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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.

SUBMITTER: Kubota Y

PROVIDER: S-EPMC3622048 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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IQ-motif proteins influence intracellular free Ca2+ in hippocampal neurons through their interactions with calmodulin.

Kubota Yoshihisa Y Putkey John A JA Shouval Harel Z HZ Waxham M Neal MN

Journal of neurophysiology 20071024 1

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 C ...[more]

PMID: 17959737

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Project description:Aging is often associated with a cognitive decline and a susceptibility to neuronal damage. It is also the most important risk factor for neurodegenerative disorders, particularly Alzheimer's disease (AD). AD is related to an excess of neurotoxic oligomers of amyloid ? peptide (A?o); however, the molecular mechanisms are still highly controversial. Intracellular Ca2+ homeostasis plays an important role in the control of neuronal activity, including neurotransmitter release, synaptic plasticity, and memory storage, as well as neuron cell death. Recent evidence indicates that long-term cultures of rat hippocampal neurons, resembling aged neurons, undergo cell death after treatment with A?o, whereas short-term cultures, resembling young neurons, do not. These in vitro changes are associated with the remodeling of intracellular Ca2+ homeostasis with aging, thus providing a simplistic model for investigating Ca2+ remodeling in aging. In vitro aged neurons show increased resting cytosolic Ca2+ concentration, enhanced Ca2+ store content, and Ca2+ release from the endoplasmic reticulum (ER). Ca2+ transfer from the endoplasmic reticulum (ER) to mitochondria is also enhanced. Aged neurons also show decreased store-operated Ca2+ entry (SOCE), a Ca2+ entry pathway related to memory storage. At the molecular level, in vitro remodeling is associated with changes in the expression of Ca2+ channels resembling in vivo aging, including changes in N-methyl-D-aspartate NMDA receptor and inositol 1,4,5-trisphosphate (IP3) receptor isoforms, increased expression of the mitochondrial calcium uniporter (MCU), and decreased expression of Orai1/Stim1, the molecular players involved in SOCE. Additionally, A?o treatment exacerbates most of the changes observed in aged neurons and enhances susceptibility to cell death. Conversely, the solely effect of A?o in young neurons is to increase ER-mitochondria colocalization and enhance Ca2+ transfer from ER to mitochondria without inducing neuronal damage. We propose that cultured rat hippocampal neurons may be a useful model to investigate Ca2+ remodeling in aging and in age-related neurodegenerative disorders.

Project description:During the acquisition of memories, influx of Ca2+ into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca2+influx during the first few seconds of activity is interpreted within the Ca2+-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity,including Ca2+/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bindup to 4 Ca2+ ions. As a first step toward clarifying how the Ca2+-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca2+, calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca2+ play a significant role in activation of CaMKII in the physiological regime,supporting the notion that processing of Ca2+ signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca2+ is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca2+ transients arises from the kinetics of interaction of fluctuating Ca2+with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning.

Dataset Information

IQ-motif proteins influence intracellular free Ca2+ in hippocampal neurons through their interactions with calmodulin.

Publications

IQ-motif proteins influence intracellular free Ca2+ in hippocampal neurons through their interactions with calmodulin.

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