Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity (original) (raw)
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Nuclear calcium: a key regulator of gene expression
Biometals, 1998
Through the evolution of multicellular organisms, calcium has emerged as the preferred ion for intracellular signalling. It now occupies a pivotal role in many cell types and nowhere is it more important than in neurons, where it mediates both the relaying and long-term storage of information. The latter is a process that enables learning and memory to be formed and requires the activation of gene expression by calcium signals. Evidence from a number of diverse organisms shows that transcription mediated by the transcription factor CREB is critical for learning and memory. Here we review the features of CREB activation by calcium signals in mammalian cells. In contrast to other transcription factors, its regulation is dependent on an elevation of nuclear calcium concentration, potentially placing this spatially distinct pool of calcium as an important mediator of information storage.
Temporal inhibition of calmodulin in the nucleus
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1998
Calmodulin (CaM) acts as a primary mediator of calcium signaling by interacting with target proteins. We have previously shown that nuclear CaM is critical for cell cycle progression using a transgene containing four repeats of a CaM inhibitor peptide and nuclear targeting signals (J. Wang et al., J. Biol. Chem. 270 (1995) 30245^30248; Biochim. Biophys. Acta 1313 (1996) 223^228). To evaluate the role of CaM in the nucleus specifically during S phase of the cell cycle, a motif which stabilizes the mRNA only during S phase was included in the transgene. The CaM inhibitor mRNA transcript contains a selfannealing stem-loop derived from histone H2B at the 3P end. This structure provides stability of the mRNA only during S phase, thereby restricting CaM inhibitor expression to S phase. The inhibitor accumulates in the nucleus, particularly in the nucleoli. Flow cytometric analysis demonstrated that the CaM inhibitor is expressed in S and G2. Transfected cells show growth inhibition and a reduction in DNA synthesis. The CaM inhibitor peptide is a versatile reagent that allows spatial as well as temporal dissection of calmodulin function. ß
Journal of Neurochemistry, 2003
Nuclear calcium signals associated with electrical activation of neurons can control the activity of the transcription factor cAMP-response element binding protein (CREB). Yet, cAMP is thought to be the key messenger that links synaptic activity to the regulation of CREB-mediated transcription. It is generally assumed that synaptic activity increases the intracellular levels of cAMP; this causes activation of the cAMP-dependent protein kinase (PKA) that regulates CREB-mediated transcription either directly or through controlling nuclear signalling of the MAP kinases/extracellular signal-regulated kinases (ERK1/2) pathway. Here we show that, in hippocampal neurons, synaptic activity failed to increase global levels of cAMP that would be required for the cAMP-PKA system to induce nuclear events. Even near-continuous bursting of action potentials, giving rise to large nuclear calcium signals and robust CREB-dependent transcription, left global intracellular levels of cAMP unchanged. These results suggest that the cAMP-PKA system does not function as the transducer of synaptic signals to the nucleus. They indicate that the known inhibitory effects of blockers of PKA on gene expression and longlasting plasticity triggered by calcium entry reflect a gating function of basal activity of PKA that renders neurons permissive for nuclear calcium-regulated, CREB/CBP-dependent gene expression.
Neuroscience, 2003
Brain-derived neurotrophic factor (BDNF) plays fundamental roles in synaptic plasticity in rat hippocampus. Recently, using rat hippocampal slices, we found that BDNF induces activation of calcium/calmodulin-dependent protein kinase 2 (CaMKII), a critical mediator of synaptic plasticity. CaMKII in turn activates the p38 subfamily of mitogen-activated protein kinases (MAPK) and its downstream effector, MAPK-activated protein kinase 2 (MAPKAPK-2). Herein, we determined whether some kinases of this pathway connect BDNF to the cyclic AMP response element-binding protein (CREB), a transcription factor also involved in plasticity and survival. Crude cytosolic and nuclear fractions were prepared from hippocampal slices of adult rat, and then kinase involvement in CREB phosphorylation was studied with a combination of pharmacologic inhibition and antibody depletion. In addition, the regional localization of this signaling pathway was immunohistochemically investigated. We show that: (i) the BDNF-stimulated CaMKII cascade phosphorylates the key positive regulatory site of CREB via its end MAP-KAPK-2 component; (ii) this process appears to be highly localized in the outermost cell layer of the dentate gyrus. The present findings suggest that CaMKII is involved in neurotrophic-dependent activation of CREB in the dentate gyrus. Such a signaling process could be important for controlling synaptic plasticity in this major area for the afferent inputs to the hippocampal formation.
