title: 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 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.
authors.affiliation: Department of Neurobiology and Anatomy, University of Texas Medical School, 6431 Fannin, Houston, Texas 77030, USA. Yoshihisa.Kubota@uth.tmc.edu
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kubota
authors.forename: John A
authors.initials: JA
authors.lastname: Putkey
authors.forename: Harel Z
authors.initials: HZ
authors.lastname: Shouval
authors.forename: M Neal
authors.initials: MN
authors.lastname: Waxham
mesh_terms: D000200:Action Potentials / Q000502:physiology; D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D002021:Buffers; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D002147:Calmodulin / Q000378:metabolism*; D003198:Computer Simulation; D003593:Cytoplasm / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051579:Neurogranin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D002021:Buffers; D002147:Calmodulin; D009419:Nerve Tissue Proteins; C489091:Pcp4 protein, mouse; D051579:Neurogranin; D002118:Calcium