In addition, NMDA receptor-dependent nuclear import of importin-a1 and -a2 as well as importin-b1 has been shown in hippocampal primary neurons. CREB2 has been shown to INCB28060 specifically associate with importin-a1 and -a6 but not -a2, -a3 and -a4. Jacob associates with importin-a1, however, it is unclear whether it will bind other importins as well. Hence, nuclear NF-kB accumulation appears to primarily require binding to importin-a3 and -a4 but other family members might contribute here as well. Moreover, at present it is also unclear whether importins and these putative synapto-nuclear protein messengers are exclusively associated with excitatory synapses that are thought to be the subject of LTP and LTD. Interestingly however a recent report documents that importin-a1 directly associates with the cytoplasmic tail of a splice isoform of the NR1 subunit of NMDA-receptors providing a direct link to NMDA-receptor signaling. It was also reported that importina1 dissociate from the NMDA-receptor in an activity and PKCdependent manner. Interestingly, in accord to the observations made in the present study no dissociation of importin-a1 from the NR1 subunit was found with stimulation protocols inducing gene transcription independent early-LTP whereas a dissociation was seen after induction of late-LTP. It is, however, unclear whether all importins associate with the same binding motif and how LTP and LTP inducing NMDA-receptor signals could provide specificity for the dissociation of certain importins. The NMDA-receptor induced Ca2+ signals that bring about either LTP or LTD differ only in their timing and duration. LTP is triggered by Ca2+ signals on the micromolar scale for shorter durations, whereas LTD is triggered by changes in free Ca2+ concentrations on the nanomolar scale for longer durations. It is therefore conceivable that the regulation of synapto-nuclear trafficking happens at the level of posttranslational modifications of importins or the messenger itself. The surprising result that Jacob translocates rapidly to the nucleus after induction of late-LTP but not LTD also raises some interesting questions about the functional role of the protein. Our previous studies suggested that Jacob is a messenger of cell death after activation of NSC 136476 extrasynaptic NMDA-receptors and might be involved in the neurodegenerative CREB-shut off pathway. However, we also observed a less prominent nuclear accumulation of the protein after triggering the activity of synaptic NMDAreceptors. In this study we could confirm both findings and it will be interesting to elucidate whether nuclear Jacob regulates different types of gene expression depending upon the synaptic or extrasynaptic location of the activated NMDARs.