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 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.
Dieterich
Daniela C
DC
AG Molecular Mechanisms of Plasticity, Department of Neurochemistry and Molecular Biology, Leibniz-Institute for Neurobiology, Magdeburg, Germany.
Karpova
Anna
A
Mikhaylova
Marina
M
Zdobnova
Irina
I
König
Imbritt
I
Landwehr
Marco
M
Kreutz
Martin
M
Smalla
Karl-Heinz
KH
Richter
Karin
K
Landgraf
Peter
P
Reissner
Carsten
C
Boeckers
Tobias M
TM
Zuschratter
Werner
W
Spilker
Christina
C
Seidenbecher
Constanze I
CI
Garner
Craig C
CC
Gundelfinger
Eckart D
ED
Kreutz
Michael R
MR
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
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