The activation of N-methyl-D-aspartate-receptors (NMDARs) in synapses provides plasticity and cell survival signals, whereas NMDARs residing in the neuronal membrane outside synapses trigger neurodegeneration. At present, it is unclear how these opposing signals are transduced to and discriminated by the nucleus. In this study, we demonstrate that Jacob is a protein messenger that encodes the origin of synaptic versus extrasynaptic NMDAR signals and delivers them to the nucleus. Exclusively synaptic, but not extrasynaptic, NMDAR activation induces phosphorylation of Jacob at serine-180 by ERK1/2. Long-distance trafficking of Jacob from synaptic, but not extrasynaptic, sites depends on ERK activity, and association with fragments of the intermediate filament α-internexin hinders dephosphorylation of the Jacob/ERK complex during nuclear transit. In the nucleus, the phosphorylation state of Jacob determines whether it induces cell death or promotes cell survival and enhances synaptic plasticity.

Jacob is a recently identified plasticity-related protein that couples N-methyl-D-aspartate receptor activity to nuclear gene expression. An expression analysis by Northern blot and in situ hybridization shows that Jacob is almost exclusively present in brain, in particular in the cortex and the limbic system. Alternative splicing gives rise to multiple mRNA variants, all of which exhibit a prominent dendritic localization in the hippocampus. Functional analysis in primary hippocampal neurons revealed that a predominant cis-acting dendritic targeting element in the 3-untranslated region of Jacob mRNAs is responsible for dendritic mRNA localization. In the mouse brain, Jacob transcripts are associated with both the fragile X mental retardation protein, a well described trans-acting factor regulating dendritic mRNA targeting and translation, and the kinesin family member 5C motor complex, which is known to mediate dendritic mRNA transport. Jacob is susceptible to rapid protein degradation in a Ca 2؉ -and Calpain-dependent manner, and Calpainmediated clipping of the myristoylated N terminus of Jacob is required for its nuclear translocation after N-methyl-D-aspartate receptor activation. Our data suggest that local synthesis in dendrites may be necessary to replenish dendritic Jacob pools after truncation of the N-terminal membrane anchor and concomitant translocation of Jacob to the nucleus.The link between excitatory neurotransmission and transcriptional and translational regulation has attracted much interest for many years because multiple processes ranging from metabolic homeostasis to learning and memory require activity-driven gene expression in neurons (1, 2). Particularly signaling from N-methyl-D-aspartate (NMDA) 3 type glutamate receptors to the nucleus has been implicated in synaptic plasticity, and some molecules have been identified that can translocate from synaptic and extrasynaptic sites to neuronal nuclei after NMDA receptor activation (3-7). In a recent study, we have identified Jacob, a protein that triggers long lasting changes in the cytoarchitecture of dendrites and the number of spine synapses in pyramidal neurons via coupling of NMDA receptor signaling to nuclear gene expression (6). Following activation of synaptic and extrasynaptic NMDA receptors, Jacob is recruited to neuronal nuclei, and this in turn results in a rapid stripping of synaptic contacts and in a drastically altered morphology of the dendritic tree (6). Nuclear import of Jacob utilizes the classical importin pathway (6, 7), and the synaptic Ca 2ϩ

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Caldendrin is a synaptic calcium sensor protein that is tightly associated with the postsynaptic density (PSD). Previous work has shown that the association of the protein with the synapse is highly dynamic and is increased in an activity-dependent manner. In the present study the caldendrin-association with the postsynaptic cytomatrix was analyzed in animal models of psychosis and drug abuse induced neurotoxicity. Subchronic administration of the N-methyl-D-aspartate (NMDA)-receptor antagonist ketamine, serving as a model of NMDA-receptor hypofunction and schizophrenia showed no significant effect on the PSD-levels of caldendrin, indicating that NMDA-receptor activity is not required to keep caldendrin at the synapse. However, administration of high doses of the serotonergic neurotoxin p-chloroamphetamine (PCA) lead to significant changes in the association of caldendrin with the PSD. These results underscore the dynamic association of caldendrin with the PSD and suggest a role of this synaptic calcium sensor in the PCA-induced serotonin syndrome.