title: Caldendrin-Jacob: a protein liaison that couples NMDA receptor signalling to the nucleus.
abstract: 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.
authors.affiliation: AG Molecular Mechanisms of Plasticity, Department of Neurochemistry and Molecular Biology, Leibniz-Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Daniela C
authors.initials: DC
authors.lastname: Dieterich
authors.forename: Anna
authors.initials: A
authors.lastname: Karpova
authors.forename: Marina
authors.initials: M
authors.lastname: Mikhaylova
authors.forename: Irina
authors.initials: I
authors.lastname: Zdobnova
authors.forename: Imbritt
authors.initials: I
authors.lastname: König
authors.forename: Marco
authors.initials: M
authors.lastname: Landwehr
authors.forename: Martin
authors.initials: M
authors.lastname: Kreutz
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Smalla
authors.forename: Karin
authors.initials: K
authors.lastname: Richter
authors.forename: Peter
authors.initials: P
authors.lastname: Landgraf
authors.forename: Carsten
authors.initials: C
authors.lastname: Reissner
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.forename: Werner
authors.initials: W
authors.lastname: Zuschratter
authors.forename: Christina
authors.initials: C
authors.lastname: Spilker
authors.forename: Constanze I
authors.initials: CI
authors.lastname: Seidenbecher
authors.forename: Craig C
authors.initials: CC
authors.lastname: Garner
authors.forename: Eckart D
authors.initials: ED
authors.lastname: Gundelfinger
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kreutz
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D002846:Chromatography, Affinity; D017931:DNA Primers; D018076:DNA, Complementary; D007150:Immunohistochemistry; D019913:Nuclear Localization Signals; D011485:Protein Binding; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques
chemical_list: D002135:Calcium-Binding Proteins; D017931:DNA Primers; D018076:DNA, Complementary; D019913:Nuclear Localization Signals; D016194:Receptors, N-Methyl-D-Aspartate; C085577:Ca2+-binding protein-1