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Caldendrin–Jacob: A Protein Liaison That Couples NMDA Receptor Signalling to the Nucleus

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(2+) sensor Caldendrin is a postsynaptic density component with high sim...

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Autores principales: Dieterich, Daniela C, Karpova, Anna, Mikhaylova, Marina, Zdobnova, Irina, König, Imbritt, Landwehr, Marco, Kreutz, Martin, Smalla, Karl-Heinz, Richter, Karin, Landgraf, Peter, Reissner, Carsten, Boeckers, Tobias M, Zuschratter, Werner, Spilker, Christina, Seidenbecher, Constanze I, Garner, Craig C, Gundelfinger, Eckart D, Kreutz, Michael R
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2253627/
https://www.ncbi.nlm.nih.gov/pubmed/18303947
http://dx.doi.org/10.1371/journal.pbio.0060034
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author Dieterich, Daniela C
Karpova, Anna
Mikhaylova, Marina
Zdobnova, Irina
König, Imbritt
Landwehr, Marco
Kreutz, Martin
Smalla, Karl-Heinz
Richter, Karin
Landgraf, Peter
Reissner, Carsten
Boeckers, Tobias M
Zuschratter, Werner
Spilker, Christina
Seidenbecher, Constanze I
Garner, Craig C
Gundelfinger, Eckart D
Kreutz, Michael R
author_facet Dieterich, Daniela C
Karpova, Anna
Mikhaylova, Marina
Zdobnova, Irina
König, Imbritt
Landwehr, Marco
Kreutz, Martin
Smalla, Karl-Heinz
Richter, Karin
Landgraf, Peter
Reissner, Carsten
Boeckers, Tobias M
Zuschratter, Werner
Spilker, Christina
Seidenbecher, Constanze I
Garner, Craig C
Gundelfinger, Eckart D
Kreutz, Michael R
author_sort Dieterich, Daniela C
collection PubMed
description 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(2+) 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(2+)-dependent manner, thereby controlling Jacob's extranuclear localization by competing with the binding of Importin-α to Jacob's nuclear localization signal. This competition requires sustained synapto-dendritic Ca(2+) levels, which presumably cannot be achieved by activation of extrasynaptic NMDA receptors, but are confined to Ca(2+) 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(2+)-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.
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spelling pubmed-22536272008-02-23 Caldendrin–Jacob: A Protein Liaison That Couples NMDA Receptor Signalling to the Nucleus Dieterich, Daniela C Karpova, Anna Mikhaylova, Marina Zdobnova, Irina König, Imbritt Landwehr, Marco Kreutz, Martin Smalla, Karl-Heinz Richter, Karin Landgraf, Peter Reissner, Carsten Boeckers, Tobias M Zuschratter, Werner Spilker, Christina Seidenbecher, Constanze I Garner, Craig C Gundelfinger, Eckart D Kreutz, Michael R PLoS Biol Research Article 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(2+) 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(2+)-dependent manner, thereby controlling Jacob's extranuclear localization by competing with the binding of Importin-α to Jacob's nuclear localization signal. This competition requires sustained synapto-dendritic Ca(2+) levels, which presumably cannot be achieved by activation of extrasynaptic NMDA receptors, but are confined to Ca(2+) 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(2+)-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. Public Library of Science 2008-02 2008-02-26 /pmc/articles/PMC2253627/ /pubmed/18303947 http://dx.doi.org/10.1371/journal.pbio.0060034 Text en © 2008 Dieterich et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Dieterich, Daniela C
Karpova, Anna
Mikhaylova, Marina
Zdobnova, Irina
König, Imbritt
Landwehr, Marco
Kreutz, Martin
Smalla, Karl-Heinz
Richter, Karin
Landgraf, Peter
Reissner, Carsten
Boeckers, Tobias M
Zuschratter, Werner
Spilker, Christina
Seidenbecher, Constanze I
Garner, Craig C
Gundelfinger, Eckart D
Kreutz, Michael R
Caldendrin–Jacob: A Protein Liaison That Couples NMDA Receptor Signalling to the Nucleus
title Caldendrin–Jacob: A Protein Liaison That Couples NMDA Receptor Signalling to the Nucleus
title_full Caldendrin–Jacob: A Protein Liaison That Couples NMDA Receptor Signalling to the Nucleus
title_fullStr Caldendrin–Jacob: A Protein Liaison That Couples NMDA Receptor Signalling to the Nucleus
title_full_unstemmed Caldendrin–Jacob: A Protein Liaison That Couples NMDA Receptor Signalling to the Nucleus
title_short Caldendrin–Jacob: A Protein Liaison That Couples NMDA Receptor Signalling to the Nucleus
title_sort caldendrin–jacob: a protein liaison that couples nmda receptor signalling to the nucleus
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2253627/
https://www.ncbi.nlm.nih.gov/pubmed/18303947
http://dx.doi.org/10.1371/journal.pbio.0060034
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