Neurophysiol 99: 264–276, 2008. First published October 24, 2007; doi:10.1152/jn.00876.2007. Calmodulin (CaM) is most recognized for its role in activating Ca –CaMdependent enzymes following increased intracellular Ca . However, CaM’s high intracellular concentration indicates CaM has the potential to play a significant role as a Ca buffer. Neurogranin (Ng) is a small neuronal IQ-motif–containing protein that accelerates Ca dissociation from CaM. In cells that contain high concentrations of both Ng and CaM, like CA1 pyramidal neurons, we hypothesize that the accelerated Ca dissociation from CaM by Ng decreases the buffering capacity of CaM and thereby shapes the transient dynamics of intracellular free Ca . We examined this hypothesis using a mathematical model constructed on the known biochemistry of Ng and confirmed the simulation results with Ca imaging data in the literature. In a single-compartment model that contains no Ca extrusion mechanism, Ng increased the steady-state free Ca . However, in the presence of a Ca extrusion mechanism, Ng accelerated the decay rate of free Ca through its ability to increase the Ca dissociation from CaM, which in turn becomes subject to Ca extrusion. Interestingly, PEP-19, another neuronal IQ-motif protein that accelerates both Ca association and dissociation from CaM, appears to have the opposite impact than that of Ng on free Ca . As such, Ng may regulate, in addition to the Ca –CaM-dependent process, Ca -sensitive enzymes by influencing the buffering capacity of CaM and subsequently free Ca levels. We examined the relative impact of these Ng-induced effects in the induction of synaptic plasticity.