Differential codes for free Ca2+–calmodulin signals in nucleus and cytosol
Current Biology, 2000
Background: Many targets of calcium signaling pathways are activated or inhibited by binding the Ca 2+-liganded form of calmodulin (Ca 2+-CaM). Here, we test the hypothesis that local Ca 2+-CaM-regulated signaling processes can be selectively activated by local intracellular differences in free Ca 2+-CaM concentration. Results: Energy-transfer confocal microscopy of a fluorescent biosensor was used to measure the difference in the concentration of free Ca 2+-CaM between nucleus and cytoplasm. Strikingly, short receptor-induced calcium spikes produced transient increases in free Ca 2+-CaM concentration that were of markedly higher amplitude in the cytosol than in the nucleus. In contrast, prolonged increases in calcium led to equalization of the nuclear and cytosolic free Ca 2+-CaM concentrations over a period of minutes. Photobleaching recovery and translocation measurements with fluorescently labeled CaM showed that equalization is likely to be the result of a diffusion-mediated net translocation of CaM into the nucleus. The driving force for equalization is a higher Ca 2+-CaM-buffering capacity in the nucleus compared with the cytosol, as the direction of the free Ca 2+-CaM concentration gradient and of CaM translocation could be reversed by expressing a Ca 2+-CaM-binding protein at high concentration in the cytosol. Conclusions: Subcellular differences in the distribution of Ca 2+-CaM-binding proteins can produce gradients of free Ca 2+-CaM concentration that result in a net translocation of CaM. This provides a mechanism for dynamically regulating local free Ca 2+-CaM concentrations, and thus the local activity of Ca 2+-CaM targets. Free Ca 2+-CaM signals in the nucleus remain low during brief or low-frequency calcium spikes, whereas high-frequency spikes or persistent increases in calcium cause translocation of CaM from the cytoplasm to the nucleus, resulting in similar concentrations of nuclear and cytosolic free Ca 2+-CaM.
Calcium regulation of neuronal gene expression
Proceedings of The National Academy of Sciences, 2001
Plasticity is a remarkable feature of the brain, allowing neuronal structure and function to accommodate to patterns of electrical activity. One component of these long-term changes is the activitydriven induction of new gene expression, which is required for both the long-lasting long-term potentiation of synaptic transmission associated with learning and memory, and the activitydependent survival events that help to shape and wire the brain during development. We have characterized molecular mechanisms by which neuronal membrane depolarization and subsequent calcium influx into the cytoplasm lead to the induction of new gene transcription. We have identified three points within this cascade of events where the specificity of genes induced by different types of stimuli can be regulated. By using the induction of the gene that encodes brain-derived neurotrophic factor (BDNF) as a model, we have found that the ability of a calcium influx to induce transcription of this gene is regulated by the route of calcium entry into the cell, by the pattern of phosphorylation induced on the transcription factor cAMP-response element (CRE) binding protein (CREB), and by the complement of active transcription factors recruited to the BDNF promoter. These results refine and expand the working model of activity-induced gene induction in the brain, and help to explain how different types of neuronal stimuli can activate distinct transcriptional responses.
An update on nuclear calcium signalling
Journal of Cell Science, 2009
Over the past 15 years or so, numerous studies have sought to characterise how nuclear calcium (Ca 2+ ) signals are generated and reversed, and to understand how events that occur in the nucleoplasm influence cellular Ca 2+ activity, and vice versa. In this Commentary, we describe mechanisms of nuclear Ca 2+ signalling and discuss what is known about the origin and physiological significance of nuclear Ca 2+ transients. In particular, we focus on the idea that the nucleus has an autonomous Ca 2+ signalling system that can generate its own Ca 2+ transients that modulate processes such as gene transcription. We also discuss the role of nuclear pores and the nuclear envelope in controlling ion flux into the nucleoplasm. [Ca 2+ ] high Messenger Ca 2+ channels: receptor operated store operated voltage operated second-messenger operated Ca 2+ pump Na + /Ca 2+ exchanger Ca 2+ pump Hormone Neurotransmitter Growth factor Sensors (e.g. calmodulin, troponin C) Buffers Buffers Ca 2+ release channel [Ca 2+ ] low
CaldendrinJacob: a protein liaison that couples NMDA receptor signalling to the nucleus
PLoS biology, 2008
NMDA (N-methyl-D-aspartate) receptors and calcium can exert multiple and very divergent effects within neuronal cells, thereby impacting opposing occurrences such as synaptic plasticity and neuronal degeneration. The neuronal Ca 2þ sensor Caldendrin is a postsynaptic density component with high similarity to calmodulin. Jacob, a recently identified Caldendrin binding partner, is a novel protein abundantly expressed in limbic brain and cerebral cortex. Strictly depending upon activation of NMDA-type glutamate receptors, Jacob is recruited to neuronal nuclei, resulting in a rapid stripping of synaptic contacts and in a drastically altered morphology of the dendritic tree. Jacob's nuclear trafficking from distal dendrites crucially requires the classical Importin pathway. Caldendrin binds to Jacob's nuclear localization signal in a Ca 2þ -dependent manner, thereby controlling Jacob's extranuclear localization by competing with the binding of Importin-a to Jacob's nuclear localization signal. This competition requires sustained synapto-dendritic Ca 2þ levels, which presumably cannot be achieved by activation of extrasynaptic NMDA receptors, but are confined to Ca 2þ microdomains such as postsynaptic spines. Extrasynaptic NMDA receptors, as opposed to their synaptic counterparts, trigger the cAMP response element-binding protein (CREB) shut-off pathway, and cell death. We found that nuclear knockdown of Jacob prevents CREB shut-off after extrasynaptic NMDA receptor activation, whereas its nuclear overexpression induces CREB shut-off without NMDA receptor stimulation. Importantly, nuclear knockdown of Jacob attenuates NMDA-induced loss of synaptic contacts, and neuronal degeneration. This defines a novel mechanism of synapse-to-nucleus communication via a synaptic Ca 2þ -sensor protein, which links the activity of NMDA receptors to nuclear signalling events involved in modelling synapto-dendritic input and NMDA receptor-induced cellular degeneration. Citation: Dieterich DC, Karpova A, Mikhaylova M, Zdobnova I, Kö nig I, et al. (2008) Caldendrin-Jacob: A protein liaison that couples NMDA receptor signalling to the nucleus. PLoS Biol 6(2): e34.