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

¹Department of Neurobiology and Anatomy and ²Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, Texas

Submitted 7 August 2007; accepted in final form 24 October 2007

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.