Synaptic Activity And The Nuclear Translocation Of Nfkb

A further Ca2+-controlled synapse-to-nucleus signaling event is constituted by the activity-dependent nuclear translocation of nuclear factor kB (NF-kB). NF-kB is a transcription factor that consists of two DNA-binding subunits: a 50 kDa subunit (p50) and a 65 kDa subunit (p65, also known as RelA). In brain NF-kB usually forms a complex with the inhibitory subunit IKB-a that masks the NLS in NF-kB. Phosphorylation of IKB-a via IkB kinase leads to its degradation and the subsequent nuclear translocation of NF-kB (Figure 22.1B). The idea that synaptic stimuli might trigger the NF-kB pathway was originally based on the observation that NF-kB is present in synapses and many reports suggest now that activation of glutamate receptors will activate NF-kB11,12. Moreover, blockade of NMDA-receptors and L-type Ca2+-channels has been shown to reduce this activation11,13,14, indirectly suggesting that a Ca2+-responsive pathway controls NF-kB activation. Part of this Ca2+-responsive pathway upstream of NF-kB seems to be CaMKII dependent, since inhibiting CaMKII reduces the Ca2+-induced activation of NF-kB, whereas a constitutively active CaMKII mutant enhances NF-kB activation13. Interestingly, stimulation of excitatory synapses also leads to a redistribution of NF-kB from neurites to the nucleus, indicating that the transcription factor can translocate from distal dendritic sites to the nucleus in response to excitatory stimuli13,15. The underlying mechanisms are not well understood but NF-kB trafficking appears to be exclusively retrograde in direction to the nucleus13,15. Although these findings make it rather plausible that synaptic activity will enhance NF-kB induced gene transcription in a spatio-temporal segregated manner, it is at present still unclear whether activity of single synapses or the integrated activity of larger dendritic segments drives this process and how this relates to plasticity processes at the synapse itself.

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