Dieterich, Daniela C. and Karpova, Anna and Mikhaylova, Marina and Zdobnova, Irina and König, Imbritt and Landwehr, Marco and Kreutz, Martin and Smalla, Karl-Heinz and Richter, Karin and Landgraf, Peter and Reissner, Carsten and Boeckers, Tobias M. and Zuschratter, Werner and Spilker, Christina and Seidenbecher, Constanze I. and Garner, Craig C. and Gundelfinger, Eckart D. and Kreutz, Michael R. (2008) Caldendrin–Jacob: A Protein Liaison That Couples NMDA Receptor Signalling to the Nucleus. PLoS Biology, 6 (2). pp. 286-306. ISSN 1544-9173 http://resolver.caltech.edu/CaltechAUTHORS:DIEplosb08
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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 Ca2+ 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 Ca2+-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 Ca2+ levels, which presumably cannot be achieved by activation of extrasynaptic NMDA receptors, but are confined to Ca2+ 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 Ca2+-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.
|Additional Information:||Copyright: © 2008 Dieterich et al. 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 credited. Received: April 16, 2007; Accepted: January 3, 2008; Published: February 26, 2008. The authors gratefully acknowledge the technical assistance of C. Borutzki, K. Pohlmann, B. Kracht, and M. Marunde. We thank Dr. C. Brüderle and S. Leal Ortiz for help with the lentiviral experiments. Finally, we thank Dr. P. Beesley for valuable comments on the manuscript. Author contributions. DCD, CIS, CCG, EDG, and MRK conceived and designed the experiments. DCD, AK, MM, IZ, IK, ML, MK, KHS, KR, PL, CR, CS, and MRK performed the experiments. TMB and WZ contributed reagents, materials/analysis tools. DCD, CIS, CCG, EDG, and MRK wrote the paper. Funding. Supported by the Bundesministerium für Bildung und Forschung (BMBF) (01GZ0307/ 01GA0505), Deutsche Forschungsgemeinschaft (DFG) (Kr1879/2–1; 2–2, SFB 779 TPB8), the Fonds der Chemische Industrie, the Max Planck Award from the Alexander von Humboldt and the Max Planck Societies, the Land Saxony-Anhalt (FKZ: 3293A/3004A/3422A, N1 TP4), the National Institutes of Health DA016758 and the Schram Foundation. IK, ML, CS, and IZ were supported by stipends from the DFG. Competing interests. The authors have declared that no competing interests exist.|
|Official Citation:||Dieterich DC, Karpova A, Mikhaylova M, Zdobnova I, König I, et al. (2008) Caldendrin–Jacob: A Protein Liaison That Couples NMDA Receptor Signalling to the Nucleus. PLoS Biol 6(2): e34 doi:10.1371/journal.pbio.0060034|
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|Deposited On:||11 Mar 2008|
|Last Modified:||26 Dec 2012 09:52|
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