RGD Reference Report - Caldendrin-Jacob: a protein liaison that couples NMDA receptor signalling to the nucleus. - Rat Genome Database

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Caldendrin-Jacob: a protein liaison that couples NMDA receptor signalling to the nucleus.

Authors: Dieterich, DC  Karpova, A  Mikhaylova, M  Zdobnova, I  Konig, I  Landwehr, M  Kreutz, M  Smalla, KH  Richter, K  Landgraf, P  Reissner, C  Boeckers, TM  Zuschratter, W  Spilker, C  Seidenbecher, CI  Garner, CC  Gundelfinger, ED  Kreutz, MR 
Citation: Dieterich DC, etal., PLoS Biol. 2008 Feb;6(2):e34. doi: 10.1371/journal.pbio.0060034.
RGD ID: 8553324
Pubmed: PMID:18303947   (View Abstract at PubMed)
PMCID: PMC2253627   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pbio.0060034   (Journal Full-text)

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-alpha 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.




Biological Process
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Cellular Component
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Original Reference(s)
NsmfRatcortical cytoskeleton located_inIDA PMID:18303947UniProt 
Kpna1Ratdendrite located_inIDA PMID:18303947UniProt 
NsmfRatdendrite located_inIDA PMID:18303947UniProt 
NsmfRateuchromatin located_inIDA PMID:18303947UniProt 
Cabp1Ratglutamatergic synapse is_active_inIMP PMID:18303947SynGO 
Cabp1Ratglutamatergic synapse is_active_inIEP PMID:18303947SynGO 
Cabp1Ratglutamatergic synapse is_active_inIDA PMID:18303947SynGO 
NsmfRatglutamatergic synapse is_active_inIDA PMID:18303947SynGO 
NsmfRatmembrane located_inIDA PMID:18303947UniProt 
NsmfRatneuron projection located_inIDA PMID:18303947UniProt 
NsmfRatnuclear envelope located_inIDA PMID:18303947UniProt 
NsmfRatnuclear matrix located_inIDA PMID:18303947UniProt 
Kpna1Ratnucleus located_inIDA PMID:18303947UniProt 
NsmfRatnucleus located_inIDA PMID:18303947UniProt 
NsmfRatpostsynapse is_active_inIDA PMID:18303947SynGO 
NsmfRatpostsynaptic density located_inIDA PMID:18303947UniProt 
NsmfRatsynapse located_inIDA PMID:18303947UniProt 
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Molecular Function
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Genes (Rattus norvegicus)
Cabp1  (calcium binding protein 1) Kpna1  (karyopherin subunit alpha 1) Kpna2  (karyopherin subunit alpha 2)
Nsmf  (NMDA receptor synaptonuclear signaling and neuronal migration factor)