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.

Gene Ontology Annotations    Click to see Annotation Detail View

Cellular Component

Molecular Function

Objects Annotated

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)


Additional Information